SNPMiner Trials by Shray Alag

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SNPMiner SNPMiner Trials (Home Page)


Report for Mutation V617F

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 54 clinical trials

Clinical Trials


1 Efficacy of Tyrosine Kinase Inhibition in Reducing Eosinophilia in Patients With Myeloid and/or Steroid-Refractory Hypereosinophilic Syndrome

The purpose of this study is to evaluate the safety and efficacy of the tyrosine kinase inhibitor, imatinib mesylate (Gleevec ) in reducing peripheral blood eosinophilia in patients with the myeloid form of hypereosinophilic syndrome (HES). Patients with the hypereosinophilic syndrome who meet a set of criteria designed to select patients with the myeloid form of the disease, as well as patients without myeloid disease who are refractory to standard therapy for HES, will be admitted on this protocol. A thorough clinical evaluation will be performed with emphasis on potential sequelae of eosinophil-mediated tissue damage. A baseline bone marrow will be obtained to exclude leukemia or lymphoma and to assess the degree and nature of eosinophilopoiesis. Bone marrow, blood cells and/or serum will also be collected to test for the presence of a recently described mutation that is associated with imatinib-responsiveness in HES, and to provide reagents (such as DNA, RNA, and specific antibodies) and for use in the laboratory to address issues related to the mechanism of action of imatinib mesylate in HES. Imatinib mesylate will be initiated at a dose of 400 mg daily, the FDA-approved dose for the treatment of chronic myelogenous leukemia. In patients who demonstrate a complete clinical and hematologic response to imatinib therapy and who do not have life-threatening disease, the dose will be decreased gradually to 100mg daily and then discontinued. In order to minimize bone marrow suppression, other myelosuppressive agents will be tapered and discontinued during the first week of therapy with imatinib mesylate. Complete blood counts will be performed weekly for the first month and biweekly thereafter. Clinical assessments will be performed every three months to assess progression of end organ damage. In patients who demonstrate a complete clinical and hematologic response to imatinib therapy and who do not have life-threatening disease, the dose will be decreased gradually to 100 mg daily and then discontinued. In the event of clinical, hematologic or molecular relapse during the taper, the imatinib dose will be increased to a maximum of 600 mg daily to achieve a second remission. Laboratory monitoring will be performed as above except for molecular monitoring which will be monitored monthly if drug is discontinued or molecular relapse occurs. Once a stable dosing regimen is achieved for greater than or equal to 6 months in subjects who have undergone dose descalation or greater than or equal to 2 years in subjects receiving 300-400 mg of imatinib daily who did not qualify for dose de-escalation, the frequency of NIH visits and end organ assessments will be decreased to 6 months, with molecular monitoring every 3 months and monthly routine laboratory assessments.

NCT00044304
Conditions
  1. Eosinophilic Myeloid Neoplasm
  2. Hypereosinophilic Syndrome
Interventions
  1. Drug: Imatinib
  2. Drug: Ruxolitinib
MeSH:Hypereosinophilic Syndrome Syndrome

abnormal tyrosine kinase (i.e., FIP1L1-PDGFRA, JAK2 V617F). --- V617F ---

Primary Outcomes

Description: The percentage of subjects who reach and eosinophil count in the normal range

Measure: peripheral blood absolute eosinophil count.

Time: one month (for imatinib) and 3 months (for ruxolitinib).

Secondary Outcomes

Description: The % of subjects who reach an eosinophil count in the normal range

Measure: peripheral blood eosinophil count

Time: 3,6,9 and 12 months

Description: The % of subjects who reach an eosinophil count below 1500/mm3

Measure: peripheral blood eosinophil count

Time: 1, 3, 6, 9, and 12 months

Description: The % of subjects who achieve molecular remission on therapy

Measure: abnormal tyrosine kinase (i.e., FIP1L1-PDGFRA, JAK2 V617F)

Time: every 3 months for 5 years

Description: The duration of remission following cessation of therapy

Measure: clinical, hematologic and molecular remission

Time: every 3 months for 5 years

2 Molecular Changes and Biomarkers in Chronic Myeloproliferative Disorders

The three main chronic myeloproliferative disorders are polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). These are clonal neoplastic diseases characterized by proliferation of one or more hematopoietic lineages. Recently a mutation of the Janus Kinase 2 (JAK2) gene that leads to the substitution of phenylalanine for valine at position 617 of the JAK2 protein, JAK2 V617F, has been found in 76% to 97% of patients with PV, 29% to 57% of patients with ET and 50% of patients with IMF. This mutation confers constitutive activity on to the JAK2 protein and appears to play an important role in the pathobiology of these conditions. However, not all patients with myeloproliferative disorders have this mutation and it may not be the primary cause of these diseases. The primary goal of this prospective natural history study is to investigate the molecular basis of these diseases in groups of patients who have JAK2 V617F and in those who do not. A second goal is to identify biomarkers for PV and the other myeloproliferative disorders that are easier to measure than JAK2 V617F. Approximately, 150 patients with myeloproliferative disorders will be studied over 3 years. The studies will involve the collection of 40 mL to 50 mL of peripheral blood from each subject. The blood will be used to assess neutrophil gene and protein expression, gene polymorphisms, and plasma protein levels.

NCT00433862
Conditions
  1. Polycythemia Vera
  2. Essential Thrombocytosis
  3. Idiopathic Myelofibrosis
  4. Neutrophils
  5. Chronic Myeloproliferative Disorders
MeSH:Polycythemia Vera Primary Myelofibrosis Polycythemia Myeloproliferative Disorders Thrombocytosis Thrombocythemia, Essential Disease
HPO:Myeloproliferative disorder Polycythemia Thrombocytosis

Recently a mutation of the Janus Kinase 2 (JAK2) gene that leads to the substitution of phenylalanine for valine at position 617 of the JAK2 protein, JAK2 V617F, has been found in 76% to 97% of patients with PV, 29% to 57% of patients with ET and 50% of patients with IMF. --- V617F ---

The primary goal of this prospective natural history study is to investigate the molecular basis of these diseases in groups of patients who have JAK2 V617F and in those who do not. --- V617F ---

A second goal is to identify biomarkers for PV and the other myeloproliferative disorders that are easier to measure than JAK2 V617F. --- V617F ---


3 A Phase 2, Prospective, Randomized, Multicenter, Double-blind, Active-control, Parallel-group Study to Determine the Safety of and to Select a Treatment Regimen of CC-4047 (Pomalidomide) Either as Single-agent or in Combination With Prednisone to Study Further in Subjects With Myelofibrosis With Myeloid Metaplasia

The purpose of this study is to determine the safety of and to select a treatment regimen of pomalidomide (CC-4047) either as single-agent or in combination with prednisone to study further in patients with myelofibrosis with myeloid metaplasia (MMM).

NCT00463385
Conditions
  1. Myelofibrosis With Myeloid Metaplasia
  2. Myeloid Metaplasia
  3. Myelofibrosis
Interventions
  1. Drug: Pomalidomide
  2. Drug: Prednisone
  3. Drug: Placebo to pomalidomide
  4. Drug: Placebo to prednisone
MeSH:Primary Myelofibrosis Metaplasia

Percentage of participants who achieved a clinical response, presented by participants with positive and negative janus kinase 2 (JAK2) V617F mutation results at Baseline.. Number of Participants With Adverse Events (AEs). --- V617F ---

Primary Outcomes

Description: A clinical responder was defined as either: A baseline red blood cell (RBC)-transfusion-dependent participant with a ≥ 56 consecutive day RBC transfusion-free period after the first dose of study drug, or A baseline RBC-transfusion-independent participant with an increase in hemoglobin of 2.0 g/dL or more from baseline for ≥ 56 consecutive days in the absence of RBC transfusions, or A participant with either a ≥ 50% reduction in palpable splenomegaly of a spleen that was ≥ 10 cm at baseline or a spleen that was palpable at > 5 cm and became not palpable. Participants who discontinued the study early without achieving clinical response were counted as non-responders.

Measure: Percentage of Participants With a Clinical Response Within the First 6 Cycles of Treatment

Time: Up to 168 days

Secondary Outcomes

Description: A clinical responder was defined as either: A baseline red blood cell (RBC)-transfusion-dependent participant with a ≥ 56 consecutive day RBC transfusion-free period after the first dose of study drug, or A baseline RBC-transfusion-independent participant with an increase in hemoglobin of 2.0 g/dL or more from baseline for ≥ 56 consecutive days in the absence of RBC transfusions, or A participant with either a ≥ 50% reduction in palpable splenomegaly of a spleen that was ≥ 10 cm at baseline or a spleen that was palpable at > 5 cm and became not palpable. Participants who discontinued the study early without achieving clinical response were counted as non-responders.

Measure: Percentage of Participants With a Clinical Response Within the First 12 Cycles of Treatment

Time: Up to 336 days

Description: The time to the first clinical response achieved within 168 days after the first study drug dosing date was calculated for participants who achieved a clinical response as: Start date of the first clinical response - the first study drug date +1. A clinical responder was defined as either: A baseline red blood cell (RBC)-transfusion-dependent participant with a ≥ 56 consecutive day RBC transfusion-free period after the first dose of study drug, or A baseline RBC-transfusion-independent participant with an increase in hemoglobin of 2.0 g/dL or more from baseline for ≥ 56 consecutive days in the absence of RBC transfusions, or A participant with either a ≥ 50% reduction in palpable splenomegaly of a spleen that was ≥ 10 cm at baseline or a spleen that was palpable at > 5 cm and became not palpable.

Measure: Time to the First Clinical Response

Time: Up to 168 days

Description: For RBC-transfusion-dependent patients, duration of response was calculated as the last day of response - first day of response +1, where the last day of response was the date of the first RBC-transfusion administrated at or more than 56 days after the response started. For patients who did not receive a subsequent transfusion after the response started, the end date of response was censored at the day of last hemoglobin assessment. For RBC-transfusion-independent patients, the duration of response was calculated as the last day of response - first day of response +1, where the last day of response was the earlier of the date of a hemoglobin increase of < 2.0 g/dL and the date of a RBC transfusion at ≥ 56 days after the response started. For patients whose hemoglobin measurements were always ≥ 2.0 g/dL and never received a RBC transfusion after response started, the end date of the response was censored at the date of last hemoglobin measurement. Kaplan-Meier methodology was used.

Measure: Duration of First Clinical Response

Time: Up to 40 months

Description: The FACT-An comprises the four subscales of the 27-item FACT-General Scale (FACT-G), Physical Well-being, Social/Family Well-being, Emotion Well-being, Functional Well-Being, and the Additional Concerns Anemia subscale. Questions are rated on a scale from 0 to 4, where higher scores indicate more impact on quality of life. Physical Well-being consists of 7 questions, the subscale score ranges from 0-28; Social/Family Well-being consists of 7 questions, the subscale score ranges from 0-28; Emotion Well-being consists of 6 questions, the subscale score ranges from 0-24; Functional Well-Being consists of 7 questions, the subscale score ranges from 0-28; Anemia subscale consists of 20 questions, the subscale score ranges from 0-80; Total FACT-An score ranges from 0-188.

Measure: Change From Baseline in Functional Assessment of Cancer Therapy-Anemia (FACT-An) Subscale and Total Scores

Time: Baseline and Cycle 6 (168 days).

Description: Change from Baseline in hemoglobin for participants with a clinical response within the first 6 cycles of treatment.

Measure: Change From Baseline in Hemoglobin Concentration for Responders

Time: Baseline, Cycle 6 (168 days)

Description: Change from Baseline in hemoglobin for participants without a clinical response within the first 6 cycles of treatment.

Measure: Change From Baseline in Hemoglobin Concentration for Non-Responders

Time: Baseline, Cycle 6 (168 days)

Description: Participants rated abdominal discomfort or pain over the previous week on a scale from zero to ten, where zero is no discomfort or pain and ten is the worst pain imaginable.

Measure: Change From Baseline in Likert Abdominal Pain Scale

Time: Baseline and Cycle 6 (168 days)

Description: Percentage of participants who achieved a clinical response, presented by participants with positive and negative janus kinase 2 (JAK2) V617F mutation results at Baseline.

Measure: Percentage of Participants With Clinical Response by Baseline JAK2 Assessment

Time: Up to 336 days

Description: A serious AE (SAE) was defined as any AE which resulted in death or was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or constituted an important medical event (events that may have jeopardized the patient or required intervention to prevent one of the outcomes listed above). The severity of AEs were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 3.0) or according to the following scale: Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Death. The Investigator determined the relationship between study drug and the occurrence of an AE as "Not Related" or "Related" (since the study was double-blinded, a patient receiving only prednisone could have an AE that was judged as related to pomalidomide, and vice-versa).

Measure: Number of Participants With Adverse Events (AEs)

Time: From date of the first dose of the study drug until discontinuation or the data cut-off date (up to approximately 45 months).

4 An Open-Label Study of Oral CEP-701 in Patients With Polycythemia Vera or Essential Thrombocytosis With the JAK2 V617F Mutation

This is an 18-week open-label, multicenter study to evaluate the efficacy and tolerability of CEP-701 (lestaurtinib) treatment in patients with Polycythemia Vera (PV) and patients with Essential Thrombocytosis (ET).

NCT00586651
Conditions
  1. Polycythemia Vera
  2. Essential Thrombocytosis
Interventions
  1. Drug: lestaurtinib
MeSH:Polycythemia Vera Polycythemia Thrombocytosis Thrombocythemia, Essential
HPO:Polycythemia Thrombocytosis

An Open-Label Study of Oral CEP-701 in Patients With Polycythemia Vera or Essential Thrombocytosis With the JAK2 V617F Mutation. --- V617F ---

Determine whether a specific reduction in the JAK2 V617F allele has been indicated in this study.. null. --- V617F ---

- The patient has a detectable JAK2 V617F mutation. --- V617F ---

Primary Outcomes

Measure: Determine whether a specific reduction in the JAK2 V617F allele has been indicated in this study.

Time: 18 weeks +

Secondary Outcomes

Measure: - improvements in hemoglobin values, neutrophil count, and platelet count. - reduction in dose of hydroxyurea - reduction in splenic enlargement - rate of phlebotomy

Time: 18 weeks +

5 A Phase IIA Study of the Histone-deacetylase Inhibitor ITF2357 in Patients With JAK-2 V617F Positive Chronic Myeloproliferative Diseases

Primary Objective: To evaluate efficacy and safety of ITF2357 in the treatment of patients with JAK2V617F positive myeloproliferative diseases [Polycythemia Vera (PV), Essential Thrombocytosis (ET), Myelofibrosis (MF)]. Efficacy was evaluated by ad hoc haematological and clinical criteria for PV and ET, and by internationally established response criteria (EUMNET criteria) for MF. Safety was evaluated by number of subjects experiencing an Adverse Event (AE), type, frequency, severity, timing and relatedness of AEs, including changes in vital signs and clinical laboratory results. Secondary Objective: To evaluate the JAK2 mutated allele burden by quantitative Real-Time Polymerase Chain Reaction (qRTPCR).

NCT00606307
Conditions
  1. Myeloproliferative Diseases
Interventions
  1. Drug: ITF2357
MeSH:Myeloproliferative Disorders
HPO:Myeloproliferative disorder

A Phase IIA Study of the Histone-deacetylase Inhibitor ITF2357 in Patients With JAK-2 V617F Positive Chronic Myeloproliferative Diseases. --- V617F ---

Phase IIA Study of the HDAC Inhibitor ITF2357 in Patients With JAK-2 V617F Positive Chronic Myeloproliferative Diseases Primary Objective: To evaluate efficacy and safety of ITF2357 in the treatment of patients with JAK2V617F positive myeloproliferative diseases [Polycythemia Vera (PV), Essential Thrombocytosis (ET), Myelofibrosis (MF)]. --- V617F ---

A serious AE (SAE) is defined as an untoward (unfavourable) medical occurrence that at any dose results in death, or is life-threatening or requires inpatient hospitalisation or prolongation of existing hospitalisation, or results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect.. Inclusion Criteria: - Signed Informed Consent Form - Male or female, age ≥ 18 years - Confirmed diagnosis of PV/ET/MF according to the revised World Health Organisation criteria - JAK-2 V617F positivity - In need of cytoreductive therapy when hydroxyurea is not indicated (e.g. --- V617F ---

positive serology IgM) - Known HIV infection - Active hepatitis B and/or C infection - History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or render the subject at high risk from treatment complications - Eastern Cooperative Oncology Group (ECOG) performance status 3 or greater - Platelets count <100x109/L within 14 days before enrolment - Absolute neutrophil count <1.2x109/L within 14 days before enrolment - Percentage of blast cells in peripheral blood >10% within 14 days before enrolment - Serum creatinine >2xULN (Upper limit of normal) - Total serum bilirubin >1.5xULN - Serum AST (aspartate aminotransferase) / ALT (alanine aminotransferase) > 3xULN - Interferon alpha within 14 days before enrolment - Hydroxyurea within 14 days before enrolment - Anagrelide within 7 days before enrolment - Any other investigational drug within 28 days before enrolment Inclusion Criteria: - Signed Informed Consent Form - Male or female, age ≥ 18 years - Confirmed diagnosis of PV/ET/MF according to the revised World Health Organisation criteria - JAK-2 V617F positivity - In need of cytoreductive therapy when hydroxyurea is not indicated (e.g. --- V617F ---

Primary Outcomes

Description: Patients with Objective Response were defined as those patients achieving a complete, major, moderate or minor (only for Myelofibrosis patients) response during the experimental treatment course. The "best response" is reported hereunder by intensity of response.

Measure: Number of Patients With Objective Responses (Complete, Major, Moderate or Minor Responses), in Terms of Best Overall Response

Time: Every single week from week 1 to week 24 of treatment

Secondary Outcomes

Description: This outcome was assessed by quantitative real time Polymerase Chain Reaction (RT PCR). At each time point, the number of patients is the following: Screening: N=29 Week 12: N=20 Week 24: N=18 EOT: N=24. End of treatment corresponds to the last visit performed before treatment discontinuation.

Measure: Change in JAK2 Mutated Allele Burden

Time: At screening, at week 12, at week 24, at the end of treatment (EOT) visit

Description: An adverse event (AE) is any untoward occurrence in a patient or clinical investigation subject administered with a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The adverse events must to be followed to the end of study (28 days after the last study drug intake). A serious AE (SAE) is defined as an untoward (unfavourable) medical occurrence that at any dose results in death, or is life-threatening or requires inpatient hospitalisation or prolongation of existing hospitalisation, or results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect.

Measure: Number of Subject Experiencing an Adverse Event

Time: At weekly visits (Days 8, 15, 22, 36, 43, 50, 64, 71, 78, 99, 127, 155); At monthly visits (Days 29, 57, 85 113, 141,169); at end of treatment visit

6 A Multicenter, Open Label Phase I/II Study of CEP-701 (Lestaurtinib) in Adults With Myelofibrosis

Myelofibrosis is the gradual replacement of bone marrow (place where most new blood cells are produced) by fibrous tissue which reduces the body's ability to produce new blood cells and results in the development of chronic anemia (low red blood cell count). One of the main distinctions of myelofibrosis is "extramedullary hematopoesis", the migration or traveling of the blood-forming cells out of the bones to other parts of the body, such as the liver or spleen, resulting in an enlarged spleen and liver. Treatment for myelofibrosis is unsatisfactory and there is no medication that is specifically used in the treatment of myelofibrosis. There is a protein that is found to be present in the majority of myelofibrosis patients (JAK2) and the drug Lestaurtinib is being studied to see if it will stop this protein from functioning and thereby help control the disease. This study is divided into two Phases (1 & 2). In phase 1 we will be looking for the dose of study medication (Lestaurtinib) that will be the highest dose a patient can take without experiencing serious side effects, maximum tolerated dose (MTD). In phase 2, after the MTD dose has been established in phase 1, we will be investigating how well CEP-701 (Lestaurtinib) works at suppressing the protein (JAK2). The investigators also wish to find out important biologic characteristics or features of myelofibrosis through an additional correlative biomarker study (MPD-RC #107). The correlative biomarker study is a study that is related to the main study, but is looking to answer different questions than the main study. The purpose of the biomarker study is to understand the causes of MPD and to develop improved methods for the diagnosis and treatment of these diseases, while the main study is trying to find out how well CEP-701 (Lestaurtinib) will work in treating the myeloproliferative disease.

NCT00668421
Conditions
  1. Myelofibrosis
  2. Essential Thrombocythemia
  3. Polycythemia Vera
Interventions
  1. Drug: CEP-701 (Lestaurtinib)
MeSH:Polycythemia Vera Primary Myelofibrosis Polycythemia Thrombocytosis Thrombocythemia, Essential
HPO:Polycythemia Thrombocytosis

To estimate the efficacy of a novel kinase inhibitor in subjects with myelofibrosis, as determined by a reduction in JAK2 V617F allele frequency in peripheral blood neutrophils.. null. --- V617F ---

3. The subject has a detectable JAK2 V617F mutation. --- V617F ---

Primary Outcomes

Measure: To determine the safety and maximum tolerated dose of a novel kinase inhibitor in subjects with myelofibrosis.

Time: 2 years

Measure: To estimate the efficacy of a novel kinase inhibitor in subjects with myelofibrosis, as determined by a reduction in JAK2 V617F allele frequency in peripheral blood neutrophils.

Time: 2 years

Secondary Outcomes

Measure: To estimate the incidence, severity, and attribution of treatment-emergent adverse events.

Time: 2 years

Measure: To estimate the rate of complete or major clinical-hematological response from treatment with Lestaurtinib (CEP-701) in this subject population as measured by the EUMNET response criteria.

Time: 2 years

7 A Phase II Study of MK-0683 in Patients With Polycythaemia Vera and Essential Thrombocythaemia.

The aim of the present study is to evaluate the efficacy and safety of MK-0683 in the treatment of PV and ET. This agent has most recently been shown to be a potent inhibitor of the autonomous proliferation of haematopoietic cells of PV and ET patients carrying the JAK2 V617F mutation. Accordingly, it may be anticipated that MK-0683 - by decreasing the JAK2 allele burden - may influence clonal myeloproliferation and in vivo granulocyte, platelet and endothelial activation , which are considered to be major determinants of morbidity and mortality ( thrombosis, bleeding, extramedullary haematopoiesis , myelofibrosis ) in these disorders. The effects of MK-0683 at the molecular level will be studied by global/ focused gene expression profiling, epigenome profiling and proteomics.

NCT00866762
Conditions
  1. Polycythemia Vera
  2. Essential Thrombocythemia
Interventions
  1. Drug: HDAC inhibitor (MK-0683)
MeSH:Polycythemia Vera Polycythemia Thrombocytosis Thrombocythemia, Essential
HPO:Polycythemia Thrombocytosis

This agent has most recently been shown to be a potent inhibitor of the autonomous proliferation of haematopoietic cells of PV and ET patients carrying the JAK2 V617F mutation. --- V617F ---

Primary Outcomes

Measure: To evaluate the efficacy of study drug (MK-0683) in the treatment of patients with PV and ET.

Time: one year

Secondary Outcomes

Measure: To study changes in bone marrow morphology before and after treatment with study drug.

Time: one year

8 Molecular Study of Factors Involved in JAK-STAT Signalling Pathway in Familial Myeloproliferative Disorders

The main goal of the study is to progress in our understanding of the molecular basis of myeloproliferative disorders of the bone marrow (polycythemia vera, essential thrombocythemia, primary myelofibrosis). The study will focus on the genes encoding factors implicated in the JAK-STAT pathway which has an essential role in these diseases

NCT00873574
Conditions
  1. Myeloproliferative Disorders
Interventions
  1. Biological: Blood samples and buccal swabs
MeSH:Myeloproliferative Disorders Disease
HPO:Myeloproliferative disorder

The recent identification of a recurrent activating tyrosine kinase mutation V617F in the JAK2 gene provides a breakthrough in the understanding of the molecular mechanisms of these diseases. --- V617F ---

The investigators have shown actually that the mutation V617F is a somatic one which is variably expressed among patients in the same family.Other somatic mutations and inherited factors, still unknown, may explain these discrepancies. --- V617F ---

JAK-STAT pathway has an essential role in non-CML MPD as was shown by the functional consequences of the V617F JAK2 mutation. --- V617F ---

Primary Outcomes

Measure: Allelic frequency comparison between the 2 cohorts

Time: At the inclusion visit

Secondary Outcomes

Measure: Undescribed gene mutations.

Time: At the inclusion visit

9 Phase II Trial of Oral Panobinostat (LBH589), a Novel Deacetylase Inhibitor (DACi) in Patients With Primary Myelofibrosis (PMF), Post Essential Thrombocythemia (ET) Myelofibrosis and Post- Polycythemia Vera (PV) Myelofibrosis

This study will assess the safety and efficacy of Panobinostat as a single agent in the treatment of Primary Myelofibrosis, Post-Polycythemia Vera and Post-Essential Thrombocythemia. There will be two cohorts - patients with JAK2 mutation and patients without JAK2 mutation.

NCT00931762
Conditions
  1. Primary Myelofibrosis
  2. Post-Polycythemia Vera
  3. Post-Essential Thrombocytopenia
Interventions
  1. Drug: Panobinostat
MeSH:Polycythemia Vera Primary Myelofibrosis Thrombocytopenia Polycythemia
HPO:Polycythemia Thrombocytopenia

To compare the response to panobinostat in patients with the JAK2 V617F mutation to those without the JAK2 V617F mutation. --- V617F ---

To compare the response to panobinostat in patients with the JAK2 V617F mutation to those without the JAK2 V617F mutation. --- V617F --- --- V617F ---

(The presence of a JAK2 V617F mutation is not required for study entry) 2. Patients must meet the following laboratory criteria: - Patients can be either JAK2 V617F mutated or wild type - Serum potassium, magnesium, phosphorous, sodium, total calcium (corrected for serum albumin) or ionized calcium within normal limits (WNL) for the institution Note: Potassium, magnesium, phosphorous, sodium, and/or calcium supplements maybe given to correct values that are < LLN. --- V617F ---

(The presence of a JAK2 V617F mutation is not required for study entry) 2. Patients must meet the following laboratory criteria: - Patients can be either JAK2 V617F mutated or wild type - Serum potassium, magnesium, phosphorous, sodium, total calcium (corrected for serum albumin) or ionized calcium within normal limits (WNL) for the institution Note: Potassium, magnesium, phosphorous, sodium, and/or calcium supplements maybe given to correct values that are < LLN. --- V617F --- --- V617F ---

Primary Outcomes

Measure: To evaluate the overall response (CR, PR, and clinical improvement) to oral panobinostat as a single agent at 40 mg daily every Monday, Wednesday and Friday in patients with myelofibrosis.

Time: Upon enrollment of 13 participants into each cohort of the study and at the end of the study.

Secondary Outcomes

Measure: To compare the response to panobinostat in patients with the JAK2 V617F mutation to those without the JAK2 V617F mutation

Time: Upon enrollment of 13 participants into the study and at the end of the study

Measure: To evaluate the symptomatic improvement of myelofibrosis patients treated with panobinostat using the Myelofibrosis Symptom Assessment Form (MF-SAF) at baseline and after 2 and 4 months of treatment

Time: Upon enrollment of 13 participants in each cohort and at the end of the study

Measure: To evaluate the symptomatic improvement of myelofibrosis patients treated with panobinostat using the Myelofibrosis Symptom Assessment Form (MF-SAF) at baseline and after 2 and 4 months of treatment

Time: throughout the study

Measure: To assess compliance to panobinostat treatment as assessed by monthly capsule counts

Time: at the end of the study

10 A Phase I Study of Oral Arsenic Trioxide With or Without Ascorbic Acid in Adults With Myelofibrosis

This phase I trial studies the side effects and best dose of arsenic trioxide with or without ascorbic acid in treating patients with myelofibrosis. Drugs used in chemotherapy, such as arsenic trioxide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving arsenic acid together with ascorbic acid may kill more cancer cells.

NCT01014546
Conditions
  1. Essential Thrombocythemia
  2. Polycythemia Vera
  3. Primary Myelofibrosis
Interventions
  1. Drug: Arsenic Trioxide
  2. Dietary Supplement: Ascorbic Acid
  3. Other: Laboratory Biomarker Analysis
  4. Other: Pharmacological Study
MeSH:Polycythemia Vera Primary Myelofibrosis Polycythemia Thrombocytosis Thrombocythemia, Essential
HPO:Polycythemia Thrombocytosis

To estimate the efficacy of arsenic trioxide with ascorbic acid in subjects with myelofibrosis, as determined by a reduction in Janus kinase 2 (JAK2) V617F, JAK22T875N, and mutations of the thrombopoietin receptor (MPL515L/K) allele frequency in peripheral blood neutrophils. --- V617F ---

Primary Outcomes

Description: The frequency of toxicities will be tabulated by grade across all dose levels and courses. The frequency of toxicities will also be tabulated for the dose chosen as the MTD.

Measure: Adverse events, and their attribution throughout the study

Time: Up to 30 days post-treatment

Description: DLT is defined as any non-hematologic treatment-emergent grade 3 or greater adverse event deemed possibly, probably, or definitely related to the study drug. Exceptions are grade 3 nausea or vomiting, unless in the setting of maximal antiemetic treatment. Hematologic toxicities are not included in the definition of a DLT. The frequency of toxicities will be tabulated by grade across all dose levels and cycles.

Measure: Dose-limiting toxicity (DLT) as assessed by the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 3.0 (Stage 1)

Time: At 28 days

Description: The frequency of toxicities will be tabulated by grade across all dose levels and cycles. The frequency of toxicities will also be tabulated for the dose chosen as the MTD.

Measure: Maximum tolerated dose (MTD), defined as the dose level at which 0 or 1 of 6 subjects experience DLT, and 2 of 3 or 2 of 6 experience DLT at the next higher dose level, assessed by the NCI CTC version 3.0 (Stage 1)

Time: At 28 days

Secondary Outcomes

Measure: Change in absolute number of circulating CD34+ cells in the peripheral blood (Stage 2 only)

Time: Baseline to 24 weeks

Measure: Change in JAK2/MPL (Stage 2 only)

Time: Baseline to 24 weeks

Description: Including: sVCAM-1, NE, MMP-2, MMP-9, SDF-1, TGF-B, and VEGF.

Measure: Change in plasma levels of chemokines as measured by ELISA (Stage 2)

Time: Baseline to 24 weeks

Description: Including: sVCAM-1, NE, MMP-2, MMP-9, SDF-1, TGF-B, and VEGF.

Measure: Change in plasma levels of cytokines as measured by ELISA (Stage 2)

Time: Baseline to 24 weeks

Description: Including: soluble vascular cell adhesion molecule 1 (sVCAM-1), neutrophil elastase (NE), matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), stromal cell derived growth factor-1 (SDF-1), TGF-B, and VEGF.

Measure: Change in plasma levels of proteases as measured by enzyme-linked immunosorbent assay (ELISA) (Stage 2)

Time: Baseline to 24 weeks

Measure: Disease response assessed using the IWG-MRT response criteria

Time: Up to 24 weeks

11 Phase II Trial of Erlotinib in Patients With JAK-2 V617F Positive Polycythemia Vera

The primary objective of this study is to determine the overall response rate to erlotinib in patients with polycythemia vera (PV). Response rate will be assessed by improvement in the complete blood count, ultrasound of the spleen, and JAK2 molecular status. It is purposed in this study to explore a possible molecular targeting of the driving mechanism of PV.

NCT01038856
Conditions
  1. Polycythemia Vera
Interventions
  1. Drug: Erlotinib
MeSH:Polycythemia Vera Polycythemia
HPO:Polycythemia

Phase II Trial of Erlotinib in Patients With JAK-2 V617F Positive Polycythemia Vera. --- V617F ---

Trial of Erlotinib in Patients With JAK-2 V617F Positive Polycythemia Vera The primary objective of this study is to determine the overall response rate to erlotinib in patients with polycythemia vera (PV). --- V617F ---

Primary Outcomes

Measure: Overall Response Rate to Include Complete Hematological Response, Complete Molecular Response, Partial Hematological Response, and Minimal Hematological Response

Time: Day 15

Secondary Outcomes

Description: Grade 3 or grade 4 toxicities as measured by CTCAE v3.0

Measure: Incidence of Toxicities

Time: First assessment at day 15, subsequent assessments at 28 day intervals for an average of 1 year

Measure: Improvement in Splenomegaly Size

Time: 4 months, end of treatment and 12 months end of treatment

Measure: Decrease of Mutant JAK2V617F Allele Burden

Time: every 2 months until end of treatment and 12 months after end of treatment

12 A Phase 1 Study of LY2784544 in Patients With JAK2 V617F-Positive Myeloproliferative Disorders

The purpose of this study is to find out the safe dose range of the study drug in patients with myeloproliferative disorders.

NCT01134120
Conditions
  1. Myeloproliferative Disorders
  2. Thrombocythemia, Essential
  3. Polycythemia Vera
  4. Primary Myelofibrosis
Interventions
  1. Drug: LY2784544
MeSH:Polycythemia Vera Primary Myelofibrosis Polycythemia Thrombocytosis Myeloproliferative Disorders Thrombocythemia, Essential
HPO:Myeloproliferative disorder Polycythemia Thrombocytosis

A Phase 1 Study of LY2784544 in Patients With JAK2 V617F-Positive Myeloproliferative Disorders. --- V617F ---

has post-ET MF - Have a quantifiable JAK2 V617F mutation - Have discontinued all previous approved therapies for myeloproliferative disorders, including any chemotherapy, immunomodulating therapy (for example, thalidomide, interferon-alpha), immunosuppressive therapy (for example, corticosteroids greater than 10 mg/day prednisone or equivalent), radiotherapy, and erythropoietin, thrombopoietin, or granulocyte colony stimulating factor for at least 14 days and recovered from the acute effects of therapy. --- V617F ---

Primary Outcomes

Measure: Determination of a recommended Phase 2 dosing regimen

Time: Time of first dose until last dose

Measure: Number of participants with clinical significant effects

Time: Time of first dose until last dose

Secondary Outcomes

Measure: Preliminary pharmacokinetics of LY2784544 (Cmax)

Time: Part A1: Day 1,2,15, and 29; Part A2: Day 7, 14, 21, 28, 29, 56, and 57; Part B: Day 1, 29, 57, and 113

Measure: Preliminary pharmacokinetics of LY2784544 (AUC)

Time: Part A1: Day 1,2,15, and 29; Part A2: Day 7, 14, 21, 28, 29, 56, and 57; Part B: Day 1, 29, 57, and 113

Measure: Malignant clone burden

Time: Part A1: Baseline (2 times), Weeks 13, 21 and every 6 months while patient is on study; Parts A2 and B: Baseline (2 times), Weeks 5, 8, 17, 25 and every 6 months while patient is on study

13 Single Arm Salvage Therapy With Pegylated Interferon Alfa-2a for Patients With High Risk Polycythemia Vera or High Risk Essential Thrombocythemia Who Are Either Hydroxyurea Resistant or Intolerant or Have Had Abdominal Vein Thrombosis

The aim of this research is to look at two conditions, Essential Thrombocythemia (ET) and Polycythemia Vera (PV). ET causes people to produce too many blood cells called platelets and PV causes too many platelets and red blood cells to be made. Platelets are particles which circulate in the blood stream and normally prevent bleeding and bruising. Having too many platelets in the blood increases the risk of developing blood clots, which can result in life threatening events like heart attacks and strokes. When the number of red blood cells is increased in PV this will slow the speed of blood flow in the body and increases the risk of developing blood clots. It is important for patients with ET or PV who are at risk of blood clots to receive drugs which will minimize the risks of developing these blood clots but at the moment the investigators are not sure which drugs will best control the disorder. The purpose of this study is to look at the effectiveness of giving patients who have been diagnosed with ET and PV a study drug regimen using Aspirin and PEGASYS (also known as Pegylated interferon alfa-2a, instead of the standard treatment drug called Hydroxyurea (or hydroxycarbamide or Hydroxyurea), for whom this drug may not be suitable. The drug may not be suitable either because it is not adequately controlling the number of blood cells or some specific side effects occur.

NCT01259817
Conditions
  1. High Risk Polycythemia Vera
  2. High Risk Essential Thrombocythemia
Interventions
  1. Drug: PEGASYS
  2. Drug: Aspirin
MeSH:Polycythemia Vera Polycythemia Thrombocytosis Thrombocythemia, Essential
HPO:Polycythemia Thrombocytosis

To measure the impact of Pegylated Interferon Alfa-2a on JAK2-V617F, CALR, hematopoietic cell clonality in platelets and granulocytes in females, bone marrow histopathology, and cytogenetic abnormalities.. --- V617F ---

For these patients the following additional inclusion/exclusion criteria apply: - > 3 months since onset of SVT - SVT treated with oral anticoagulants but no aspirin - Liver enzymes not > 2 times the normal value - Absence of encephalopathy, refractory or infected ascites, esophageal varicose of grade > 1 at time of trial entry - Bone marrow biopsy confirmed diagnosis of PV or ET - JAK2-V617F mutations present - These patients may have a normal blood count at trial entry - Age over 18 years (no upper age limit) - Able and willing to comply with study criteria - Signed and informed consent to participant in this study - Willing to participate in associated correlative science biomarker study - Serum creatinine < 1.5 x upper limit of normal - AST and ALT < 2 x upper limit of normal - Total bilirubin within normal limits Exclusion Criteria: - Patients cannot have any other form of chemotherapy for their MPD (other than hydroxyurea). --- V617F ---

The point mutation in JAK2 encodes a valine to phenylalanine change at position 617 (JAK2 V617F), and confers constitutive tyrosine kinase activity. --- V617F ---

Introducing the mutation into the bone marrow of mouse models recapitulates the PV phenotype (complete with evolution to bone marrow fibrosis) and inhibitors of JAK2 attenuate the growth of cell lines bearing the mutation in vitro and in vivo, suggesting that JAK2 V617F is a pathophysiologically relevant therapeutic target. --- V617F ---

It is estimated that 95% of PV cases carry JAK2 V617F, while 50 to 60% of ET and PMF cases are JAK2 V617F+. --- V617F ---

Primary Outcomes

Measure: Evaluate the ability of Pegylated Interferon Alfa-2a to achieve Complete Response or Partial Response in patients with (1) high risk polycythemia vera or (2) high risk essential thrombocythemia or (3) splanchnic vein thrombosis

Time: 4 years

Secondary Outcomes

Measure: To evaluate the toxicity and tolerability of therapy Pegylated Interferon Alfa-2a in each of the 3 strata by recording the number of adverse events that occur during the study by using CTC 4.0 as the guide.

Time: 4 years

Measure: To measure the impact of Pegylated Interferon Alfa-2a on key biomarkers of the disease(s)by measuring the JAK2 allele burden.

Time: 4 years

Description: Improvement in disease symptoms will be measured by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) instrument being used in this study.

Measure: To evaluate specific pre-defined toxicity and tolerance of Pegylated Interferon Alfa-2a through a sequential structured symptom assessment package of patient reported outcome instruments.

Time: 4 years

Description: We plan to capture the rate of disease progression to a more advanced myeloid malignancy.

Measure: To estimate survival, and incidence of development of myelodysplastic syndrome, myelofibrosis, or leukemic transformation during therapy Pegylated Interferon Alfa-2a.

Time: 4 years

Description: Capture and record the cardiovascular events that occur during the study.

Measure: Estimate the observed incidence of major cardiovascular events during therapy Pegylated Interferon Alfa-2a.

Time: 4 years

Description: The impact of PEGASYS on JAK2 will be measured by the allele burden; hematopoietic cell clonality will be measured by whether patients with clonal disease return to polyclonal; bone marrow histopathology will be measured by going from abnormal to normal; cytogenetic abnormalities will be measured by seeing if the cytogenetics go from abnormal to normal.

Measure: To measure the impact of Pegylated Interferon Alfa-2a on JAK2-V617F, CALR, hematopoietic cell clonality in platelets and granulocytes in females, bone marrow histopathology, and cytogenetic abnormalities.

Time: 4 years

14 Randomized Trial of Pegylated Interferon Alfa-2a Versus Hydroxyurea Therapy in the Treatment of High Risk Polycythemia Vera (PV) and High Risk Essential Thrombocythemia (ET)

This research is looking at two conditions, Essential Thrombocythemia (ET) and Polycythemia Vera (PV). ET causes people to produce too many blood cells called platelets and PV causes too many platelets and red blood cells to be made. Platelets are particles which circulate in the blood stream and normally prevent bleeding and bruising. Having too many platelets in the blood increases the risk of developing blood clots, which can result in life threatening events like heart attacks and strokes. When the number of red blood cells is increased in PV this will slow the speed of blood flow in the body and increases the risk of developing blood clots. The purpose of this study is to look at the effectiveness of giving participants who have been diagnosed with ET or PV one of two different study regimens over time. The study subject will be followed for their condition for about 5 years. The subject will be randomized into one of two study regimens, either Pegylated Interferon Alfa-2a (PEGASYS) or Aspirin and Hydroxyurea (also called Hydroxycarbamide). The subject must be newly diagnosed or already receiving treatment for either PV or ET. Each of the study drugs used in this study is already being used to treat subjects with ET or PV currently, but the investigators are unsure which study drug is better.

NCT01259856
Conditions
  1. High Risk Polycythemia Vera
  2. High Risk Essential Thrombocythemia
Interventions
  1. Drug: PEGASYS
  2. Drug: Hydroxyurea
  3. Drug: Aspirin
MeSH:Polycythemia Vera Polycythemia Thrombocytosis Thrombocythemia, Essential
HPO:Polycythemia Thrombocytosis

The impact of PEGASYS on JAK2 will be measured by the allele burden; hematopoietic cell clonality will be measured by whether patients with clonal disease return to polyclonal; bone marrow histopathology will be measured by going from abnormal to normal; cytogenetic abnormalities will be measured by seeing if the cytogenetics go from abnormal to normal.To compare the impact of therapy on JAK2-V617F (JAK2), CALR, hematopoietic cell clonality in platelets and granulocytes in females, bone marrow histopathology, and cytogenetic abnormalities.. Number of Participants With Progression of Disease or Death. --- V617F ---

Primary Outcomes

Description: Number of participants with Complete Remission after 12 months of therapy assessed by hematologic response rates two strata of patients with high risk polycythemia vera (PV) or high risk essential thrombocythemia (ET). Complete remission means no evidence of disease.

Measure: Number of Participants With Complete Remission (CR)

Time: 12 months

Description: Number of participants with Partial Remission after 12 months of therapy assessed by hematologic response rates two strata of patients with high risk polycythemia vera (PV) or high risk essential thrombocythemia (ET). Partial Remission means decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment.

Measure: Number of Participants With Partial Remission (PR)

Time: 12 months

Secondary Outcomes

Description: Number of Participants with Grade 3 and Grade 4 Hematological and Non-hematological Events using the Common Terminology Criteria for Adverse Events (CTCAE) 4.0 to assess the toxicity, safety and tolerability of therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea).

Measure: Number of Participants With Grade 3 and Grade 4 Hematological and Non-hematological Events

Time: 4 years

Description: Change in the Total Symptom Score which assessed improvement in disease symptoms measured by the change in TSS from the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) instrument being used in this study from baseline to 12 months. This 19 item instrument includes the previously validated 9 item brief fatigue inventory (BFI), symptoms related to splenomegaly, inactivity, cough, night sweats, pruritus, bone pains, fevers, weight loss, and an overall quality of life assessment. Each item is scored from 0-10 with full scale from 0-190, with higher scores mean worse symptoms.

Measure: Change in the Total Symptom Score (TSS)

Time: baseline and 12 months

Description: To compare the impact of therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea) on key biomarkers of the disease(s) by measuring the JAK2 allele burden.

Measure: JAK2 Allele Burden

Time: 4 years

Description: The impact of PEGASYS on JAK2 will be measured by the allele burden; hematopoietic cell clonality will be measured by whether patients with clonal disease return to polyclonal; bone marrow histopathology will be measured by going from abnormal to normal; cytogenetic abnormalities will be measured by seeing if the cytogenetics go from abnormal to normal.To compare the impact of therapy on JAK2-V617F (JAK2), CALR, hematopoietic cell clonality in platelets and granulocytes in females, bone marrow histopathology, and cytogenetic abnormalities.

Measure: Allele Burden

Time: 4 years

Description: Survival and incidence of development of myelodysplastic syndrome, myelofibrosis, or leukemic transformation after therapy To estimate survival and incidence of development of myelodysplastic syndrome, myelofibrosis, or leukemic transformation after therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea) by capturing the rate of progression to a more advanced myeloid malignancy.

Measure: Number of Participants With Progression of Disease or Death

Time: 4 years

Measure: Number of Participants With Major Cardiovascular Events After Therapy

Time: 4 years

15 Natural Killer Cells and Polycythemia Vera (Vaquez's Disease)

Natural Killer cells (NK) are pivotal cells of innate immunity, that sense defective expression of HLA class I molecules and are complementary to specific cytotoxic T lymphocytes. A defect in NK cell cytotoxicity has been described in some hematopoietic malignancies such as acute myeloid leukemia, multiple myeloma, myelodysplastic syndroms. This defect is at least partially linked to a decreased or absent expression of some activating NK cell molecules, more particularly the so-called Natural Cytotoxicity Receptors (NCRs) NKp30, NKp44 and NKp46. Some old publications have demonstrated defective NK cytotoxicity in myeloproliferative syndroms (chronic myeloid leukemia, primary thrombocytosis, polycythemia vera). The investigators more particularly focused their attention on polycythemia vera (Vaquez's disease), a myeloproliferative disease characterized by the recently describet mutation V617F of the JAK2 tyrosine kinase. The investigators will precise the mechanisms leading to this cytotoxicity defect, the investigators also will evaluate the implication of V617F mutation on NK physiology, and will study the interactions between NK cells and hematopoietic progenitors.

NCT01284712
Conditions
  1. Polycythemia Vera
Interventions
  1. Biological: blood sample
MeSH:Polycythemia Vera Polycythemia
HPO:Polycythemia

The investigators more particularly focused their attention on polycythemia vera (Vaquez's disease), a myeloproliferative disease characterized by the recently describet mutation V617F of the JAK2 tyrosine kinase. --- V617F ---

The investigators will precise the mechanisms leading to this cytotoxicity defect, the investigators also will evaluate the implication of V617F mutation on NK physiology, and will study the interactions between NK cells and hematopoietic progenitors. --- V617F ---

Primary Outcomes

Measure: To describe immunologic anomalies in polycythemia vera

Time: 2 years

16 An Exploratory, Observational, Multicentre Study to Investigate the Impact of the Presence of JAK2 (V617F) Mutation on Treatment Response in Patients With Essential Thrombocythaemia Treated With XAGRID® (Anagrelide Hydrochloride)

This study is hypothesis-generating to explore the impact of JAK2 (V617F) mutation status on the treatment response to anagrelide hydrochloride

NCT01352585
Conditions
  1. Essential Thrombocythemia (ET)
Interventions
  1. Drug: Anagrelide hydrochloride
MeSH:Thrombocytosis Thrombocythemia, Essential
HPO:Thrombocytosis

An Exploratory, Observational, Multicentre Study to Investigate the Impact of the Presence of JAK2 (V617F) Mutation on Treatment Response in Patients With Essential Thrombocythaemia Treated With XAGRID® (Anagrelide Hydrochloride). --- V617F ---

Exploratory Multi-centre Trial In Patients With ET Treated With XAGRID® This study is hypothesis-generating to explore the impact of JAK2 (V617F) mutation status on the treatment response to anagrelide hydrochloride Number of Patients With Platelet Count ≤600x10^9/L After 12 Months. --- V617F ---

Primary Outcomes

Description: A platelet count of ≤600x10^9/L after 12 months is considered at least a partial response.

Measure: Number of Patients With Platelet Count ≤600x10^9/L After 12 Months

Time: 1 year

Secondary Outcomes

Description: A platelet count of ≤400x10^9/L after 12 months is considered a complete response.

Measure: Number of Patients With Platelet Count ≤400x10^9/L After 12 Months

Time: 1 year

Measure: Platelet Count

Time: 1 year

Measure: Red Blood Cell (RBC) Count

Time: 1 year

Measure: White Blood Cell (WBC) Count

Time: 1 year

Measure: Differential WBC Count

Time: 1 year

Measure: Hemoglobin Concentration

Time: 1 year

Measure: Hematocrit Level

Time: 1 year

17 Danish Study of Low-dose Interferon Alpha Versus Hydroxyurea in the Treatment of Philadelphia Chromosome Negative (Ph-)Chronic Myeloid Neoplasms.

The purpose of the study is to compare the efficacy and toxicity including quality of life of two types of low-dose interferon alpha compounds (PegIntron and Pegasys) with hydroxyurea (Hydrea), and to investigate the occurence of neutralizing antibodies against recombinant interferon.

NCT01387763
Conditions
  1. Polycythemia Vera
  2. Essential Thrombocythemia
  3. Primary Myelofibrosis
Interventions
  1. Drug: PegIntron
  2. Drug: Pegasys
  3. Drug: PegIntron
  4. Drug: Pegasys
  5. Drug: Hydrea
MeSH:Neoplasms Polycythemia Vera Primary Myelofibrosis Polycythemia Thrombocytosis Thrombocythemia, Essential
HPO:Neoplasm Polycythemia Thrombocytosis

Molecular responses (JAK V617F allele burden) are assessed by qPCR according to the ELN guidelines.. toxicity (discontinuation of therapy due to intolerability). --- V617F ---

In 2005 major breakthrough in our understanding of the molecular pathophysiology was achieved with the identification of the JAK2 V617F mutation which is present in almost all patients with PV (98%) and about half of patients with ET and PMF. --- V617F ---

Within recent years IFN-alpha has demonstrated a capacity of inducing deep molecular remission (evaluated by JAK2 V617F qPCR) and normalisation of bone marrow morphology. --- V617F ---

If patients have a sustained deep molecular response (below 1 % JAK2 V617F mutated alleles for 12 months) therapy will be stopped to asses the sustainability of the remission off therapy.Patients over the age of 75 and intolerant or resistant to hydroxyurea will be offered rescue treatment with orally busulfan (Myleran). --- V617F ---

Primary Outcomes

Description: Molecular responses (JAK V617F allele burden) are assessed by qPCR according to the ELN guidelines.

Measure: molecular response (changes from baseline)

Time: 18, 36 and 60 months

Secondary Outcomes

Description: The proportion of patients treated with PegIntron, Pegasys and Hydrea who need to discontinue therapy due to intolerability

Measure: toxicity (discontinuation of therapy due to intolerability)

Time: 18 months

Description: Quality of life will be evaluated according to EORTC QLQ C-30 and MPN-SAF

Measure: Quality of life (changes from baseline)

Time: 4, 12, 24, 36, 48 and 60 months

Description: A bone marrow sample will be evaluated in order to detect and grade changes in bone marrow morphology.

Measure: Histopathological response (changes from baseline)

Time: 36 and 60 months

Description: investigation of the sustainability of an obtained molecular remission (< 1% JAK2V617F mutated alleles) after discontinuation of interferon- alpha( Pegasys, PegIntron, Multiferon) or Hydrea.

Measure: Sustained molecular response (changes from level at time of discontinuation of therapy)

Time: 12, 24 and 36 months

Description: Proportion of patients treated with Peintron and Pegasys who have developed neutralizing antibodies.

Measure: Neutralizing antibodies against PegIntron and Pegasys

Time: 24 months

Description: Hematological response will be evaluated according to the ELN guidelines.

Measure: hematological response

Time: 12 months

18 A Phase II, Multicenter, Open Label, Single Arm Study of SAR302503 in Subjects Previously Treated With Ruxolitinib and With a Current Diagnosis of Intermediate or High-Risk Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis

Primary Objective: - To evaluate the efficacy of once daily dose of SAR302503 in subjects previously treated with ruxolitinib and with a current diagnosis of intermediate-1 with symptoms, Intermediate-2 or high-risk primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (Post-PV MF), or post-essential thrombocythemia myelofibrosis (Post-ET MF) based on the reduction of spleen volume at the end of 6 treatment cycles; Secondary Objectives: - To evaluate the effect of SAR302503 on Myelofibrosis (MF) associated symptoms as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) diary - To evaluate the durability of splenic response - To evaluate the splenic response to SAR302503 by palpation at the end of Cycle 6 - To evaluate the splenic response to SAR302503 at the end of Cycle 3 - To evaluate the effect of SAR302503 on the Janus kinase 2 (JAK2) V617F allele burden - To evaluate the safety and tolerability of SAR302503 in this population - To evaluate plasma concentrations of SAR302503 for population PK analysis, if warranted

NCT01523171
Conditions
  1. Hematopoietic Neoplasm
Interventions
  1. Drug: SAR302503
MeSH:Hematologic Neoplasms Primary Myelofibrosis
HPO:Hematological neoplasm Leukemia

Phase II, Open Label, Single Arm Study of SAR302503 In Myelofibrosis Patients Previously Treated With Ruxolitinib Primary Objective: - To evaluate the efficacy of once daily dose of SAR302503 in subjects previously treated with ruxolitinib and with a current diagnosis of intermediate-1 with symptoms, Intermediate-2 or high-risk primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (Post-PV MF), or post-essential thrombocythemia myelofibrosis (Post-ET MF) based on the reduction of spleen volume at the end of 6 treatment cycles; Secondary Objectives: - To evaluate the effect of SAR302503 on Myelofibrosis (MF) associated symptoms as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) diary - To evaluate the durability of splenic response - To evaluate the splenic response to SAR302503 by palpation at the end of Cycle 6 - To evaluate the splenic response to SAR302503 at the end of Cycle 3 - To evaluate the effect of SAR302503 on the Janus kinase 2 (JAK2) V617F allele burden - To evaluate the safety and tolerability of SAR302503 in this population - To evaluate plasma concentrations of SAR302503 for population PK analysis, if warranted Response Rate (RR), defined as the proportion of subjects who have a ≥35% reduction from baseline in volume of spleen at the end of Cycle 6 as measured by Magnetic Resonance Imaging (MRI) (or CT scan in subjects with contraindications for MRI). --- V617F ---

Primary Outcomes

Measure: Response Rate (RR), defined as the proportion of subjects who have a ≥35% reduction from baseline in volume of spleen at the end of Cycle 6 as measured by Magnetic Resonance Imaging (MRI) (or CT scan in subjects with contraindications for MRI)

Time: 6 months

Secondary Outcomes

Measure: Symptom Response Rate (SRR): Proportion of subjects with a ≥50% reduction from baseline to the end of Cycle 6 in the total symptom score using the modified MFSAF

Time: 6 months

Measure: Duration of spleen response, measured by MRI (or CT scan in subjects with contraindications for MRI)

Time: 6 months

Measure: Proportion of subjects with a ≥50% reduction in length of spleen by palpation from baseline at the end of Cycle 6

Time: 6 months

Measure: Response Rate at the end of Cycle 3, defined as the proportion of subjects who have a ≥35% reduction from baseline in volume of spleen at the end of Cycle 3 as measured by MRI (or CT scan in subjects with contraindications for MRI)

Time: 6 months

Measure: Percent change of spleen volume at the end of Cycles 3 and 6 from baseline as measured by MRI (or CT scan in subjects with contraindications for MRI)

Time: 6 months

Measure: Safety, as assessed by clinical, laboratory, ECG, and vital sign events; graded by the NCI CTCAE v4.03

Time: approximately 5 years

Measure: Plasma concentrations of SAR302503

Time: 4 months

Measure: The effect of SAR302503 on the JAK2V617F allele burden

Time: 2 years

19 A Phase 2 Study of LY2784544 in Patients With Myeloproliferative Neoplasms

The primary purpose of this study is to measure the response rate in participants with the myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET), or myelofibrosis (MF) when treated with LY2784544, including those who have demonstrated an intolerance to, failure of primary response to, or have demonstrated disease progression while on ruxolitinib.

NCT01594723
Conditions
  1. Neoplasms, Hematologic
Interventions
  1. Drug: 120 mg LY2784544
MeSH:Neoplasms Hematologic Neoplasms Myeloproliferative Disorders
HPO:Hematological neoplasm Leukemia Myeloproliferative disorder Neoplasm

Inclusion Criteria: - Have a diagnosis of polycythemia vera (PV), essential thrombocythemia (ET), or myelofibrosis (MF) as defined by the World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms (Swerdlow et al. 2008) and meet the following additional subtype specific criteria: - PV: have failed or is intolerant of standard therapies or refuses to take standard medications - ET: have failed or is intolerant of standard therapies or refuses to take standard medications - MF (participants with MF must meet at least 1 of the following): have intermediate 1, intermediate 2, or high-risk MF according to the Dynamic International Prognostic Scoring System (DIPPS Plus) for Primary Myelofibrosis (Gangat et al. 2011); or have symptomatic MF with spleen greater than 10 centimeter (cm) below left costal margin; or have post-polycythemic MF; or have post-ET MF - All PV, ET, and MF participants must meet the following criteria: o Have a quantifiable level of janus kinase 2 with a valine to phenylalanine substitution at amino acid 617 (JAK2 V617F) mutation. --- V617F ---

This inclusion criterion will not apply to the subset of participants in Cohorts 10 and 11 that must be negative for the JAK2 V617F mutation - Are ≥ 18 years of age - Have given written informed consent prior to any study-specific procedures - Have adequate organ function, including: Hepatic: Direct bilirubin ≤1.5 times upper limits of normal (ULN), alanine transaminase (ALT), and aspartate transaminase (AST) ≤2.5 times ULN; Renal: Serum creatinine ≤1.5 times ULN; Bone Marrow Reserve: Absolute neutrophil count (ANC) ≥1000/microliter (mcL), platelets ≥50,000/mcL for participants with ET or PV and ≥25,000/mcL for participants with MF - Have a performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) scale - Have discontinued all previous approved therapies for Myeloproliferative Neoplasms (MPNs), including any chemotherapy, immunomodulating therapy (for example, thalidomide, interferon-alpha), immunosuppressive therapy (for example, corticosteroids >10 mg/day prednisone or equivalent), radiotherapy, and erythropoietin, thrombopoietin, or granulocyte colony stimulating factor for at least 14 days and recovered from the acute effects of therapy. --- V617F ---

An exception to this criterion will be allowed for participants with a prior history of Budd-Chiari Syndrome who are being treated with warfarin or one of its derivatives - Have received a hematopoietic stem cell transplant - Have a second primary malignancy that in the judgment of the Investigator and Sponsor may affect the interpretation of results - Have an active fungal, bacterial, and/or known viral infection including human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis (screening is not required) - Have a history of congestive heart failure with New York Heart Association (NYHA) Class >2 (NYHA Class 1 and 2 are eligible), unstable angina, recent myocardial infarction (within 6 months prior to administration of study drug), or documented history of ventricular arrhythmia Inclusion Criteria: - Have a diagnosis of polycythemia vera (PV), essential thrombocythemia (ET), or myelofibrosis (MF) as defined by the World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms (Swerdlow et al. 2008) and meet the following additional subtype specific criteria: - PV: have failed or is intolerant of standard therapies or refuses to take standard medications - ET: have failed or is intolerant of standard therapies or refuses to take standard medications - MF (participants with MF must meet at least 1 of the following): have intermediate 1, intermediate 2, or high-risk MF according to the Dynamic International Prognostic Scoring System (DIPPS Plus) for Primary Myelofibrosis (Gangat et al. 2011); or have symptomatic MF with spleen greater than 10 centimeter (cm) below left costal margin; or have post-polycythemic MF; or have post-ET MF - All PV, ET, and MF participants must meet the following criteria: o Have a quantifiable level of janus kinase 2 with a valine to phenylalanine substitution at amino acid 617 (JAK2 V617F) mutation. --- V617F ---

Primary Outcomes

Measure: Percentage of Participants with an Objective Response (Objective Response Rate)

Time: Baseline until Disease Progression (PD) or Participant Stops Study (Estimated up to 24 Months)

Secondary Outcomes

Measure: Percentage of Participants with a Molecular Response (Molecular Response Rate)

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Percentage of Participants with Hematological Improvement (Hematological Improvement Rate)

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Change in Spleen Size

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Change in Bone Marrow Fibrosis Grade

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Change in Number of Thrombotic or Hemorrhagic Events

Time: 3 Months prior to Study Drug (historic) until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Change in Number of Phlebotomies and Transfusions

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Duration of Response

Time: Confirmed Response to PD or Death from Any Cause (Estimated up to 24 Months)

Measure: Time to Best Response

Time: Baseline to Confirmed Response (Estimated up to 6 Months)

Measure: Change in Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF)

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Time to Treatment Failure

Time: Baseline to PD, Death from Any Cause or Participant Stops Study (Estimated up to 24 Months)

Measure: Time to Disease Progression

Time: Baseline to Measured PD (Estimated up to 24 Months)

Measure: Progression Free Survival (PFS)

Time: Baseline to PD or Death from Any Cause (Estimated up to 24 Months)

Measure: Change in Activities of Daily Living (ADL)/ Instrumental Activities of Daily Living (IADL)

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Change in EuroQol - 5 dimensions (EQ-5D) Index Score

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Change in International Prognosis Scoring System Scales (IPSS)

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2784544

Time: Predose up to Day 84

Measure: PK: Time of Maximal Concentration (Tmax) of LY2784544

Time: Predose up to Day 84

Measure: Change in Liver Size

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

Measure: Change in 6-item Physician Symptom Assessment

Time: Baseline until PD or Participant Stops Study (Estimated up to 24 Months)

20 A Large-scale Trial Testing the Intensity of CYTOreductive Therapy to Prevent Cardiovascular Events In Patients With Polycythemia Vera (PV)

CYTO-PV is a phase III Prospective, Randomized, Open-label, with Blinded Endpoint evaluation (PROBE), multi-center, clinical trial in patients with diagnosis of Polycythemia vera (PV) treated at the best of recommended therapies (e.g.adequate control of standard cardiovascular risk factors). Irrespective of randomized interventions, all patients will be administered low-dose aspirin (when not contraindicated), i.e.the standard antithrombotic treatment in PV patients. The purpose of this study to demonstrate that a more intensive cytoreductive therapy, plus low-dose aspirin when not contraindicated, with phlebotomy and/or hydroxyurea (HU), aimed at maintaining hematocrit (HCT) < 45% is more effective than a less intensive cytoreduction (either with phlebotomy or HU plus low-dose aspirin when not contraindicated) maintaining HCT in the range of 45-50% in the reduction of CV deaths plus thrombotic events (stroke, acute coronary syndrome [ACS], transient ischemic attack [TIA], pulmonary embolism [PE], splanchnic thrombosis, deep vein thrombosis [DVT], and any other clinically relevant thrombotic event), in patients with Polycythemia Vera treated at the best of recommended therapies (e.g. adequate control of standard cardiovascular risk factors).

NCT01645124
Conditions
  1. Polycythemia Vera
Interventions
  1. Drug: Hydroxyurea
  2. Procedure: Phlebotomy
MeSH:Polycythemia Vera Polycythemia
HPO:Polycythemia

However, both pragmatic reasons and the consideration of the clinical condition under study (see: age, comorbidity, polytherapy) support the decision to adopt a generalized policy of surveillance specifically on: Hypotension or syncope after phlebotomy; renal dysfunction (creatinine); liver dysfunction (ALT, AST, symptoms); White blood cell count; Platelet count; Bleeding.. Inclusion Criteria: Males and females aged 18 years or more are eligible for the study if they meet all the following inclusion criteria: - New diagnosis of PV according to WHO 2007 diagnostic criteria including Jak 2 V617F mutation status; - Old diagnosis of PV confirmed with JAK-2 positivity and clinical course of the disease; - Ability and willingness to comply with all study requirements; - Written informed consent (obtained before any study specific procedure). --- V617F ---

Inclusion Criteria: Males and females aged 18 years or more are eligible for the study if they meet all the following inclusion criteria: - New diagnosis of PV according to WHO 2007 diagnostic criteria including Jak 2 V617F mutation status; - Old diagnosis of PV confirmed with JAK-2 positivity and clinical course of the disease; - Ability and willingness to comply with all study requirements; - Written informed consent (obtained before any study specific procedure). --- V617F ---

Primary Outcomes

Description: To demonstrate that in patients with PV treatment with aggressive cytoreductive therapy aimed at maintaining HCT < 45% is more effective than cytoreductive therapy aimed at maintaining HCT between 45 and 50% in the reduction CV deaths plus thrombotic events (PEP: stroke, acute coronary syndrome [ACS], transient ischemic attack [TIA], pulmonary embolism [PE], abdominal thrombosis, deep vein thrombosis [DVT], and peripheral arterial thrombosis). The minimum clinically relevant beneficial effect is set at a 30% reduction of risk of the PEP.

Measure: Reduction of PEP (Primary End Point)defined as CV deaths plus thrombotic events

Time: Expected average of 5 years

Secondary Outcomes

Description: The events included in the PEP, arterial and venous thrombosis, major and minor thrombosis as well as hospitalization for any reason, hospitalization for CV reason, malignancy and PV-related malignancy (progression to myelofibrosis, myelodysplastic or leukemic transformation) will be analyzed separately to assess the full benefit/risk profile of experimental treatments.

Measure: PEP plus minor thrombosis, hospitalization and malignancy

Time: Expected average of 5 years

Other Outcomes

Description: Background knowledge suggests that no specific safety precautions are to be adopted for phlebotomy and HU administration. However, both pragmatic reasons and the consideration of the clinical condition under study (see: age, comorbidity, polytherapy) support the decision to adopt a generalized policy of surveillance specifically on: Hypotension or syncope after phlebotomy; renal dysfunction (creatinine); liver dysfunction (ALT, AST, symptoms); White blood cell count; Platelet count; Bleeding.

Measure: Aadverse Events

Time: Expected average of 5 years

21 Long-term Study Evaluating the Effect of Givinostat in Patients With JAK2V617F Positive Chronic Myeloproliferative Neoplasms

This is a multicenter, open label, long-term study testing the long-term safety, tolerability and efficacy of Givinostat in patients with Polycythemia Vera, Essential Thrombocythemia, primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis following core protocols in chronic myeloproliferative neoplasms and/or patient-named compassionate use program (if regulated/allowed by the local regulations, e.g. for Italy D.M. 8/5/2003 "Uso terapeutico di medicinale sottoposto a sperimentazione clinica" published on G.U. n. 173 of 28 July 2003, and the following amendments). Patients will continue at their last tolerable dose and treatment schedule of Givinostat monotherapy. If patients previously received Givinostat in combination with other drugs during a core protocol or a compassionate use program (if regulated/allowed by the local regulations, e.g. for Italy D.M. 8/5/2003 "Uso terapeutico di medicinale sottoposto a sperimentazione clinica" published on G.U. n. 173 of 28 July 2003, and the following amendments), they will be treated at the last tolerable dose of the combination. Assessment of safety and efficacy will be performed at each quarterly visit and each visit will also include laboratory tests and ECG examination. During the visits the clinical benefit will be assessed by Investigator according to the revised European LeukemiaNet response criteria (for PV and ET) and EUMNET response criteria (for MF). The dose of Givinostat will be modified for protocol specified toxicities. The treatment may continue up to Marketing Authorization of Givinostat, currently planned in the next 5 years (note: only for Germany, this long-term study is initially limited up to 2 years of treatment). Patients may discontinue study treatment at any time and remain on study therapy as long as they derive clinical benefit. Safety will be monitored at each visit throughout the entire duration of the study. In case the approved label will not cover the whole study population, Givinostat will be provided by the Sponsor to those patients not fulfilling the criteria for the approved label of the drug that are still deriving benefit from Givinostat at the time of its commercial availability.

NCT01761968
Conditions
  1. Chronic Myeloproliferative Neoplasms
Interventions
  1. Drug: Givinostat
MeSH:Neoplasms Myeloproliferative Disorders
HPO:Myeloproliferative disorder Neoplasm

reduction of the allele burden of the mutated Janus Kinase 2 in the position V617F). --- V617F ---

Primary Outcomes

Description: To obtain information on the long-term efficacy of Givinostat in patients with chronic myeloproliferative neoplasms following core protocols or compassionate use program: Number of patients experiencing adverse events; Type, incidence, and severity of treatment-related adverse events. To determine the long term safety and tolerability of Givinostat in patients with chronic myeloproliferative neoplasms following core protocols or compassionate use program: For Polycythemia Vera and Essential Thrombocythemia, Complete response and partial response rate according to the revised clinico-haematological European LeukemiaNet response criteria; For Myelofibrosis, complete response, major response, moderate response and minor response rate according to European Myelofibrosis Network response criteria. Note that these assessment will be repeated periodically (each 3 months) during the study. In fact, the treatment will continue up to Marketing Authorisation of Givinostat.

Measure: Long-term safety and efficacy

Time: 3 months

Other Outcomes

Description: To evaluate the effect of Givinostat on each single response parameter according to the revised European LeukemiaNet (for Polycythemia Vera and Essential Thrombocythemia) and European European Myelofibrosis Network response criteria (for Myelofibrosis). Note that this assessment will be repeated periodically (each year) during the study. In fact, the treatment will continue up to Marketing Authorisation of Givinostat.

Measure: Clinical exploratory endpoint

Time: 1 year

Description: To evaluate the molecular response (i.e. reduction of the allele burden of the mutated Janus Kinase 2 in the position V617F). Note that this assessment will be repeated periodically (each year) during the study. In fact, the treatment will continue up to Marketing Authorisation of Givinostat.

Measure: Molecular exploratory endpoint

Time: 1 year

Description: To identify potential other markers predictive of clinical benefit of Givinostat (e.g. potential pharmacodynamic markers). Note that this assessment will be repeated periodically (each year) during the study. In fact, the treatment will continue up to Marketing Authorisation of Givinostat.

Measure: Biomolecular exploratory endpoint

Time: 1 year

22 A Two-part Study Top Assess the Safety and Preliminary Efficacy of Givinostat in Patients With JAK2V617F Positive Polycythemia Vera

This is a two-part, multicenter, open label, non-randomized, phase Ib/II study to assess the safety and tolerability, Maximum Tolerated Dose and preliminary efficacy of Givinostat in patients with JAK2V617F positive Polycythemia Vera. Part A is the dose finding part while Part B is assessing the preliminary efficacy. Patients will be enrolled either in Part A or Part B and transition from one part to the other is not allowed. Eligible patients for this study will have a confirmed diagnosis of Polycythemia Vera according to the revised World Health Organization criteria. Only if the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 months), eligibility for this part of the study may be expanded to all patients with chronic myeloproliferative neoplasms. Study therapy will be administered in 28 day cycles (4 weeks of treatment). Disease response will be evaluated according to the European LeukemiaNet criteria after 3 and 6 cycles (i.e. at weeks 12 and 24, respectively) of treatment with Givinostat for both parts of the study. All phlebotomies performed in the first 3 weeks of treatment will not be counted to assess the clinico-haematological response. The study will last up to a maximum of 24 weeks of treatment. However, after completion of the trial, all patients achieving clinical benefit will be allowed to continue treatment with Givinostat (at the same dose and schedule) in a long-term study. Safety will be monitored at each visit throughout the entire duration of the study. Treatment will be administered on an outpatient basis and patients will be followed regularly with physical and laboratory tests, as specified in the protocol; in case of hospitalization, the treatment will be continued or interrupted according to the Investigators' decision.

NCT01901432
Conditions
  1. Polycythemia Vera
Interventions
  1. Drug: Givinostat
MeSH:Polycythemia Vera Polycythemia
HPO:Polycythemia

dose group was not available for PK analysis.. Inclusion Criteria: 1. Patients must be able to provide informed consent and be willing to sign an informed consent form; 2. Patients must have an age ≥18 years; 3. Patients must have a confirmed diagnosis of Polycythemia Vera according to the revised World Health Organization criteria; 4. Patients must have mutated Janus Kinase 2 (mutation V617F) positive disease; 5. Patients must have an active/not controlled disease defined as 1. hematocrit ≥ 45% or hematocrit <45% in need of phlebotomy, and 2. platelet count > 400 x109/L, and 3. white blood cell count > 10 x109/L; 6. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 in Part A, ECOG performance status ≤ 2 in Part B within 7 days of initiating study drug; 7. Female patient of childbearing potential has a negative serum or urine pregnancy test within 72 hours of the first dose of study therapy; 8. Use of an effective means of contraception for women of childbearing potential and men with partners of childbearing potential; 9. Adequate and acceptable organ function within 7 days of initiating study drug; 10. --- V617F ---

Inclusion Criteria: 1. Patients must be able to provide informed consent and be willing to sign an informed consent form; 2. Patients must have an age ≥18 years; 3. Patients must have a confirmed diagnosis of Polycythemia Vera according to the revised World Health Organization criteria; 4. Patients must have mutated Janus Kinase 2 (mutation V617F) positive disease; 5. Patients must have an active/not controlled disease defined as 1. hematocrit ≥ 45% or hematocrit <45% in need of phlebotomy, and 2. platelet count > 400 x109/L, and 3. white blood cell count > 10 x109/L; 6. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 in Part A, ECOG performance status ≤ 2 in Part B within 7 days of initiating study drug; 7. Female patient of childbearing potential has a negative serum or urine pregnancy test within 72 hours of the first dose of study therapy; 8. Use of an effective means of contraception for women of childbearing potential and men with partners of childbearing potential; 9. Adequate and acceptable organ function within 7 days of initiating study drug; 10. --- V617F ---

Primary Outcomes

Description: Evaluations were performed on the type, incidence and severity of TEAEs, graded according to Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03, following administration of givinostat for up to 6 cycles of treatment in Part A. Grades 1 through 5 were as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life threatening consequences; Grade 5: Death related to AE. Results are reported as number of patients with TEAEs for each of the indicated categories. Definitions: drug-related TEAE / treatment-emergent serious adverse event (TESAE) corresponded to reasonable suspicion that the TEAE / TESAE was associated with the use of the study drug, according to investigator assessment; discontinuation refers to discontinuation from treatment.

Measure: Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study

Time: 168 days (up to Cycle 6 Day 28 in Part A).

Description: The MTD of givinostat was based only on Cycle 1 DLTs. A DLT was defined as the following drug-related toxicity: Grade 4 hematological toxicity, or Grade 3 febrile neutropenia, or Grade ≥3 non-hematological toxicity (with the exception Grade 3 diarrhea without adequate supportive care lasting less than 3 days, and Grade 3 nausea or vomiting without adequate supportive care lasting less than 3 days), or Any drug-related serious AE, or Any toxicity clearly not related to disease progression or intercurrent illness requiring interruption of dosing for more than 3 days during first cycle. At end of Cycle 1, for the third patient in each DL, the safety of the 3 patients treated for 1 cycle was reviewed and it was decided if the dose should be escalated or not. Results are reported as the number of patients with DLT events for Cycle 1 in Part A.

Measure: Number of Dose Limiting Toxicities (DLTs) After 1 Cycle in Part A of the Study

Time: 28 days (up to Cycle 1 Day 28 in Part A).

Description: Evaluations were performed on the type, incidence and severity of TEAEs, graded according to CTCAE v. 4.03, following administration of givinostat at the MTD for up to 3 cycles of treatment in Part B. Grades 1 through 5 were as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life threatening consequences; Grade 5: Death related to AE. Results are reported as number of patients with TEAEs for each of the indicated categories. Definitions: drug-related TEAE / TESAE corresponded to reasonable suspicion that the TEAE / TESAE was associated with the use of the study drug, according to investigator assessment; discontinuation refers to discontinuation from treatment.

Measure: Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study

Time: 84 days (up to Cycle 3 Day 28 in Part B).

Description: ORR, CR and PR following administration of givinostat at MTD for 3 cycles in Part B, reported as percentage of patients with a response. Response was evaluated according to the clinico-hematological European LeukemiaNet (ELN) response criteria. If Investigator's clinical response assessment (taking into account the overall medical judgment of the specific patient's case) was not in agreement with exact application of the ELN response criteria, the Investigator's assessment superseded the mathematical application of these criteria and was used for analysis. CR defined as: Hematocrit (HCT) <45% without phlebotomy, and Platelets ≤400 x10^9/litre (L), and White Blood Cell count ≤10 x10^9/L, and Normal spleen size, and No disease-related systemic symptoms (i.e. pruritus, headache, microvascular disturbances). PR defined as: Patients not fulfilling CR and HCT <45% without phlebotomy, or Response in ≥3 other criteria.

Measure: Overall Response Rate (ORR) (i.e. Complete Response [CR] and Partial Response [PR]) After 3 Cycles in Part B of the Study

Time: 84 days (up to cycle 3 Day 28 in Part B).

Secondary Outcomes

Description: ORR following administration of givinostat after 3 cycles and after 6 cycles in Part A, reported as percentage of patients with a response. Response was evaluated according to the clinico-hematological ELN response criteria. If Investigator's clinical response assessment (taking into account the overall medical judgment of the specific patient's case) was not in agreement with exact application of the ELN response criteria, the Investigator's assessment superseded the mathematical application of these criteria and was used for analysis. Analysis performed using the dataset for all Part A patients combined.

Measure: ORR After 3 Cycles and After 6 Cycles in Part A of the Study

Time: 84 and 168 days (up to Cycle 3 Day 28 and Cycle 6 Day 28 in Part A).

Description: ORR following administration of givinostat at the MTD for 6 cycles in Part B, reported as percentage of patients with a response. Response was evaluated according to the clinico-hematological ELN response criteria. If Investigator's clinical response assessment (taking into account the overall medical judgment of the specific patient's case) was not in agreement with exact application of the ELN response criteria, the Investigator's assessment superseded the mathematical application of these criteria and was used for analysis.

Measure: ORR After 6 Cycles in Part B of the Study

Time: 168 days (up to Cycle 6 Day 28 in Part B).

Description: Evaluations were performed on the type, incidence and severity of TEAEs, graded according to CTCAE v. 4.03, following administration of givinostat at the MTD for up to 6 cycles of treatment in Part B. Grades 1 through 5 were as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life threatening consequences; Grade 5: Death related to AE. Results are reported as number of patients with TEAEs for each of the indicated categories. Definitions: drug-related TEAE / TESAE corresponded to reasonable suspicion that the TEAE / TESAE was associated with the use of the study drug, according to investigator assessment; discontinuation refers to discontinuation from treatment. Results are reported as number of patients with TEAEs for each of the indicated categories.

Measure: Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study

Time: 168 days (up to Cycle 6 Day 28 in Part B).

Description: Pharmacokinetic (PK) evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Cmax following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis.

Measure: Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

Time: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Description: PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tmax following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis.

Measure: Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

Time: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Description: PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tlast following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis.

Measure: Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

Time: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Description: PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUClast following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis.

Measure: Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

Time: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Description: PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUC0-12 following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis and AUC0-12 was calculated using the linear trapezoidal rule. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Note:concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) across all dose groups and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis.

Measure: Assessment of Area Under Plasma Concentration Versus the Time Curve in the Dosing Interval (0-12 Hours) (AUC0-12) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

Time: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Description: PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Cmax following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B. Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis.

Measure: Assessment of Cmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

Time: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Description: PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tmax following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B. Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis.

Measure: Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

Time: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Description: PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tlast following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B. Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis.

Measure: Assessment of Tlast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

Time: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Description: PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUClast following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the for the doses administered during Part B. Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis.

Measure: Assessment of AUClast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

Time: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Description: PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUC0-12 following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B. Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2374 (Cycle 1 Day 28) across all dose groups and for ITF2375 in the 50 mg b.i.d. dose group was not available for PK analysis.

Measure: Assessment of AUC0-12 of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

Time: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

23 Hydroxyurea in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a serious and eventually fatal disease damaging the lungs and the heart. It results from narrowing and eventual blockage of small blood vessels in the lung, due to abnormal proliferation of cells in the blood vessel (arterial). Patients with PAH suffer from fatigue, shortness of breath, low oxygen levels, blood clots and heart failure. No therapies reverse the disease process in the lung arteries, however there are three approved drugs that can temporarily dilate the vessels and improve symptoms. However, all three drugs have significant side effects and toxicities, they do not work effectively in many patients, survival remains on average only 2 to 3 years once symptoms begin, and none of these drugs prevent the underlying disease process in the small arteries of the lung. PAH is known to develop in patients with a pre-existing class of bone marrow diseases called myeloproliferative disorders (MPDs). We and others have recently shown that patients with PAH have bone marrow changes similar to those seen in patients with MPDs, even without other signs and symptoms of those bone marrow diseases such as anemia or high platelet and white blood cell counts. Compared to healthy volunteers, patients with PAH have a higher frequency of immature stem and progenitor cells able to produce blood cells and vascular wall cells in their bone marrow. They also have higher circulating numbers of these cells in the blood, and increased localization of these cells in the lung blood vessels. When immature bone marrow cells from PAH patients and normal volunteers were infused into mice, the mice receiving PAH marrow cells developed similar lung and heart problems to PAH patients, suggesting that the bone marrow problem is a primary cause of the lung problems, and that the increased numbers of immature bone marrow cells in the bone marrow and blood of PAH patients causes the lung blood vessel disease. The drug hydroxyurea is used to inhibit the abnormally high level of bone marrow cell proliferation in patients with MPDs. It has been shown to reduce the numbers of circulating immature bone marrow cells in patients with MPDs. Hydroxyurea has been available for almost fifty years, and has been used to treat patients with MPDs, sickle cell anemia, and congenital heart disease for very prolonged periods of time, up to twenty or more years in individual patients. It has an excellent long-term safety profile and few side effects and is generally well tolerated. It does not appear to result in an increased rate of leukemia even with many years of treatment. In the current protocol, we hypothesize that treating patients with PAH with hydroxyurea will decrease the level of circulating immature bone marrow cells and interrupt the abnormal narrowing and occlusion of lung arteries. We will treat patients with moderately severe primary (no known underlying cause) PAH with 6 months of hydroxyurea, carefully monitoring side effects and adjusting dosage as necessary, and measure the effect on circulating immature cells, lung blood vessel pressures, other blood markers of active PAH, and exercise tolerance.

NCT01950585
Conditions
  1. Pulmonary Hypertension
Interventions
  1. Drug: Hydroxyurea
MeSH:Hypertension, Pulmonary Familial Primary Pulmonary Hypertension Hypertension
HPO:Hypertension Pulmonary arterial hypertension

- HIV positivity - Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient s ability to tolerate protocol therapy, or that death within 30 days is likely - Presence of 9;22 BCR/ABL translocation as detected by conventional bone marrow cytogenetics or PCR for BCR/ABL transcript, or presence of JAK2 V617F mutation in bone marrow or peripheral blood cells. --- V617F ---

Primary Outcomes

Measure: The change in concentration of CD34+ circulating progenitors from baseline to 6 months (24 weeks (+/- 7 days)) on hydroxyurea.

Time: ongoing

24 Effects of Sympathicomimetic Agonists on the Disease Course and Mutant Allele Burden in Patients With JAK2-mutated Myeloproliferative Neoplasms. A Multicenter Phase II Trial.

The aim of this phase II study is to test a novel concept in the treatment of patients with myeloproliferative neoplasms (MPN), a disease of the bone marrow. With no current cure available, MPN are a group of chronic leukemias (blood cancers) in which patients produce too many blood cells. These increased blood cell numbers cause problems to the patient such as bleedings or thrombosis and some patients may progress to acute leukemia, a life threatening condition. Most MPN patients have a gene mutation called JAK2-V617F. The disease is maintained by mutant MPN stem cells that reside in the bone marrow in specialized locations called "niches". These niches need connections to the nervous system. New findings show that these connections are destroyed by the presence of the mutated MPN stem cells. Research teams found that some drugs (beta3-sympathicomimetics) can restore these damaged niches and at the same time reduce the MPN disease manifestation in a mouse model of MPN. Such sympathicomimetic drugs are already being used to treat patients with asthma or hyperactive bladder. These drugs have shown to have only few side effects. The study tests the effects of the beta-3-sympathicomimetic drug Mirabegron (Betmiga®) on MPN disease in 39 patients that carry a JAK2-V617F mutation. The hypothesis is that Mirabegron will have a beneficial effect on bone marrow niche cells and will thereby improve the disease manifestation in MPN patients. This study should provide a rapid answer whether targeting the nervous system of the niche cells could be useful for patients with MPN and warrants to be tested in larger and more long-term studies.

NCT02311569
Conditions
  1. Myeloproliferative Neoplasm
  2. Primary Myelofibrosis
  3. Essential Thrombocythemia
  4. Polycythemia Vera
Interventions
  1. Drug: Mirabegron
MeSH:Neoplasms Polycythemia Vera Primary Myelofibrosis Myeloproliferative Disorders Polycythemia Thrombocytosis Thrombocythemia, Essential
HPO:Myeloproliferative disorder Neoplasm Polycythemia Thrombocytosis

Most MPN patients have a gene mutation called JAK2-V617F. --- V617F ---

The study tests the effects of the beta-3-sympathicomimetic drug Mirabegron (Betmiga®) on MPN disease in 39 patients that carry a JAK2-V617F mutation. --- V617F ---

Patients are defined as success for this endpoint, if they show a reduction of the JAK2-V617F allelic burden of 50% or more 24 weeks ± 4 weeks after registration when compared to baseline, and if they did not start a new MPN treatment before. --- V617F ---

Reduction in the burden of mutated alleles of ≥25% at 24 weeks (Red-25@24): Patients are defined as success for the Red-25@24 endpoint, if they show a reduction of the Jak2-V617F allelic burden of 25% or more 24 weeks ± 4 weeks after registration when compared to baseline, and if they did not start a new MPN treatment before. --- V617F ---

Reduction in the burden of mutated alleles of ≥25% at 12 weeks (Red-25@12) defined in the same way as the Red-25@24 endpoint, but evaluated at 12 weeks ± 4 weeks after registration.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of JAK2-V617F positive ET, PV or PMF at primary diagnosis or pretreated - JAK2-V617F mutant allele burden > 20% in the peripheral blood at study entry - Patient must give written informed consent before registration - WHO performance status 0-2 - Age ≥ 18 years - Adequate hematological values: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/ L - Adequate hepatic function: bilirubin ≤ 1.5 x ULN, AST/ALT/AP ≤ 2.5 x ULN - Adequate renal function (calculated creatinine clearance > 50 mL/min, according to the formula of Cockcroft-Gault) - Women are not breastfeeding. --- V617F ---

Reduction in the burden of mutated alleles of ≥25% at 12 weeks (Red-25@12) defined in the same way as the Red-25@24 endpoint, but evaluated at 12 weeks ± 4 weeks after registration.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of JAK2-V617F positive ET, PV or PMF at primary diagnosis or pretreated - JAK2-V617F mutant allele burden > 20% in the peripheral blood at study entry - Patient must give written informed consent before registration - WHO performance status 0-2 - Age ≥ 18 years - Adequate hematological values: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/ L - Adequate hepatic function: bilirubin ≤ 1.5 x ULN, AST/ALT/AP ≤ 2.5 x ULN - Adequate renal function (calculated creatinine clearance > 50 mL/min, according to the formula of Cockcroft-Gault) - Women are not breastfeeding. --- V617F --- --- V617F ---

Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of JAK2-V617F positive ET, PV or PMF at primary diagnosis or pretreated - JAK2-V617F mutant allele burden > 20% in the peripheral blood at study entry - Patient must give written informed consent before registration - WHO performance status 0-2 - Age ≥ 18 years - Adequate hematological values: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/ L - Adequate hepatic function: bilirubin ≤ 1.5 x ULN, AST/ALT/AP ≤ 2.5 x ULN - Adequate renal function (calculated creatinine clearance > 50 mL/min, according to the formula of Cockcroft-Gault) - Women are not breastfeeding. --- V617F ---

Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of JAK2-V617F positive ET, PV or PMF at primary diagnosis or pretreated - JAK2-V617F mutant allele burden > 20% in the peripheral blood at study entry - Patient must give written informed consent before registration - WHO performance status 0-2 - Age ≥ 18 years - Adequate hematological values: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/ L - Adequate hepatic function: bilirubin ≤ 1.5 x ULN, AST/ALT/AP ≤ 2.5 x ULN - Adequate renal function (calculated creatinine clearance > 50 mL/min, according to the formula of Cockcroft-Gault) - Women are not breastfeeding. --- V617F --- --- V617F ---

Three genes are frequently mutated in MPN and are implicated to be the phenotypic driver mutations: more than 95% of PV patients carry a somatic JAK2-V617F mutation, while about half of the remaining PV patients (2-3%) display mutations in JAK2 exon 12. Thus, almost all patients with PV have somatic mutations in the JAK2 gene. --- V617F ---

The mutational profiles of ET and PMF are more diverse: JAK2-V617F is found in 50-60% of the patients, whereas the recently described mutations in calreticulin (CALR) occur in 20-25% of the patients. --- V617F ---

Ruxolitinib, recently approved for PMF with splenomegaly, is effective in reducing spleen size and improving quality of life, but has little effect on the JAK2-V617F mutant allele burden and has so far not been reported to induce remissions. --- V617F ---

Furthermore, in a mouse model of MPN expressing the human JAK2-V617F mutation, this effect was found to be caused by early glial and sympathetic nerve damage and apoptosis of nestin+ MSCs triggered by the mutant HSCs. --- V617F ---

Mice with JAK2-V617F driven MPN treated with a beta-3-sympathicomimetic agonist not only restored nestin+ MSCs numbers, but also showed correction of thrombocytosis, neutrophilia, and bone marrow fibrosis, and efficiently reduced mutant hematopoietic progenitor numbers in bone marrow and peripheral blood. --- V617F ---

Primary Outcomes

Description: Primary endpoint of the trial is reduction in the burden of mutated alleles of ≥50% at 24 weeks (Red-50@24). Patients are defined as success for this endpoint, if they show a reduction of the JAK2-V617F allelic burden of 50% or more 24 weeks ± 4 weeks after registration when compared to baseline, and if they did not start a new MPN treatment before. All other evaluable patients will be considered as failures for this endpoint.

Measure: Reduction in the burden of mutated alleles of ≥50% at 24 weeks.

Time: at 24 weeks

Secondary Outcomes

Description: Reduction in the burden of mutated alleles of ≥50% at 12 weeks (Red-50@12) defined in the same way as the primary endpoint, but evaluated at 12 weeks ± 4 weeks after registration.

Measure: Reduction in the burden of mutated alleles of ≥50%

Time: at 12 weeks

Description: Reduction in the burden of mutated alleles of ≥25% at 24 weeks (Red-25@24): Patients are defined as success for the Red-25@24 endpoint, if they show a reduction of the Jak2-V617F allelic burden of 25% or more 24 weeks ± 4 weeks after registration when compared to baseline, and if they did not start a new MPN treatment before. All other evaluable patients will be considered as failures for this endpoint.

Measure: Reduction in the burden of mutated alleles of ≥25%

Time: at 24 weeks

Description: Reduction in the burden of mutated alleles of ≥25% at 12 weeks (Red-25@12) defined in the same way as the Red-25@24 endpoint, but evaluated at 12 weeks ± 4 weeks after registration.

Measure: Reduction in the burden of mutated alleles of ≥25%

Time: at 12 weeks

25 Phase II Study of P1101 in Early Myelofibrosis

This pilot phase II trial studies P1101 (polyethyleneglycol [PEG]-proline-interferon alpha-2b) in treating patients with myelofibrosis. PEG-proline-interferon alpha-2b is a substance that can improve the body's natural response and may slow the growth of myelofibrosis.

NCT02370329
Conditions
  1. Primary Myelofibrosis
  2. Secondary Myelofibrosis
Interventions
  1. Other: Laboratory Biomarker Analysis
  2. Biological: PEG-Proline-Interferon Alfa-2b
  3. Other: Quality-of-Life Assessment
MeSH:Primary Myelofibrosis

To evaluate the impact of P1101 on bone marrow and histological features of myelofibrosis including cytogenetics, blast percentage, fibrosis, and JAK2-V617F allele burden by cohort (early vs intermediate-2/high risk). --- V617F ---

Primary Outcomes

Description: The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.

Measure: Best overall response (CR, PR, or CI) as determined by International Working Group Criteria

Time: Up to 3 years

Secondary Outcomes

Description: The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.

Measure: Incidence of adverse events, as measured by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4)

Time: Up to 3 years

Description: The distribution of survival time will be estimated using the method of Kaplan-Meier.

Measure: Survival time

Time: Time from registration to death due to any cause, assessed up to 3 years

Other Outcomes

Description: Patient-reported symptoms and QOL will be described at each time point using the mean, confidence interval, median, and range. Changes in individual symptoms, changes in a symptom scale composed of symptoms specific to MF patients, and changes in the MPN TSS will be investigated. Graphical procedures will include stream plots of individual patient scores and plots of average values over time. Correlational analyses will be done to determine the relationships among patients-reported symptoms and QOL, as well as with clinical outcomes and clinician-assessed symptoms.

Measure: Changes in patient-reported symptoms and QOL as measured by MPN-SAF

Time: Baseline to up to 3 years

26 Molecular Disease Profile of Haematological Malignancies. A Prospective Registry Study by the Rete Ematologica Lombarda (REL) Clinical Network

In this prospective multicentric study, the University of Pavia together with the Fondazione IRCCS Policlinico San Matteo, Pavia and the IRCCS Fondazione Maugeri, Pavia, Italy will provide a systematic analysis of gene mutations in hematological malignancies by using NGS techniques. Patients with a conclusive diagnosis of haematological malignancies according to WHO criteria referred to the Rete Ematologica Lombarda clinical network (REL, www.rel-lombardia.net) will be enrolled. The investigators will analyse genomic DNA extracted from hematopoietic cells at different time points of patient disease. The study contemplates the use of molecular platforms (Next Generation Sequencing, NGS) aimed at the identification of recurrent mutations in myeloid and lymphoid neoplasms, respectively. Screening of gene mutations by NGS will be prospectively implemented in the context of REL clinical network. Patient samples will be analyzed at diagnosis and sequentially during the course of the disease at specific timepoints. The researchers will analyze the correlations between somatic mutations, specific clinical phenotypes (according to the WHO classification) and disease evolution. This will allow to: 1) identify new recurrent genetic mutations involved in the molecular pathogenesis of hematological malignancies; 2) define the role of mutated genes, distinguishing between genes which induce a clonal proliferation of hematopoietic stem cells, and genes which determine the clinical phenotype of the disease; 3) identify mutations which are responsible for disease evolution; 4) define the diagnostic/prognostic role of the identified mutations, and update the current disease classifications and prognostic scores by including molecular parameters. A systematic biobanking of biological material will be provided.

NCT02459743
Conditions
  1. Hematological Malignancies
MeSH:Neoplasms Hematologic Neoplasms
HPO:Hematological neoplasm Leukemia Neoplasm

In 2005 the University of Pavia described the diagnostic and prognostic significance of the JAK2 V617F mutation in myeloproliferative neoplasms (MPN): this mutation was included into the WHO classification of MPN and innovative anti-JAK2 drugs were developed. --- V617F ---

Primary Outcomes

Measure: Cumulative incidence of gene mutations in principal clone and subclones in each hematological malignancy

Time: 3 years

Secondary Outcomes

Measure: Genotype-phenotype correlations between clinical characteristics and mutational status

Time: 3 years

Measure: Overall survival and disease-free survival according to clinical and biological risk factors at diagnosis and during disease evolution

Time: 3 years

27 Ruxolitinib in Combination With High Dose Therapy and Autologous Stem Cell Transplantation for Myelofibrosis

To determine the safety of the approach of giving RUXOLITINIB before and after an autologous stem cell transplant, as measured by graft failure or death.

NCT02469974
Conditions
  1. Myelofibrosis
  2. MF
Interventions
  1. Drug: RUXOLITINIB / INC 424
  2. Drug: Filgrastim
  3. Drug: Busulfan
MeSH:Primary Myelofibrosis

Changes in Jak 2 V617F allele burden when present will be measured by quantitative RT-PCR. --- V617F ---

Primary Outcomes

Description: Safety of this approach as measured by graft failure or death

Measure: Safety of combining ruxolitinib with autologous HSCT measured by graft failure or death

Time: 2 years

Secondary Outcomes

Description: Total CD34+ cell dose will be calculated based on results of flow cytometric analysis and patient's weight.

Measure: CD34 cells

Time: 4 years

Measure: The regimen related mortality (RRM)

Time: day 100

Measure: The regimen related mortality (RRM)

Time: day 365

Measure: Rate of engraftment/graft failure

Time: 4 years

Measure: Time of engraftment for neutrophils and platelets

Time: 4 years

Measure: The incidence of serious infectious complications

Time: up to 1 year post transplant

Description: The myelofibrosis score will be assessed as per the European Consensus Grading published by Thiele Grading Description at 365 days as compared to 180 days

Measure: Changes in marrow fibrosis score

Time: at 180 and 365 days post-transplant

Description: Changes in FISH abnormalities when present will be measured by cytogenetics.

Measure: Change in FISH allele

Time: at 365 days post-transplant

Description: Changes in Jak 2 V617F allele burden when present will be measured by quantitative RT-PCR

Measure: Change in JAK allele

Time: at 365 days post-transplant

Description: Overall efficacy will be rated on a scale as complete remission, partial remission, clinical improvement, or stable disease

Measure: Rate of response

Time: at 6 months post-transplant

Description: Overall efficacy will be rated on a scale as complete remission, partial remission, clinical improvement, or stable disease

Measure: Rate of response

Time: at 1 year post-transplant

28 A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma

This is a Phase I, open-label, dose escalation and dose expansion study with BID (suspension) and TID (tablet) oral dose of tazemetostat. Subjects will be screened for eligibility within 14 days of the planned first dose of tazemetostat. A treatment cycle will be 28 days. Response assessment will be evaluated after 8 weeks of treatment and subsequently every 8 weeks while on study. The study has two parts: Dose Escalation and Dose Expansion. Dose escalation for subjects with the following relapsed/refractory malignancies: - Rhabdoid tumors: - Atypical teratoid rhabdoid tumor (ATRT) - Malignant rhabdoid tumor (MRT) - Rhabdoid tumor of kidney (RTK) - Selected tumors with rhabdoid features - INI1-negative tumors: - Epithelioid sarcoma - Epithelioid malignant peripheral nerve sheath tumor - Extraskeletal myxoid chondrosarcoma - Myoepithelial carcinoma - Renal medullary carcinoma - Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) (with Sponsor approval) - Synovial Sarcoma with a SS18-SSX rearrangement Dose Expansion at the MTD or the RP2D - Cohort 1 -(closed to enrollment) ATRT - Cohort 2 - MRT/RTK/selected tumors with rhabdoid features - Cohort 3 - INI-negative tumors: - Epithelioid sarcoma - Epithelioid malignant peripheral nerve sheath tumor - Extraskeletal myxoid chondrosarcoma - Myoepithelial carcinoma - Renal medullary carcinoma - Chordoma (poorly differentiated or de-differentiated) - Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) with Sponsor approval - Cohort 4 -(closed to enrollment) Tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement

NCT02601937
Conditions
  1. Rhabdoid Tumors
  2. INI1-negative Tumors
  3. Synovial Sarcoma
  4. Malignant Rhabdoid Tumor of Ovary
Interventions
  1. Drug: Tazemetostat
MeSH:Neoplasms Sarcoma Sarcoma, Synovial Rhabdoid Tumor
HPO:Neoplasm Sarcoma Soft tissue sarcoma Synovial sarcoma

JAK2 V617F) observed in cytogenetic testing and DNA sequencing. --- V617F ---

Primary Outcomes

Description: The incidence and severity of treatment-emergent adverse events (AEs) qualifying as protocol-defined DLTs in Cycle 1 will guide establishment of the protocol defined RP2D and/or MTD

Measure: To determine the MTD or the RP2D (Dose Escalation)

Time: 1 cycle/28 days

Measure: Dose expansion: Number of subjects with objective response using disease appropriate standardized response criteria

Time: Assessed every 8 weeks for duration of study participation which is estimated to be 24 months

Secondary Outcomes

Measure: Dose escalation: Number of subjects with objective response using disease appropriate standardized response criteria

Time: Assessed every 8 weeks for duration of study participation which is estimated to be 24 months

Measure: Dose Expansion: Progression-free survival (PFS)

Time: At 24 and 56 weeks post treatment using Kaplan-Meier method

Measure: Dose Expansion: Overall Survival (OS)

Time: At 24 and 56 weeks post treatment using Kaplan-Meier method

Measure: Incidence of treatment-emergent adverse events as a measure of safety and tolerability

Time: Adverse events assessed from first dose through 30 days post last dose

Measure: Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Cmax

Time: Days 1 and 15

Measure: Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Tmax

Time: Days 1 and 15

Measure: Pharmacokinetics profile of tazemetostat and its metabolite (plasma): AUC(0-t)

Time: Days 1 and 15

Measure: Pharmacokinetics profile of tazemetostat and its metabolite (plasma): AUC(0-12)

Time: Days 1 and 15

Measure: Pharmacokinetics profile of tazemetostat and its metabolite (plasma): t1/2

Time: Days 1 and 15

Measure: Pharmacokinetics profile of tazemetostat and its metabolite (plasma): CL/F

Time: Day 15

Measure: Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Vd/F

Time: Day 15

Measure: Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Ka

Time: Day 15

Measure: Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Ctrough

Time: Day 1 of cycles 2, 3 and 4

29 A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma

This is a Phase II, multicenter, open-label, single arm, 2-stage study of tazemetostat 800 mg BID (twice daily) and 1600 mg QD (once daily). Subjects will be screened for eligibility within 21 days of the planned date of the first dose of tazemetostat and enrolled into one of 8 cohorts: Cohort using tazemetostat 800 mg BID - Cohort 1 (Closed for enrollment): MRT, RTK, ATRT, and selected tumors with rhabdoid features, including small cell carcinoma of the ovary hypercalcemic type [SCCOHT], also known as malignant rhaboid tumor of the ovary [MRTO] - Cohort 2 (Closed for enrollment): Relapsed or refractory synovial sarcoma with SS18-SSX rearrangement - Cohort 3 (Closed for enrollment): Other INI1 negative tumors or any solid tumor with an EZH2 gain of function (GOF) mutation, including: epithelioid malignant peripheral nerve sheath tumor (EMPNST), extraskeletal myxoid chondrosarcoma (EMC), myoepithelial carcinoma, other INI1-negative malignant tumors with Sponsor approval (e.g., dedifferentiated chordoma) any solid tumor with an EZH2 GOF mutation including but not limited to Ewing's sarcoma and melanoma - Cohort 4 (Closed for enrollment): Renal medullary carcinoma (RMC) - Cohort 5 (Closed for enrollment): Epithelioid sarcoma (ES) - Cohort 6 (Opened for enrollment): Epithelioid sarcoma (ES) undergoing mandatory tumor biopsy - Cohort 7 (Opened for enrollment): Poorly differentiated chordoma (or other chordoma with Sponsor approval) Cohort using tazemetostat 1600 mg QD • Cohort 8 (Opened for enrollment): Epitheliod sarcoma Subjects will be dosed in continuous 28-day cycles. (Note: if treatment with study drug is discontinued prior to completing 2 years, subjects will be followed for a maximum duration of 2 years from start of study drug dosing.) Response assessment will be performed every 8 weeks while on study. Treatment with tazemetostat will continue until disease progression, unacceptable toxicity or withdrawal of consent, or termination of the study.

NCT02601950
Conditions
  1. Malignant Rhabdoid Tumors (MRT)
  2. Rhabdoid Tumors of the Kidney (RTK)
  3. Atypical Teratoid Rhabdoid Tumors (ATRT)
  4. Selected Tumors With Rhabdoid Features
  5. Synovial Sarcoma
  6. INI1-negative Tumors
  7. Malignant Rhabdoid Tumor of Ovary
  8. Renal Medullary Carcinoma
  9. Epithelioid Sarcoma
  10. Poorly Differentiated Chordoma (or Other Chordoma With Sponsor Approval)
  11. Any Solid Tumor With an EZH2 GOF Mutation
Interventions
  1. Drug: Tazemetostat
MeSH:Neoplasms Sarcoma Sarcoma, Synovial Rhabdoid Tumor Chordoma Carcinoma, Medullary Kidney Neoplasms
HPO:Chordoma Neoplasm Renal neoplasm Sarcoma Soft tissue sarcoma Synovial sarcoma

JAK2 V617F) observed in cytogenetic testing and DNA sequencing. --- V617F ---

Primary Outcomes

Measure: Number of subjects with objective response using disease appropriate standardized response criteria

Time: Assessed every 8 weeks for duration of study participation which is estimated to be 24 months

Description: The number of subjects with CR, PR, or stable disease (SD) at 16 week assessment

Measure: Progression-free survival (PFS) rate for Cohort 2 (Relapsed/Refractory Synovial Sarcoma)

Time: 16 weeks of treatment

Measure: Assess the effects of tazemetostat on tumor immune priming for Cohort 6

Time: Through study completion, an average of 2 years

Measure: Assess the safety and tolerability of tazemetostat 1600 mg QD for Cohort 8

Time: Through study completion, an average of 2 years

Secondary Outcomes

Measure: Duration of response in subjects in Cohorts 1, 2, 3, 4, 5, 6 and 7 and in Cohorts 1, 3, 4, 5, 6 and 7 combined for subjects achieving a complete response (CR) and partial response (PR) following oral administration of tazemetostat 800 mg BID

Time: Assess every 8 weeks for duration of study participation which is estimated to be 24 months

Description: The number of subjects with confirmed CR, PR or SD at 32 week assessment

Measure: Disease control rate (DCR) in subjects with epithelioid sarcoma (Cohort 5) and epithelioid sarcoma undergoing mandatory biopsy (Cohort 6) following oral administration of tazemetostat 800 mg BID

Time: 32 weeks of treatment

Description: ORR (confirmed CR+PR, RECIST 1.1)

Measure: Overall response rate ORR for Cohort 2 (relapsed/refractory synovial sarcoma) and Cohort 6 (epithelioid sarcoma undergoing mandatory biopsy) following oral administration of tazemetostat 800 mg BID

Time: Assessed every 8 weeks for duration of study participation which is estimated to be 24 months

Description: The time from date of first dose of study treatment to the earlier of the date of first documented disease progression or date of death due to any cause

Measure: PFS for each cohort

Time: 24, 32 and 56 weeks of treatment

Description: The time from the date of the first dose of study treatment to the date of death due to any cause

Measure: OS for each cohort

Time: 24, 32 and 56 weeks of treatment

Measure: Incidence of treatment-emergent adverse events as a measure of safety and tolerability

Time: Adverse events assessed from first dose through 30 days post last dose

Measure: Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Cmax

Time: Days 1 and 15

Measure: Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Tmax

Time: Days 1 and 15

Measure: Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): AUC(0-t)

Time: Days 1 and 15

Measure: Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): AUC(0-12)

Time: Days 1 and 15

Measure: Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): t1/2

Time: Days 1 and 15

Measure: Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): CL/F

Time: Days 1, 15, 29, 43, and 57

Measure: Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Vd/F

Time: Days 1, 15, 29, 43, and 57

Measure: Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Ka

Time: Days 1, 15, 29, 43, and 57

Measure: Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Ctrough

Time: Days 29, 43 and 57

Description: IHC assessments of changes in the level of H3K27-Me3 following tazemetostat dosing

Measure: Investigate the pharmacodynamics (PD) effects of tazemetostat in tumor tissue

Time: At week 8

Measure: Duration of response in subjects with epithelioid sarcoma in Cohort 8 at 1600 mg QD.

Time: Assess every 8 weeks for duration of study participation which is estimated to be 24 months

Description: The number of subjects with confirmed CR, PR or SD at 32 week assessment

Measure: Disease control rate (DCR) in subjects with epithelioid sarcoma (Cohort 8) following oral administration of tazemetostat 1600 mg QD

Time: 32 weeks of treatment

Description: ORR (confirmed CR+PR, RECIST 1.1)

Measure: Overall response rate ORR for subjects with epithelioid sarcoma (Cohort 8) following oral administration of tazemetostat 1600 mg QD

Time: Assessed every 8 weeks for duration of study participation which is estimated to be 24 months

30 Risk Factors for Variceal Bleeding in Egyptian Patients With Non-Cirrhotic Portal Hypertension

Background & Aims: Non-cirrhotic portal hypertension (NCPH) represents a relatively infrequent group of conditions. This work aimed at determining causes of NCPH and evaluating the role of some clinical, laboratory, imaging and endoscopic parameters in prediction of variceal bleeding in an Egyptian cohort with NCPH. Methods: Sixty patients with non-cirrhotic portal hypertension and oesophageal varices were included. All underwent complete clinical evaluation, laboratory investigations, Color Doppler ultrasonography, platelet count/spleen diameter (mm) ratio and upper gastrointestinal endoscopy. Patients were classified into two groups according to variceal bleeding: (1) Group I: twenty six patients with history of bleeding or had an attack of bleeding during one year follow-up; and (2) Group II: thirty four patients without bleeding.

NCT02635815
Conditions
  1. Portal Hypertension
Interventions
  1. Procedure: Upper gastrointestinal endoscopy
MeSH:Hypertension, Portal Hypertension
HPO:Hypertension Portal hypertension

It was done only for patients with Budd-Chiari syndrome and extrahepatic portal vein thrombosis: anticardiolipin antibodies, lupus anticoagulant, antinuclear antibodies, protein C, S, antithrombin III, factor V Leiden G1691A mutation, prothrombin gene G20210A mutation, methylene tetrahydrofolate reductase C677T mutation by PCR, Janus tyrosine kinase-2 (JAK II) V617F mutation by PCR (to exclude myeloproliferative disorders) and flow cytometry for CD55 and CD59 (to exclude paroxysmal nocturnal hemoglobinuria); (4) Abdominal ultrasonography: for liver size, echogenicity, spleen size, portal vein diameter and ascites; (5) Color Doppler ultrasonographic study: was done in the morning after an overnight fasting using a color Doppler unit with a 3.5 MHz convex probe for confirmation of portal vein (PV) patency and diameter, mean PV flow velocity (mean PVV) (cm/sec), PV direction of flow, splenic vein patency and diameter, presence of portosystemic collaterals and patency of hepatic veins; (6) Platelet count/spleen diameter ratio: calculated as: platelet count/ maximum spleen bipolar diameter by ultrasound in mm; (7) Ultrasonography guided liver biopsy: for diagnosis of NCPH and exclusion of cirrhotic portal hypertension; and (8) Upper gastrointestinal endoscopy using the Pentax video endoscope EG 3440. --- G1691A --- --- G20210A --- --- C677T --- --- V617F ---

Primary Outcomes

Measure: The presence or absence of variceal bleeding within one year of follow up.

Time: 1 year

31 A Phase II Single-Arm Study of the Efficacy and Safety of Oral Rigosertib in Patients With Myelofibrosis (MF) and Anemia

The goal of this clinical research study is to learn if rigosertib can help to control MF in patients with anemia. The safety of this drug will also be studied. This is an investigational study. Rigosertib is not FDA-approved or commercially available. It is currently being used for research purposes only. The study doctor can explain how the study drug is designed to work. Up to 35 participants will be enrolled in this study. All will be enrolled at MD Anderson.

NCT02730884
Conditions
  1. Leukemia
  2. Myelofibrosis
  3. Anemia
  4. Splenomegaly
Interventions
  1. Drug: Rigosertib
  2. Behavioral: Questionnaire
MeSH:Anemia Primary Myelofibrosis Splenomegaly
HPO:Anemia Splenomegaly

Measurement of JAK2 V617F allele burden in Bone Marrow (BM) samples, if not done within 6 months prior to Screening, must be provided with the Screening BM biopsy/aspirate report (patients are eligible regardless of JAK2 mutation status); 3. Anemia or RBC-transfusion dependence defined as follows: a) Anemia: defined for the purpose of this protocol as 1) a hemoglobin level <10 g/L on every determination over 84 days before study-entry, without red blood cell (RBC)-transfusions, or 2) a hemoglobin level <10 g/L on a patient that is receiving RBC-transfusions periodically but not meeting criteria for transfusion-dependent patient as defined below. --- V617F ---

Primary Outcomes

Description: Spleen response defined as ≥ 35% spleen volume reduction from Baseline, which must be confirmed by MRI or CT measurement per revised International Working Group for Myelofibrosis Research and Treatment (IWG MRT) response criteria.

Measure: Number of Participants With Spleen Volume Response

Time: Baseline and 48 weeks

Description: Anemia response defined as the proportion of transfusion-independent patients with Hgb increase of at least 2 g/dL from Baseline or the proportion of transfusion-dependent patients becoming transfusion independent for at least 12 weeks as defined in 2013 International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria.

Measure: Participants With Anemia Response

Time: Baseline and 48 weeks

Secondary Outcomes

Description: Symptoms response defined as the proportion of patients achieving ≥ 50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) at any time before Week 48.

Measure: Symptoms Response

Time: 48 weeks

32 Assessment of the Prevalence of Major Psychiatric Disorders in a Cohort of Women With Clinical Criteria Corresponding to Pure, Abortive-form, Obstetrical, Antiphospholipid Syndrome

The primary objective of this study was to evaluate and compare the prevalence of the following psychiatric pathologies (based on the MINI5.0.0 questionnaire) among 3 groups of women (Leiden versus aP1Ab-positive versus thrombophilia-negative) with similar obstetrical histories 10 years after their initial assessment/diagnosis. - Mood disorders, including depressive episodes during the previous two weeks, recurrent depressive disorders at any point in life, dysthymia in the last two years, or any current or past manic episode; - Anxiety disorders, including current agoraphobia, current panic disorders, agoraphobia with panic disorders, current social phobia, generalized anxiety in the last 6 months, or current posttraumatic stress syndrome; - Apparent psychotic syndromes, including isolated or recurrent psychotic syndromes, past or present (clinically validated), - Current alcohol or drug problems (dependence or abuse).

NCT02833194
Conditions
  1. Antiphospholipid Syndrome
  2. Factor V Leiden Thrombophilia
MeSH:Thrombophilia Antiphospholipid Syndrome Syndrome Mental Disorders Problem Behavior
HPO:Behavioral abnormality Hypercoagulability

Exclusion Criteria: - Any history of thrombotic events or any treatment given during previous pregnancies that might have modified the natural course of the condition - Women whose pregnancy losses could be explained by infectious, metabolic, anatomic or hormonal facotrs, or associated with paternal or maternal chromosomal causes - Seropositivity for HIV, hepatitis B or C - Women with antithrombin, protein C, or protein S deficiency, and women with abnormal fibrinogen or with the JAK2 V617F mutation were further excluded. --- V617F ---

Primary Outcomes

Measure: Mini Internationl Neuropsychiatric Interview 5.0.0

Time: 10 years

33 The Prognostic Value of PGF and sFlt1 Variations Induced by the First Low-molecular-weight-heparin Injections in Women With Obstetrical Antiphospholipids Antibody Syndrome Starting a New Pregnancy and Following Treatment in Accordance With International Recommendations

The primary objective of this study is to evaluate plasmatic concentrations of free PGF and sFlt1 for blood samples taken before a first low-molecular-weight-heparin injection and also for blood samples taken on the 4th day of injections (the latter correspond to the first systematic control of platelet counts) in women who have an obstetric antiphospholipid antibody syndrome and who are initiating a new pregnancy with recommended treatment. Our goal is to test the prognostic value of these data on the occurrence of: - pregnancy loss categorized as embryonic loss (before 10 weeks gestation), fetal death (before 20 weeks gestation), stillbirths (from 20 weeks gestation to delivery), and neonatal death defined before reaching 28 days of age. - ischemic placental pathology (pre-eclampsia, retro-placental hematoma, birth of a small-for-gestational-age infant)

NCT02855047
Conditions
  1. Antiphospholipid Syndrome
MeSH:Antiphospholipid Syndrome Syndrome

- Women in the APS subgroup: persistently positive for LA, and/or aCL and/or aBeta2GP1 - Women initiating a new pregnancy during the 18 month observational period after obstetric APS diagnosis Exclusion Criteria: - Any history of thrombotic events or any treatment given during previous pregnancies that might have modified the natural course of the condition - Women whose pregnancy losses could be explained by infectious, metabolic, anatomic or hormonal factors, or associated with paternal or maternal chromosomal causes - Seropositivity for HIV, hepatitis B or C - Women with antithrombin, protein C, or protein S deficiency, and women with abnormal fibrinogen or with the JAK2 V617F mutation were further excluded. --- V617F ---

Primary Outcomes

Description: The primary endpoint was a composite outcome that included any of the following events occurring after 19 completed weeks during the observed pregnancy: preeclampsia, abruptio placenta, or fetal growth restriction (< 10th percentile), summarized as the so-called placenta-mediated complications PMCs.

Measure: Presence/absence of at least one of the following: preeclampsia, abruptio placenta, or fetal growth restriction (< 10th percentile)

Time: 19 weeks gestation

34 Efficacy of Heat-shock Protein (HSP) Inhibitors in Myeloproliferative Syndromes (MPS): Fundamental Observational in Vitro Study Using Samples From a Collection

Heat-shock proteins (HSP) have been very highly conserved throughout the evolution of species and are characterized by their chaperone function, thanks to their ability to prevent aggregation and to promote the renaturation/break down of damaged proteins. Among other targets, they also chaperone JAK2, a key step that is deregulated in signalling in myeloproliferative syndromes (MPS) because of the JAK2V617F mutation. These HSP also have a potent cytoprotective action through their multiples inhibiting effects on apoptotic processes. Little is known about levels of HSP expression, in particular for HSP70 and HSP27, in MPS cells. However, in vitro studies of different cell models have shown the interest of HSP90 inhibitors in slowing cell proliferation in MPS. These results have been confirmed in animal models with results in terms of blood counts and overall survival. In addition, it seems that the V617F mutated form of JAK2 is more sensitive than the wild-type to HSP90 inhibitors. Finally, inhibitors of HSP90 remain efficacious with regard to the inhibition of cell growth, even in cases of resistance to JAK2 inhibitors. Nonetheless, HSP90 inhibitors are known to stimulate the expression of other HSP, notably HSP27 and HSP70, which are, through their properties, tumorigenic and could lead to an escape phenomenon. Thus the combined use of several HSP inhibitors could be beneficial, and eventually present synergistic effects on the inhibition of tumour processes.

NCT02873832
Conditions
  1. Myeloproliferative Syndrome
Interventions
  1. Biological: Blood sample
  2. Other: Flow cytometry
  3. Other: western blot
MeSH:Myeloproliferative Disorders Syndrome
HPO:Myeloproliferative disorder

In addition, it seems that the V617F mutated form of JAK2 is more sensitive than the wild-type to HSP90 inhibitors. --- V617F ---

Primary Outcomes

Description: Level of protein expression using flow cytometry and western blot

Measure: Comparing the level of expression of HSP (HSP90, HSP70, HSP27) between cells from a collection of samples of patients with myeloproliferative disease and healthy controls .

Time: through study completion, an average of 1 year

Secondary Outcomes

Measure: Cell death after in vitro treatment with different HSP inhibitors

Time: through study completion, an average of 1 year

35 A Phase 1 Study of Ruxolitinib, Steroids and Lenalidomide for Relapsed/Refractory Multiple Myeloma (RRMM) Patients

This is a phase 1, multicenter, open-label study evaluating the safety and efficacy of ruxolitinib, steroids and lenalidomide among MM patients who currently show progressive disease.

NCT03110822
Conditions
  1. Multiple Myeloma
Interventions
  1. Drug: Ruxolitinib Oral Tablet [Jakafi]
  2. Drug: Lenalidomide
  3. Drug: Methylprednisolone
MeSH:Multiple Myeloma Neoplasms, Plasma Cell
HPO:Multiple myeloma

The activating JAK2 V617F mutation results in uncontrolled cytokine and growth factor signaling, and is believed to play a key role in the pathophysiology of myeloproliferative neoplasms. --- V617F ---

Primary Outcomes

Description: MTD will be determined by measuring incidence of the dose-limiting toxicities (DLTs) per dose level, of ruxolitinib in combination with steroids and lenalidomide for MM patients currently with progressive disease.

Measure: Determination of maximum tolerated dose (MTD) of ruxolitinib in combination with steroids and lenalidomide [Tolerability].

Time: 30 months

Description: Safety will be measured by counting the occurrence of adverse events throughout the study, graded via Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 criteria

Measure: Incidence of Treatment-Emergent Adverse Events [Safety]

Time: 54 months

Secondary Outcomes

Description: Overall response rate (ORR) is defined as CR + VGPR + PR

Measure: Overall response rate (ORR) as a measure of efficacy

Time: 54 months

Description: Clinical benefit rate is defined as ORR + MR

Measure: Clinical benefit rate (CBR) as a measure of efficacy

Time: 54 months

Description: Progression-free survival will be measured in months as the time from initiation of therapy to progressive disease or death from any cause, whichever occurs first

Measure: Progression Free Survival (PFS)

Time: 54 months

Description: Time to response, defined as the time from the initiation of therapy to the first evidence of confirmed clinical benefit defined as > minimal response (MR, including patients who achieved a complete response (CR), very good partial response (VGPR), partial response (PR), or MR

Measure: Assessment of the time to response as a measure of efficacy

Time: 54 months

Description: Duration of response, defined as the time (in months) from the first response to progressive disease

Measure: Assessment of the duration of response as a measure of efficacy

Time: 54 months

Description: Overall survival, defined as the time (in months) from initiation of therapy to death from any cause or last follow-up visit

Measure: Assessment of the overall survival (OR) as a measure of efficacy

Time: 54 months

Description: Response to initial therapy (ruxolitinib and methylprednisolone alone) will be compared to the response to therapy with addition of lenalidomide (ruxolitinib, lenalidomide, methylprednisolone)

Measure: Assessment of response in additional cohort

Time: 54 months

36 A Phase I Study of Single Agent Tazemetostat in Subjects With Advanced Solid Tumors and B-Cell Lymphomas With Hepatic Dysfunction

This phase I trial studies the best dose and side effects of tazemetostat in treating patients with solid tumors or B-cell lymphomas with liver dysfunction that have spread to other places in the body or cannot be removed by surgery. Tazemetostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

NCT03217253
Conditions
  1. Ann Arbor Stage III B-Cell Non-Hodgkin Lymphoma
  2. Ann Arbor Stage IV B-Cell Non-Hodgkin Lymphoma
  3. Metastatic Malignant Solid Neoplasm
  4. Stage III Hepatocellular Carcinoma AJCC v7
  5. Stage IIIA Hepatocellular Carcinoma AJCC v7
  6. Stage IIIB Hepatocellular Carcinoma AJCC v7
  7. Stage IIIC Hepatocellular Carcinoma AJCC v7
  8. Stage IV Hepatocellular Carcinoma AJCC v7
  9. Stage IVA Hepatocellular Carcinoma AJCC v7
  10. Stage IVB Hepatocellular Carcinoma AJCC v7
  11. Unresectable Solid Neoplasm
Interventions
  1. Other: Laboratory Biomarker Analysis
  2. Other: Pharmacological Study
  3. Drug: Tazemetostat
MeSH:Lymphoma Carcinoma Neoplasms Lymphoma, Non-Hodgkin Carcinoma, Hepatocellular Lymphoma, B-Cell
HPO:B-cell lymphoma Carcinoma Hepatocellular carcinoma Lymphoma Neoplasm Non-Hodgkin lymphoma

JAK2 V617F) observed in cytogenetic testing and DNA sequencing - Has a prior history of T-acute lymphoblastic lymphoma (T-LBL)/T-acute lymphoblastic leukemia (ALL) Inclusion Criteria: - Patients must have histologically and/or cytologically confirmed solid tumors or B cell lymphoma that are metastatic or unresectable and for which standard treatment options do not exist; patients with hepatocellular carcinoma are eligible without pathological diagnosis if diagnosed on the basis of blood work and imaging - Patients with evaluable disease will be eligible - All patients must have completed any prior chemotherapy, targeted therapy and major surgery, >= 28 days before study entry; for daily or weekly chemotherapy without the potential for delayed toxicity, a washout period of 14 days may be acceptable, and questions related to this can be discussed with study principal investigator - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade =< 1 (except alopecia) at the time of enrollment - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Hemoglobin >= 90 g/L (9.0 g/dL) - Creatinine within normal institutional limits OR calculated creatinine clearance >= 60 mL/min/1.73 --- V617F ---

JAK2 V617F) observed in cytogenetic testing and DNA sequencing - Has a prior history of T-acute lymphoblastic lymphoma (T-LBL)/T-acute lymphoblastic leukemia (ALL) Ann Arbor Stage III B-Cell Non-Hodgkin Lymphoma Ann Arbor Stage IV B-Cell Non-Hodgkin Lymphoma Metastatic Malignant Solid Neoplasm Stage III Hepatocellular Carcinoma AJCC v7 Stage IIIA Hepatocellular Carcinoma AJCC v7 Stage IIIB Hepatocellular Carcinoma AJCC v7 Stage IIIC Hepatocellular Carcinoma AJCC v7 Stage IV Hepatocellular Carcinoma AJCC v7 Stage IVA Hepatocellular Carcinoma AJCC v7 Stage IVB Hepatocellular Carcinoma AJCC v7 Unresectable Solid Neoplasm Lymphoma Carcinoma Neoplasms Lymphoma, Non-Hodgkin Carcinoma, Hepatocellular Lymphoma, B-Cell PRIMARY OBJECTIVES: I. To determine safety, tolerability and recommended phase 2 dose (RP2D) of tazemetostat in patients with varying degrees of hepatic dysfunction. --- V617F ---

Primary Outcomes

Description: Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to study treatment.

Measure: Incidence of adverse events of tazemetostat in patients with varying degrees of hepatic dysfunction assessed using Common Terminology Criteria for Adverse Events version 5.0

Time: Up to 2 years

Description: RP2D will be determined.

Measure: Recommended phase 2 dose (RP2D) of tazemetostat in patients with varying degrees of hepatic dysfunction

Time: Up to 2 years

Secondary Outcomes

Description: Plasma concentrations will be measured by Q2 Solutions using a validated Liquid chromatography (LC)/mass spectrometry (MS)/MS assay. Molecular and clinical predictors of clinical outcomes will be investigated using logistic regression and Cox proportional hazards models. Potential predictors include clinical predictors and molecular correlates. Descriptive statistics and plotting of data will also be used to better understand potential relationships. Given the small sample size, and exploratory nature of these endpoints, all pharmacodynamic analyses conducted will be considered exploratory. All analyses will be considered exploratory and inference will be performed with appropriate caution.

Measure: Pharmacokinetic (PK) profiles of tazemetostat in patients with varying degrees of hepatic dysfunction

Time: Up to course 4 day 1 (day 85)

Description: Molecular and clinical predictors of clinical outcomes will be investigated using logistic regression and Cox proportional hazards models. Potential predictors include clinical predictors and molecular correlates. Descriptive statistics and plotting of data will also be used to better understand potential relationships. All analyses will be considered exploratory and inference will be performed with appropriate caution.

Measure: Antitumor activity of tazemetostat

Time: Up to 2 years

Description: Molecular and clinical predictors of clinical outcomes will be investigated using logistic regression and Cox proportional hazards models. Potential predictors include clinical predictors and molecular correlates. Descriptive statistics and plotting of data will also be used to better understand potential relationships. All analyses will be considered exploratory and inference will be performed with appropriate caution.

Measure: Antitumor activity of tazemetostat in population with tumors with aberrations in EZH2 or SWI/SNF complex pathways

Time: Up to 2 years

Description: Response will be assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1

Measure: Objective confirmed response

Time: Up to 2 years

Description: Response will be assessed using the RECIST criteria 1.1.

Measure: Duration of response

Time: Up to 2 years

Description: Response will be assessed using the RECIST criteria 1.1.

Measure: Best response

Time: Up to 2 years

37 Genomic Screening for Hereditary Erythrocytosis and Related Diseases

Unexplained polycythemias are rare diseases, and therefore, the collection of data inherent to these diseases will not only improve their characterisation, but also allow stratification according to the risks and the course of the disease. The objective of this project is to constitute a database on the disease which will allow us to better understand it and in due course improve its management. The GENRED project thus bears uniquely on the collection of information, which will be gathered throughout the usual management of patients for this type of disease.

NCT03263364
Conditions
  1. Hereditary Erythrocytosis/Idiopathic Erythrocytosis
MeSH:Polycythemia
HPO:Polycythemia

The required tests are: complete blood counts - Blood electrolytes - Arterial and venous gazes - Serum erythropoietin dosage - Liver function tests - JAK2 mutations (both V617F and exon 12) - Bone marrow aspirate and/or biopsy and/or endogenous BFU-E culture - Abdominal ultrasound - Lung function tests Inclusion Criteria: The characteristics of the patients included in the database will be described in terms of numbers and percentages for qualitative variables and in terms of means and standard deviations or medians and interquartile intervals for quantitative variables. --- V617F ---

The required tests are: complete blood counts - Blood electrolytes - Arterial and venous gazes - Serum erythropoietin dosage - Liver function tests - JAK2 mutations (both V617F and exon 12) - Bone marrow aspirate and/or biopsy and/or endogenous BFU-E culture - Abdominal ultrasound - Lung function tests Hereditary Erythrocytosis/Idiopathic Erythrocytosis Polycythemia null --- V617F ---

Primary Outcomes

Measure: Germline mutations that cause Hereditary Erythrocytosis/Idiopathic Erythrocytosis

Time: at baseline

38 A Phase II Study of Tazemetostat (EPZ-6438) in Recurrent or Persistent Endometrioid or Clear Cell Carcinoma of the Ovary, and Recurrent or Persistent Endometrioid Endometrial Adenocarcinoma

This phase II trial studies how well tazemetostat works in treating patients with ovarian or endometrial cancer that has come back (recurrent). Chemotherapy drugs, such as tazemetostat, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

NCT03348631
Conditions
  1. FIGO Grade 1 Endometrial Endometrioid Adenocarcinoma
  2. FIGO Grade 2 Endometrial Endometrioid Adenocarcinoma
  3. Recurrent Endometrial Endometrioid Adenocarcinoma
  4. Recurrent Ovarian Carcinoma
  5. Recurrent Ovarian Clear Cell Adenocarcinoma
  6. Recurrent Ovarian Endometrioid Adenocarcinoma
  7. Recurrent Uterine Corpus Cancer
Interventions
  1. Other: Laboratory Biomarker Analysis
  2. Drug: Tazemetostat
MeSH:Carcinoma Adenocarcinoma Carcinoma, Endometrioid Adenocarcinoma, Clear Cell
HPO:Carcinoma

JAK2 V617F) observed in cytogenetic testing and deoxyribonucleic acid (DNA) sequencing - A prior history of T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia (T-ALL) - Severe, active co-morbidity per the treating investigator's discretion - Pregnant or lactating patients - Known human immunodeficiency virus (HIV) positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with tazemetostat; in addition, treatments involved in this protocol may be immunosuppressive, increasing the risk of lethal infections in this patient population - Treatment with strong inhibitors or inducers of CYP3A within 14 days of registration and during the study treatment Inclusion Criteria: - Pathologically (histologically or cytologically) proven diagnosis of recurrent or persistent ovarian endometrioid or clear cell carcinoma, OR recurrent or persistent endometrioid endometrial adenocarcinoma; patients with recurrent endometrial cancer must have mismatch repair (MMR) immunohistochemistry completed; if they are found to be mismatch repair deficient, they should be offered treatment with immune checkpoint inhibition before consideration for treatment on trial; primary ovarian tumors must be at least 50% endometrioid or clear cell morphology, or have histologically documented recurrence with at least 50% endometrioid or clear cell morphology; institutional pathology reports must be provided indicating at least 50% endometrioid or clear cell morphology for ovarian tumors (primary or recurrent lesions) - All patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1; measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be >= 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or >= 20 mm when measured by chest x-ray; lymph nodes must be > 15 mm in short axis when measured by CT or MRI - Patients must have had at least one, but no more than 3, prior cytotoxic regimens for management of primary disease; unlimited prior hormonal therapy, targeted therapy (including immunotherapy) or antiangiogenic therapy will be permitted - Patients must have completed prior therapy: - Chemotherapy: cytotoxic - At least 28 days since last dose of chemotherapy prior to registration. --- V617F ---

JAK2 V617F) observed in cytogenetic testing and deoxyribonucleic acid (DNA) sequencing - A prior history of T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia (T-ALL) - Severe, active co-morbidity per the treating investigator's discretion - Pregnant or lactating patients - Known human immunodeficiency virus (HIV) positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with tazemetostat; in addition, treatments involved in this protocol may be immunosuppressive, increasing the risk of lethal infections in this patient population - Treatment with strong inhibitors or inducers of CYP3A within 14 days of registration and during the study treatment FIGO Grade 1 Endometrial Endometrioid Adenocarcinoma FIGO Grade 2 Endometrial Endometrioid Adenocarcinoma Recurrent Endometrial Endometrioid Adenocarcinoma Recurrent Ovarian Carcinoma Recurrent Ovarian Clear Cell Adenocarcinoma Recurrent Ovarian Endometrioid Adenocarcinoma Recurrent Uterine Corpus Cancer Carcinoma Adenocarcinoma Carcinoma, Endometrioid Adenocarcinoma, Clear Cell PRIMARY OBJECTIVE: I. To assess the clinical activity (overall response rate) of tazemetostat in patients with recurrent or persistent endometrioid or clear cell ovarian carcinoma, and patients with recurrent or persistent endometrioid endometrial adenocarcinoma. --- V617F ---

Primary Outcomes

Description: Will be defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1.

Measure: Tumor response

Time: Up to 6 months

Secondary Outcomes

Description: Will be defined by RECIST v 1.1.

Measure: Tumor response in patients with ARID1A mutations using tumor response

Time: Up to 6 months

Description: Will be assessed according to grade of toxicity by organ or organ system.

Measure: Incidence of adverse events

Time: Up to 5 years

Description: Will be characterized by quartiles and the median of the distribution with confidence intervals. Kaplan-Meier plots will show an estimate of the survival function for these populations.

Measure: Progression-free survival

Time: From study entry to time of progression or death, whichever occurs first, assessed up to 5 years

Description: Will be characterized by quartiles and the median of the distribution with confidence intervals. Kaplan-Meier plots will show an estimate of the survival function for these populations.

Measure: Overall survival

Time: From study entry to time of death or the date of last contact, assessed up to 5 years

Other Outcomes

Description: Associations between BAF250a and ARID1A mutations may be examined with contingency table analysis (e.g. potentially including Chi-square analyses or Spearman's correlation).

Measure: ARID1A mutational status

Time: Up to 6 months

Description: Will be assessed by immunohistochemistry. Associations between BAF250a and ARID1A mutations may be examined with contingency table analysis (e.g. potentially including Chi-square analyses or Spearman's correlation).

Measure: BAF250a expression

Time: Up to 6 months

39 Concomitant Ruxolitinib Induction and Maintenance With Cytarabine Based Chemotherapy in Secondary Acute Myelogenous Leukemia Evolving From Myeloproliferative Neoplasm

This trial aimed to investigate the therapeutic efficacy of ruxolitinib in combination with cytotoxic chemotherapy for post-myeloproliferative neoplasm secondary acute myeloid leukemia.

NCT03558607
Conditions
  1. Secondary Acute Myelogenous Leukemia Evolving From Myeloproliferative Disorder
Interventions
  1. Drug: Ruxolitinib
MeSH:Leukemia Neoplasms Neoplasm Metastasis Leukemia, Myeloid Leukemia, Myeloid, Acute Myeloproliferative Disorders
HPO:Acute megakaryocytic leukemia Acute myeloid leukemia Leukemia Myeloid leukemia Myeloproliferative disorder Neoplasm

JAK2 V617F mutation, which is a hallmark of MPN, has been reported to be carried in approximately 35-50% of patients with post-MPN AML. --- V617F ---

Primary Outcomes

Measure: complete remission rate

Time: After 12 months from induction chemotherapy

Measure: complete remission with incompletre recovery rate

Time: After 12 months from induction chemotherapy

Secondary Outcomes

Description: from the date of transplantation to death from any cause

Measure: Overall survival

Time: 3, 6, 12, 24 months after induction chemotherapy

Description: from the date of transplantation to the date of disease progression or death from any cause

Measure: Progression-free survival

Time: 3, 6, 12, 24 months after induction chemotherapy

Description: according to CTCAE version 4.03

Measure: Toxicity profile

Time: 3, 6, 12, 24 months after induction chemotherapy

40 Arterial Function and Atherosclerosis in Patients With JAK2 V167F Positive Essential Thrombocythemia

The aim of the study is to examine (a) whether patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of arterial stiffness, pulse-wave velocity and coronary calcium score in a 4 year observation period, and (b) whether the burden of JAK2 V617F mutation correlates with the measured vascular parameters. All subjects will be examined twice. The first visit already took place between the years 2014 - 2015 and the second visit will take place between 2018-2019. All participants will have signed their informed consent before entering the study. Each visit will consist of completing a structured questionnaire (on personal and family medical history, risk factors for CVD and medication), physical examination, donating a blood sample for laboratory tests and undergoing carotid ultrasound and coronary calcium measurement oft the extent of coronary artery calcification. At the first and the second examination the JAK2 V617F allele burden, i.e. the percentage of mutated alleles, will be determined from genomic DNA in peripheral blood.

NCT03828422
Conditions
  1. Atherosclerosis
Interventions
  1. Diagnostic Test: imaging
MeSH:Atherosclerosis Thrombocytosis Thrombocythemia, Essential
HPO:Atherosclerosis Thrombocytosis Type IV atherosclerotic lesion

Arterial Function and Atherosclerosis in Essential Thrombocythemia The aim of the study is to examine (a) whether patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of arterial stiffness, pulse-wave velocity and coronary calcium score in a 4 year observation period, and (b) whether the burden of JAK2 V617F mutation correlates with the measured vascular parameters. --- V617F ---

Arterial Function and Atherosclerosis in Essential Thrombocythemia The aim of the study is to examine (a) whether patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of arterial stiffness, pulse-wave velocity and coronary calcium score in a 4 year observation period, and (b) whether the burden of JAK2 V617F mutation correlates with the measured vascular parameters. --- V617F --- --- V617F ---

At the first and the second examination the JAK2 V617F allele burden, i.e. the percentage of mutated alleles, will be determined from genomic DNA in peripheral blood. --- V617F ---

Change of carotid artery stiffness (expressed by beta-stiffness index and pulse wave velocity) in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.. Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of carotid artery stiffness (expressed as two interrelated parameters, the beta-stiffness index and the pulse wave velocity) in a 4 year observation period?. --- V617F ---

Change of carotid artery stiffness (expressed by beta-stiffness index and pulse wave velocity) in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.. Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of carotid artery stiffness (expressed as two interrelated parameters, the beta-stiffness index and the pulse wave velocity) in a 4 year observation period?. --- V617F --- --- V617F ---

Change of carotid artery plaque score in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.. Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of carotid plaque score in a 4 year observation period? --- V617F ---

Change of carotid artery plaque score in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.. Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of carotid plaque score in a 4 year observation period? --- V617F --- --- V617F ---

Thus, the carotid plaque score ranges from 0 (absence of plaques, best) to 6 (plaques present in all segments on both sides, worst outcome).. Change of coronary calcium burden in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.. Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of coronary calcium score in a 4 year observation period?. --- V617F ---

Thus, the carotid plaque score ranges from 0 (absence of plaques, best) to 6 (plaques present in all segments on both sides, worst outcome).. Change of coronary calcium burden in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.. Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of coronary calcium score in a 4 year observation period?. --- V617F --- --- V617F ---

Change of digital endothelial function, expressed as the Reactive Hyperemia Index, in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.. Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show greater changes digital endothelial function, expressed as the Reactive Hyperemia Index (RHI), in a 4 year observation period? --- V617F ---

Change of digital endothelial function, expressed as the Reactive Hyperemia Index, in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.. Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show greater changes digital endothelial function, expressed as the Reactive Hyperemia Index (RHI), in a 4 year observation period? --- V617F --- --- V617F ---

RHI ranges from 1 (no augmentation of pulsation with reactive hyperemia, i.e. worst outcome) to values above 2 (good endothelial response to reactive hyperemia).. Association of the JAK2 V617F mutation burden with the coronary calcium burden.. Quantification of JAK2 V617F mutation burden and its correlation with the coronary calcium burden.. Inclusion Criteria: - patients with JAK2 V617F positive essential thrombocythemia - age-and sex-matched apparently healthy control subjects Exclusion Criteria: - personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) - chronic kidney disease stage 3 and above - known cancer - chronic inflammatory disease - autoimmune disease - pregnancy Inclusion Criteria: - patients with JAK2 V617F positive essential thrombocythemia - age-and sex-matched apparently healthy control subjects Exclusion Criteria: - personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) - chronic kidney disease stage 3 and above - known cancer - chronic inflammatory disease - autoimmune disease - pregnancy Atherosclerosis Atherosclerosis Thrombocytosis Thrombocythemia, Essential 1. Patients and control subjects Patients are selected from the database of the Department of Haematology at University Medical Centre Ljubljana, Slovenia, who were diagnosed with JAK2 V617F positive ET between 2011 and 2014. --- V617F ---

RHI ranges from 1 (no augmentation of pulsation with reactive hyperemia, i.e. worst outcome) to values above 2 (good endothelial response to reactive hyperemia).. Association of the JAK2 V617F mutation burden with the coronary calcium burden.. Quantification of JAK2 V617F mutation burden and its correlation with the coronary calcium burden.. Inclusion Criteria: - patients with JAK2 V617F positive essential thrombocythemia - age-and sex-matched apparently healthy control subjects Exclusion Criteria: - personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) - chronic kidney disease stage 3 and above - known cancer - chronic inflammatory disease - autoimmune disease - pregnancy Inclusion Criteria: - patients with JAK2 V617F positive essential thrombocythemia - age-and sex-matched apparently healthy control subjects Exclusion Criteria: - personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) - chronic kidney disease stage 3 and above - known cancer - chronic inflammatory disease - autoimmune disease - pregnancy Atherosclerosis Atherosclerosis Thrombocytosis Thrombocythemia, Essential 1. Patients and control subjects Patients are selected from the database of the Department of Haematology at University Medical Centre Ljubljana, Slovenia, who were diagnosed with JAK2 V617F positive ET between 2011 and 2014. --- V617F --- --- V617F ---

RHI ranges from 1 (no augmentation of pulsation with reactive hyperemia, i.e. worst outcome) to values above 2 (good endothelial response to reactive hyperemia).. Association of the JAK2 V617F mutation burden with the coronary calcium burden.. Quantification of JAK2 V617F mutation burden and its correlation with the coronary calcium burden.. Inclusion Criteria: - patients with JAK2 V617F positive essential thrombocythemia - age-and sex-matched apparently healthy control subjects Exclusion Criteria: - personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) - chronic kidney disease stage 3 and above - known cancer - chronic inflammatory disease - autoimmune disease - pregnancy Inclusion Criteria: - patients with JAK2 V617F positive essential thrombocythemia - age-and sex-matched apparently healthy control subjects Exclusion Criteria: - personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) - chronic kidney disease stage 3 and above - known cancer - chronic inflammatory disease - autoimmune disease - pregnancy Atherosclerosis Atherosclerosis Thrombocytosis Thrombocythemia, Essential 1. Patients and control subjects Patients are selected from the database of the Department of Haematology at University Medical Centre Ljubljana, Slovenia, who were diagnosed with JAK2 V617F positive ET between 2011 and 2014. --- V617F --- --- V617F --- --- V617F ---

RHI ranges from 1 (no augmentation of pulsation with reactive hyperemia, i.e. worst outcome) to values above 2 (good endothelial response to reactive hyperemia).. Association of the JAK2 V617F mutation burden with the coronary calcium burden.. Quantification of JAK2 V617F mutation burden and its correlation with the coronary calcium burden.. Inclusion Criteria: - patients with JAK2 V617F positive essential thrombocythemia - age-and sex-matched apparently healthy control subjects Exclusion Criteria: - personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) - chronic kidney disease stage 3 and above - known cancer - chronic inflammatory disease - autoimmune disease - pregnancy Inclusion Criteria: - patients with JAK2 V617F positive essential thrombocythemia - age-and sex-matched apparently healthy control subjects Exclusion Criteria: - personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) - chronic kidney disease stage 3 and above - known cancer - chronic inflammatory disease - autoimmune disease - pregnancy Atherosclerosis Atherosclerosis Thrombocytosis Thrombocythemia, Essential 1. Patients and control subjects Patients are selected from the database of the Department of Haematology at University Medical Centre Ljubljana, Slovenia, who were diagnosed with JAK2 V617F positive ET between 2011 and 2014. --- V617F --- --- V617F --- --- V617F --- --- V617F ---

RHI ranges from 1 (no augmentation of pulsation with reactive hyperemia, i.e. worst outcome) to values above 2 (good endothelial response to reactive hyperemia).. Association of the JAK2 V617F mutation burden with the coronary calcium burden.. Quantification of JAK2 V617F mutation burden and its correlation with the coronary calcium burden.. Inclusion Criteria: - patients with JAK2 V617F positive essential thrombocythemia - age-and sex-matched apparently healthy control subjects Exclusion Criteria: - personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) - chronic kidney disease stage 3 and above - known cancer - chronic inflammatory disease - autoimmune disease - pregnancy Inclusion Criteria: - patients with JAK2 V617F positive essential thrombocythemia - age-and sex-matched apparently healthy control subjects Exclusion Criteria: - personal history of any atherosclerotic vascular disease (myocardial infarction, angina pectoris, peripheral arterial disease, aortic disease, transient ischemic attack or ischemic stroke) - chronic kidney disease stage 3 and above - known cancer - chronic inflammatory disease - autoimmune disease - pregnancy Atherosclerosis Atherosclerosis Thrombocytosis Thrombocythemia, Essential 1. Patients and control subjects Patients are selected from the database of the Department of Haematology at University Medical Centre Ljubljana, Slovenia, who were diagnosed with JAK2 V617F positive ET between 2011 and 2014. --- V617F --- --- V617F --- --- V617F --- --- V617F --- --- V617F ---

40 patients (14 male and 26 female) with JAK2 V617F positive ET without clinically apparent cardiovascular disease signed the informed consent and were enrolled in the study in 2014 - 2015 for the first examination and 36 (12 male and 24 female) of them are expected to participate also in 2018-19. --- V617F ---

3. JAK2 V617F/G1849T allele burden The ipsogen JAK2 MutaQuant Kit, Qiagen (ZDA) (Ref: No. 673523) will be used for the detection and quantification of JAK2 V617F/G1849T allele in genomic DNA extracted from peripheral blood of patients and also control subjects. --- V617F ---

3. JAK2 V617F/G1849T allele burden The ipsogen JAK2 MutaQuant Kit, Qiagen (ZDA) (Ref: No. 673523) will be used for the detection and quantification of JAK2 V617F/G1849T allele in genomic DNA extracted from peripheral blood of patients and also control subjects. --- V617F --- --- V617F ---

A SNP specific primer selectively amplifies the JAK2 V617F allele which is detected with a real-time qPCR instrument that quantifies the PCR products. --- V617F ---

The JAK2 V617F allele burden will be calculated and expressed as the percentage of JAK2 V617F mutated alleles throughout the whole JAK2 record. --- V617F ---

The JAK2 V617F allele burden will be calculated and expressed as the percentage of JAK2 V617F mutated alleles throughout the whole JAK2 record. --- V617F --- --- V617F ---

The association between the parameters of vascular function / morphology and the JAK2 V617F allele burden will be assessed by the Pearson correlation coefficient. --- V617F ---

Primary Outcomes

Description: Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of carotid artery stiffness (expressed as two interrelated parameters, the beta-stiffness index and the pulse wave velocity) in a 4 year observation period?

Measure: Change of carotid artery stiffness (expressed by beta-stiffness index and pulse wave velocity) in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.

Time: the first visit in 2014-2015 and the second visit in 2018-2019

Description: Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of carotid plaque score in a 4 year observation period? Scoring of atherosclerotic plaques will be done according to the Rotterdam Study. The presence of at least one plaque in each segment of the extracranial carotid arterial bed, (the common carotid artery and the bulb, the internal carotid artery and the external carotid artery) on either side is scored 1 point. Thus, the carotid plaque score ranges from 0 (absence of plaques, best) to 6 (plaques present in all segments on both sides, worst outcome).

Measure: Change of carotid artery plaque score in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.

Time: the first visit in 2014-2015 and the second visit in 2018-2019

Description: Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show more advanced progression of coronary calcium score in a 4 year observation period?

Measure: Change of coronary calcium burden in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.

Time: the first visit in 2014-2015 and the second visit in 2018-2019

Description: Do patients with JAK2 V617F positive ET in comparison to age-and sex-matched, apparently healthy control subjects show greater changes digital endothelial function, expressed as the Reactive Hyperemia Index (RHI), in a 4 year observation period? The RHI is the ratio of the pletysmographic amplitude of the digital arteries during maximal reactive hyperemia and the basal amplitude. RHI ranges from 1 (no augmentation of pulsation with reactive hyperemia, i.e. worst outcome) to values above 2 (good endothelial response to reactive hyperemia).

Measure: Change of digital endothelial function, expressed as the Reactive Hyperemia Index, in JAK2 V617F positive ET patients in comparison to healthy control subjects in a 4-year period.

Time: the first visit in 2014-2015 and the second visit in 2018-2019

Description: Quantification of JAK2 V617F mutation burden and its correlation with the coronary calcium burden.

Measure: Association of the JAK2 V617F mutation burden with the coronary calcium burden.

Time: at inclusion in the years 2014-2015, and at the second visit in 2018-2019

41 A Pilot Study of Tazemetostat and MK-3475 (Pembrolizumab) in Advanced Urothelial Carcinoma

This phase I/II trial studies the side effects and best dose of tazemetostat and how well it works when given together with pembrolizumab in treating patients with urothelial carcinoma that has spread to nearby tissue or lymph nodes or other places in the body (locally advanced/metastatic). Tazemetostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving tazemetostat and pembrolizumab may work better in treating patients with urothelial carcinoma compared to pembrolizumab without tazemetostat.

NCT03854474
Conditions
  1. Locally Advanced Urothelial Carcinoma
  2. Metastatic Urothelial Carcinoma
  3. Stage III Bladder Cancer AJCC v8
  4. Stage IIIA Bladder Cancer AJCC v8
  5. Stage IIIB Bladder Cancer AJCC v8
  6. Stage IV Bladder Cancer AJCC v8
  7. Stage IVA Bladder Cancer AJCC v8
  8. Stage IVB Bladder Cancer AJCC v8
Interventions
  1. Biological: Pembrolizumab
  2. Drug: Tazemetostat
MeSH:Carcinoma Urinary Bladder Neoplasms Carcinoma, Transitional Cell
HPO:Bladder neoplasm Carcinoma

JAK2 V617F) observed in cytogenetic testing and deoxyribonucleic acid (DNA) sequencing are not eligible - Patients with a prior history of T-cell lymphoblastic lymphoma (T-LBL) or T-cell acute lymphoblastic leukemia (T-ALL) are not eligible - Patients who have received prior PD-L1/PD-1/PD-L2 or EZH2 inhibitor therapy are not eligible - Patients who have had a prior monoclonal antibody within 4 weeks prior to study day 1 are not eligible - Patients with a known additional malignancy that is progressing or requires active treatment are not eligible. --- V617F ---

Primary Outcomes

Description: Response rates will be summarized in each cohort by proportions and 95% exact confidence intervals. Time to progression will be summarized using the Kaplan-Meier product limit curve.

Measure: Objective response rate (ORR)

Time: Up to 1 year

Secondary Outcomes

Description: Will be assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5. All adverse events will be summarized as to type, grade, timing, frequency and attribution using frequencies and percentages

Measure: Incidence of adverse events

Time: Up to 30 days after treatment discontinuation

Other Outcomes

Description: Will determine if EZH2, H3K27me3 and mutations in genes associated with histone methylation determine disease response to EZH2 and PD1. Each gene will be related to response using Fisher's exact test.

Measure: EZH2 and H3K27me3 chromatin methylation and mutations in genes associated with histone methylation

Time: Baseline

42 Tazemetostat Expanded Access Program for Adults With Solid Tumors

Patients with following conditions are eligible to enroll in the EAP: - Epithelioid Sarcoma (ES) - Spindle cell sarcoma - Sinonasal carcinoma - Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) - Thoracic sarcoma - Poorly differentiated chordoma These conditions must be serious or life-threatening at the time of enrollment and appropriate, comparable, or satisfactory alternative treatments must have been tried without clinical success. Patients with conditions not listed above are not eligible for the tazemetostat EAP

NCT03874455
Conditions
  1. Epithelioid Sarcoma
  2. Spindle Cell Sarcoma
  3. Sinonasal Carcinoma
  4. Small Cell Carcinoma of the Ovary Hypercalcemic Type
  5. Thoracic Sarcoma
  6. Poorly Differentiated Chordoma
Interventions
  1. Drug: Tazemetostat
MeSH:Carcinoma Sarcoma Chordoma Carcinoma, Small Cell Small Cell Lung Carcinoma Carcinoma, Ovarian Epithelial
HPO:Carcinoma Chordoma Sarcoma Small cell lung carcinoma Soft tissue sarcoma

JAK2 V617F) observed in cytogenetic testing and DNA sequencing. --- V617F ---


43 PCM1-JAK2 Fusion Gene Detection in Patients With Therapy Related Myelodysplastic Syndrome / Acute Myeloid Leukemia Patients

The term "therapy-related" leukemia is descriptive and is based on a patient's history of exposure to cytotoxic agents. Although a causal relationship is implied, the mechanism remains to be proven. These neoplasms are thought to be the direct consequence of mutational events induced by the prior therapy Therapy-related myelodysplastic syndromes / acute myeloid leukemia (t- MDS / t-AML) is now considered a single entity, called therapy-related myeloid neoplasms based on the current World Health Organization WHO classification2,. It is a well-recognized clinical syndrome occurring as a late complication following Cytotoxic agents and ionizing radiotherapy in the treatment of most cancer types: Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), sarcoma, and ovarian and testicular cancerThe incidence of t-MDS/AML following conventional therapy ranges from 0.8% to 6.3% at 20 years. The median time to development of t-MDS/AML is 3 to 5 years, with the risk decreasing markedly after the first decade Two types of t-MDS/AML are recognized in the WHO classification depending on the causative therapeutic exposure: an alkylating agent/radiation-related type and a topoisomerase II inhibitor-related type. Alkylating agent-related t-MDS/AML usually appears 4 to 7 years after exposure to the mutagenic agent .The reciprocal translocation t(8;9) (p22;p24) between the short arm of chromosome 8 and the long arm of chromosome 9 is a recurrent abnormality that fuses the Janus activated kinase 2 (JAK2) to the human autoantigen pericentriolar material 1 gene (PCM1) , with breakage and reunion at bands 8p11 and 9q3410Due to PCM1-JAK2 gene fusion, the coiled-coil domains of PCM1 mediate an oligomerization that brings together the linked JAK2 domains resulting in a constitutively activated tyrosine kinase domain of JAK2The most common mechanism for JAK2 activation in hematologic malignancies is the point mutation at position 617 (V617F). The consequences of JAK2 activation are neoplastic transformation and abnormal cell proliferation in various malignancies - So, translocations involving the JAK2 locus are considered of oncogenic importance in acute leukemias and myelodysplastic/ myeloproliferative diseases. - Patients with this abnormality present with broad clinical spectrum ranging from chronic to acute hematological diseases with myeloid or lymphoid appearance

NCT03943394
Conditions
  1. Detection of PCM1-JAK2 Fusion Gene by FISH in the Two Types of t-MDS/AML and Relationship Between PCM1-JAK2 Fusion Gene and Cumulative Dose, Dose Intensity
Interventions
  1. Other: fresh samples are obtained from patients for detction of PCM1- JAK2 fusion gene

Alkylating agent-related t-MDS/AML usually appears 4 to 7 years after exposure to the mutagenic agent .The reciprocal translocation t(8;9) (p22;p24) between the short arm of chromosome 8 and the long arm of chromosome 9 is a recurrent abnormality that fuses the Janus activated kinase 2 (JAK2) to the human autoantigen pericentriolar material 1 gene (PCM1) , with breakage and reunion at bands 8p11 and 9q3410Due to PCM1-JAK2 gene fusion, the coiled-coil domains of PCM1 mediate an oligomerization that brings together the linked JAK2 domains resulting in a constitutively activated tyrosine kinase domain of JAK2The most common mechanism for JAK2 activation in hematologic malignancies is the point mutation at position 617 (V617F). --- V617F ---

The most common mechanism for JAK2 activation in hematologic malignancies is the point mutation at position 617 (V617F). --- V617F ---

Primary Outcomes

Description: Using fresh sample from patients with myeloid neoplasm to search for PCM1-JAK2 fusion gene in the 2 types of thaerap related myeloid neoplasm , studying relationship between PCM1-JAK2 and dose intensity and time of exposure, and studying relationship between PCM1-JAK2 and other cytogenetic abnormalities by using FISH technique and

Measure: Detection of PCM1-JAK2fusion gene

Time: 24 months

44 Modulation of Morbidity and Disease Progression in Polycythemia Vera (PV) and Essential Thrombocythemia (ET) Patients With Obstructive Sleep Apnea (OSA) by CPAP

This early phase I trial studies how well the use of a continuous positive airway pressure (CPAP) machine works in treating obstructive sleep apnea in patients with polycythemia vera or essential thrombocythemia. Obstructive sleep apnea is a condition where a person stops breathing during sleep, and is estimated to affect 30 to 50 percent of patients with polycythemia vera or essential thrombocythemia. A patient with obstructive sleep apnea typically snores, has disrupted sleep, experiences morning headaches, and has daytime sleepiness. Patients diagnosed with obstructive sleep apnea are typically treated with a device called CPAP. The CPAP provides pressurized air that keeps upper air passages open during sleep and may prevent them from narrowing or collapsing as occurs during snoring or sleep apnea.

NCT03972943
Conditions
  1. CALR Gene Mutation
  2. Essential Thrombocythemia
  3. JAK2 Gene Mutation
  4. MPL Gene Mutation
  5. Obstructive Sleep Apnea Syndrome
  6. Polycythemia Vera
Interventions
  1. Procedure: Continuous Positive Airway Pressure
  2. Other: Patient Observation
  3. Other: Questionnaire Administration
MeSH:Polycythemia Vera Apnea Sleep Apnea Syndromes Sleep Apnea, Obstructive Polycythemia Thrombocytosis Thrombocythemia, Essential
HPO:Apnea Obstructive sleep apnea Polycythemia Sleep apnea Thrombocytosis

Paired Wilcoxon tests will be used to analyze variables that are highly skewed or otherwise non-Gaussian in distribution.. Change in JAK2 V617F allele burden. --- V617F ---

Primary Outcomes

Description: Will be tested at the two-sided 0.025 significance level to provide overall control of the type I error for the co-primary endpoints at 0.05. The endpoints will be summarized by mean, median, range, standard deviation, interquartile range and boxplots. Scatterplots will be used to show bivariate associations. An assessment of normality will be made prior to statistical testing. Paired t tests will be used to analyze endpoints that are sufficiently Gaussian in distribution. Paired Wilcoxon tests will be used to analyze variables that are highly skewed or otherwise non-Gaussian in distribution.

Measure: Change in Myeloproliferative Neoplasm Symptom Assessment Form - Total Symptom Score (MPN-SAF TSS)

Time: Baseline, after 3 months, and after 6 months on trial

Description: Will be tested at the two-sided 0.025 significance level to provide overall control of the type I error for the co-primary endpoints at 0.05. The endpoints will be summarized by mean, median, range, standard deviation, interquartile range and boxplots. Scatterplots will be used to show bivariate associations. An assessment of normality will be made prior to statistical testing. Paired t tests will be used to analyze endpoints that are sufficiently Gaussian in distribution. Paired Wilcoxon tests will be used to analyze variables that are highly skewed or otherwise non-Gaussian in distribution.

Measure: Change in JAK2 V617F allele burden

Time: Baseline, after 3 months, and after 6 months on trial

Other Outcomes

Description: Assessed by Snoring, Tiredness, Observed Apnea, Blood Pressure, Body Mass Index, Age, Neck Circumference and Gender (STOP-BANG) questionnaire. The proportion of patients whose results indicate a diagnosis of OSA will be calculated. All patients with a diagnosis of OSA, regardless of whether they are enrolled to the treatment component of the study, will be counted towards the assessment of prevalence. An assessment of normality will be made prior to statistical testing. Paired t tests will be used to analyze endpoints that are sufficiently Gaussian in distribution. Paired Wilcoxon tests will be used to analyze variables that are highly skewed or otherwise non-Gaussian in distribution.

Measure: Proportion of patients with a diagnosis of obstructive sleep apnea (OSA)

Time: During the OSA screening

Description: The endpoints will be summarized by mean, median, range, standard deviation, interquartile range and boxplots. Scatterplots will be used to show bivariate associations. An assessment of normality will be made prior to statistical testing. Paired t tests will be used to analyze endpoints that are sufficiently Gaussian in distribution. Paired Wilcoxon tests will be used to analyze variables that are highly skewed or otherwise non-Gaussian in distribution.

Measure: Leucocytes, platelets, red cell counts, and tumor necrosis factor (TNF) analysis

Time: Baseline, after 3 months, and after 6 months on trial

Description: Will be measured in blood samples taken from all patients. OSA-related adverse events reported in the Treatment Cohort at these timepoints will be correlated with these marker levels. Pearson or Spearman correlation will be used to assess correlation between thrombo-inflammatory markers and oximetric abnormalities.

Measure: Thrombotic and inflammatory marker levels for all patients

Time: Baseline, after 3 months, and after 6 months on trial

45 A Phase III, Randomised, Open-label, Multicenter International Trial Comparing Ruxolitinib With Either HydRoxycarbamIDe or Interferon Alpha as First Line ThErapy for High Risk Polycythemia Vera

The trial will be a phase III, randomised-controlled, multi-centre, international, open-label trial consisting of ruxolitinib versus best available therapy, where best available therapy is a choice of interferon alpha, any formulation permitted (IFN) or hydroxycarbamide (HC), and which will be elected by the Investigator prior to randomisation.

NCT04116502
Conditions
  1. Polycythemia Vera
Interventions
  1. Drug: Ruxolitinib
  2. Drug: Hydroxycarbamide
  3. Drug: Interferon-Alpha
MeSH:Polycythemia Vera Polycythemia
HPO:Polycythemia

Peripheral blood JAK2 V617F allele burden. --- V617F ---

Symptom burden/(QALY)quality of life years gained 7. Health economics including cost utility and cost effectiveness analyses 8. Peripheral blood JAK2 V617F allele burden according to ELN response criteria 9. Rates of discontinuation 10. --- V617F ---

Primary Outcomes

Description: Event Free Survival

Measure: Event Free Survival (EFS)

Time: the time from randomisation to the date of the first major thrombosis/haemorrhage, death,transformation to Myelodisplastic Syndromes, Acute Myeloid Leukaemia or Post-polycythemia Vera Myelofibrosis, if within the ~3 year trial period

Secondary Outcomes

Description: As defined in the protocol, combined and split to venous and arterial

Measure: Major thrombosis

Time: Occuring while on treatment (over 3 years)

Description: As defined in the protocol

Measure: Major haemorrhage

Time: Occuring while on treatment (over 3 years)

Description: Transformation to PPV-MF

Measure: Transformation to PPV-MF

Time: Occuring while on treatment (over 3 years)

Description: Transformation to MDS and/or AML

Measure: Transformation to MDS and/or AML

Time: Occuring while on treatment (over 3 years)

Description: As defined by ELN response criteria at 1 year

Measure: Complete Haematological remission (CHR)

Time: 1 year post-treatment

Description: As measured via MPN-SAF

Measure: Symptom burden/Quality of life (MPN-SAF)

Time: Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36

Description: As measured via MDASI

Measure: Symptom burden/Quality of life (MDASI)

Time: Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36

Description: As measured via EQ-5D

Measure: Symptom burden/Quality of life (EQ-5D)

Time: Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36

Description: Including cost utility and cost effectiveness analyses as defined by the protocol (e.g. QALYs)

Measure: Health economics

Time: At the end of the trial (trial duration of approximately 8 years)

Description: According to ELN response criteria

Measure: Peripheral blood JAK2 V617F allele burden

Time: At baseline and annually throughout the trial (from baseline until approximately 3 years post-randomisation)

Description: Trial discontinuation

Measure: Rates of discontinuation

Time: From treatment prior to protocol defined 3 years

Description: collected according to CTCAE version 4.0 and the MITHRIDATE protocol

Measure: Rate and severity of adverse events

Time: Continuous throughout the trial (from randomisation until approximately 3 years post-randomisation))

Description: in patients with splenomegaly

Measure: Spleen response

Time: Response at 1 year post randomisation

Description: Time free from venesection

Measure: Time free from venesection

Time: Defined as the mean time between venesections while on trial treatment (treatment duration of 3 years)

Description: Malignancy independent to the original diagnosis

Measure: Secondary malignancy

Time: Occuring throughout the trial (from randomisation until approximately 3 years post-randomisation)

Description: Change in QRisk score

Measure: Change in QRisk score

Time: Collected at baseline and years 1, 2 and 3

Other Outcomes

Description: Progression of marrow fibrosis (bone marrow collected and analysed at the Weatherall Institute of Molecular Medicine (WIMM) in Oxford

Measure: Progression of marrow fibrosis

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: Impact of treatment on molecular signatures of disease (as analysed by the WIMM in Oxford)

Measure: Impact of treatment on molecular signatures of disease

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: within the stem/progenitor cell compartment (as analysed by the WIMM in Oxford)

Measure: Clonal involvement

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: (acquisition of additional mutations, as analysed by the WIMM in Oxford)

Measure: Clonal evolution

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: of other disease-association mutations (as analysed by the WIMM in Oxford)

Measure: Reduction of peripheral blood allele burden

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: and any change over time (as analysed by the WIMM in Oxford)

Measure: Assessment of the prevalence of clonality markers for haematological disease

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: (angina, acute coronary syndrome, acute MI; arrhythmia)

Measure: Cardiac event

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: Pulmonary hypertension as assessed clinically

Measure: Pulmonary hypertension

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: e.g. angiogram, angioplasty, CABG

Measure: Coronary intervention

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: e.g. LVEF% on ECHO/MUGA and/or NYHA classification

Measure: Deterioration in cardiac function

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: TIA, haemorrhagic CVA, non-haemorrhagic CVA

Measure: Cerebrovascular event

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: peripheral vascular disease: claudication, carotid stenosis

Measure: Arterial vascular event

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: including DVT, PE, Cerebral, splanchnic, other

Measure: Venous thrombosis

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Description: Pregnancy loss

Measure: Pregnancy loss

Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)

46 Tazemetostat Expanded Access Program for Adults With Epithelioid Sarcoma

A multicenter, open-label expanded access program to provide access to tazemetostat to Epithelioid Sarcoma (ES) patients in serious need who are otherwise unable to participate in a clinical study or whom access is not available through marketed product in the US.

NCT04225429
Conditions
  1. Epithelioid Sarcoma
Interventions
  1. Drug: Tazemetostat
MeSH:Sarcoma
HPO:Sarcoma Soft tissue sarcoma

JAK2 V617F) observed in cytogenetic testing and DNA sequencing. --- V617F ---


47 A Prospective, Single-center Clinical Trial of Pegylated Interferon Alfa-2b Versus Interferon Alfa Therapy in the Treatment of Childhood Essential Thrombocythemia

Objectives: To compare the efficacy and safety in children (<18 years) diagnosed as essential thrombocythemia treated with the Pegylated Interferon Alfa-2b vs. Interferon Alfa. Study Design: A prospective, open-label, nonrandomized, single-center clinical trial

NCT04226950
Conditions
  1. Essential Thrombocytopenia
Interventions
  1. Drug: Recombinant Interferon Alpha
  2. Drug: Pegylated interferon alfa-2b
MeSH:Thrombocytopenia Thrombocytosis Thrombocythemia, Essential
HPO:Thrombocytopenia Thrombocytosis

- Platelet count ≥ 450 × 109 / L for more than 6 months(If the patient has JAK2 V617F, CALR or MPL gene mutation, the history may be less than 6 months) - Platelet count ≥ 1000 × 109 / L at screening - The guardians has provided written informed consent prior to enrollment Exclusion Criteria: - Known to meet the criteria for primary myelofibrosis or polycythemia vera by 2016 WHO criteria - Presence of any life-threatening co-morbidity - Secondary thrombocytosis - Familial thrombocytosis - Resistance, or intolerance, or any contraindications to interferon - Interferon is used in the past 1 month before enrollment - Patients with previous or present thrombosis or active bleeding - WBC<4× 109 / L - HGB<110g/L - Poor control of thyroid dysfunction - Patients with a prior malignancy within the last 3 years - Patients with severe cardiac or pulmonary dysfunction - Severe renal damage (creatinine clearance < 30 ml / min) - Severe liver dysfunction (ALT or AST > 2.5×ULN) - Patients diagnosed as diabetes with poor control - Patients with hepatitis B virus, hepatitis C virus replication or HIV infection - Patients with a history of drug / alcohol abuse (within 2 years before the study) - Patients that have participated in other experimental researches within one month before enrollment - History of psychiatric disorder - Any other circumstances that the investigator considers that the patient is not suitable to participate in the trial Inclusion Criteria: - <18 years old - Male or Female - Diagnosis of essential thrombocythemia according to the 2016 WHO criteria. --- V617F ---

- Platelet count ≥ 450 × 109 / L for more than 6 months(If the patient has JAK2 V617F, CALR or MPL gene mutation, the history may be less than 6 months) - Platelet count ≥ 1000 × 109 / L at screening - The guardians has provided written informed consent prior to enrollment Exclusion Criteria: - Known to meet the criteria for primary myelofibrosis or polycythemia vera by 2016 WHO criteria - Presence of any life-threatening co-morbidity - Secondary thrombocytosis - Familial thrombocytosis - Resistance, or intolerance, or any contraindications to interferon - Interferon is used in the past 1 month before enrollment - Patients with previous or present thrombosis or active bleeding - WBC<4× 109 / L - HGB<110g/L - Poor control of thyroid dysfunction - Patients with a prior malignancy within the last 3 years - Patients with severe cardiac or pulmonary dysfunction - Severe renal damage (creatinine clearance < 30 ml / min) - Severe liver dysfunction (ALT or AST > 2.5×ULN) - Patients diagnosed as diabetes with poor control - Patients with hepatitis B virus, hepatitis C virus replication or HIV infection - Patients with a history of drug / alcohol abuse (within 2 years before the study) - Patients that have participated in other experimental researches within one month before enrollment - History of psychiatric disorder - Any other circumstances that the investigator considers that the patient is not suitable to participate in the trial Essential Thrombocytopenia Thrombocytopenia Thrombocytosis Thrombocythemia, Essential This is a prospective, open-label, nonrandomized, single-center clinical trial between Interferon Alfa and Pegylated Interferon Alfa-2b in childhood essential thrombocythemia (<18 years). --- V617F ---

Primary Outcomes

Description: Proportion of subjects with a platelet count <600×109/L after 3 months of treatment will be evaluated.

Measure: Change in platelet count

Time: 3 months

Secondary Outcomes

Description: To compare the complete hematologic response rates between different treatment groups

Measure: The complete hematologic response rates

Time: 3 months

Description: Time to response in platelet count (<600×109/L) between different treatment groups

Measure: Time to response in platelet count

Time: 3 months

Description: To compare the proportion of subjects that display change on key biomarkers of the disease- JAK2V617F, CALR, MPL mutations.

Measure: Impact of therapy on key biomarkers

Time: 12 months

Description: To estimate incidence of major cardiovascular and thrombotic events (defined as cardiovascular death, myocardial infarction, stroke, transient ischemic attack, pulmonary embolism, Budd Chiari syndrome, deep vein thrombosis, and any other clinically relevant thrombotic event) while on active treatment or observation following end of treatment between different treatment groups

Measure: Incidence of major cardiovascular and thrombotic events

Time: 12 months

Description: To estimate incidence of development of myelodysplastic disorders, myelofibrosis, or leukemic transformation between different treatment groups

Measure: Incidence of development of myelodysplastic disorders, myelofibrosis, or leukemic transformation.

Time: 12 months

Description: To compare the proportion of subjects that display change in Myeloproliferative Neoplasm Symptom Assessment Form total symptom score (0-100 scores, higher scores mean a worse outcome) between different treatment groups.

Measure: Change in Myeloproliferative Neoplasm Symptom Assessment Form total symptom score

Time: 3 months

Description: To compare incidence of specific pre-defined toxicity including fatigue, flu-like symptoms, dizziness, injection site necrosis, dyspnea, pain, depression, blurred Vision, insomnia, anorexia, weight Loss, weakness, pruritis, sweating, fever, decreased Libido, hot Flashes, flushing.

Measure: Specific pre-defined toxicity

Time: 12 months

Description: To compare the proportion of subjects that display change on bone marrow histopathology

Measure: Impact of therapy on bone marrow histopathology

Time: 12 months

Description: To compare the proportion of subjects that display change on cytogenetic abnormalities.

Measure: Impact of therapy on cytogenetic abnormalities

Time: 12 months

Description: To compare the incidence of death while on active treatment or observation following end of treatment

Measure: Death while on active treatment or observation following end of treatment

Time: 12 months

48 A Phase I, Open-label Multi-dose Pharmacokinetic and Safety Study of Oral Tazemetostat in Subjects With Moderate and Severe Hepatic Impairment With Advanced Malignancies

This is a phase 1, 2-part, global, multicenter, open-label, PK, safety and tolerability study of oral tazemetostat in subjects with either advanced solid tumors, or hematological malignancies and normal hepatic function or moderate, or severe hepatic impairment.

NCT04241835
Conditions
  1. Hepatic Impairment
  2. Advanced Malignant Solid Tumor
Interventions
  1. Drug: Tazemetostat
MeSH:Liver Diseases
HPO:Abnormality of the liver Decreased liver function Elevated hepatic transaminase

JAK2 V617F) observed in cytogenetic testing and DNA sequencing 12. --- V617F ---

Primary Outcomes

Description: When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function

Measure: To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration

Time: 0 to 72 hours post dose on Day 1 and Day 15

Description: When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function

Measure: To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, AUC0-∞: area under the plasma concentration-time curve from time 0 extrapolated to infinity

Time: 0 to 72 hours post dose on Day 1 and Day 15

Description: When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function

Measure: To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, AUC0-72: area under the plasma concentration-time curve from time 0 to 72 hours post dose

Time: 0 to 72 hours post dose on Day 1 and Day 15

Description: When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function

Measure: To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, Cmax: observed maximum plasma concentration

Time: 0 to 72 hours post dose on Day 1 and Day 15

Description: When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function

Measure: To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, Tmax: observed time at Cmax

Time: 0 to 72 hours post dose on Day 1 and Day 15

Description: When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function

Measure: To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, λz: terminal phase elimination rate constant

Time: 0 to 72 hours post dose on Day 1 and Day 15

Description: When administered as a single and multi-dose in subjects with advanced malignancies and moderate or severe hepatic impairment, compared with subjects with advanced malignancies and normal hepatic function

Measure: To evaluate the pharmacokinetics (PK) of tazemetostat and its metabolite EPZ 6930, t1/2: terminal elimination half-life

Time: 0 to 72 hours post dose on Day 1 and Day 15

Secondary Outcomes

Description: Severity of adverse events experienced by all subjects with at least 1 dose or partial dose of tazemetostat will be evaluated by the Investigator based on the CTCAE, version 5.0

Measure: To evaluate the number of participants with treatment-emergent adverse events as assessed by CTCAE v5.0

Time: Through study completion, an average of 1 year

Description: Investigators will note any new clinically significant findings (e.g., not noted at screening) or changes in intensity of conditions that occurred after the initial tazemetostat administration

Measure: To evaluate the number of abnormalities or changes in intensity of conditions noted during the physical exam

Time: Through study completion, an average of 1 year

Description: Investigators will note any clinically significant changes from baseline in systolic and diastolic blood pressure measured in units of millimeters of mercury (mmHg)

Measure: To evaluate change in blood pressure

Time: Through study completion, an average of 1 year

Description: Investigators will note any clinically significant changes from baseline in heart rate measured in units of beats per minute (BPM)

Measure: To evaluate change in heart rate

Time: Through study completion, an average of 1 year

Description: Investigators will note any clinically significant changes from baseline in body temperature measured in degrees Fahrenheit or Celsius

Measure: To evaluate change in body temperature

Time: Through study completion, an average of 1 year

Description: Investigators will note any changes in concomitant medications from baseline in all subjects with at least 1 dose or partial dose of tazemetostat

Measure: To evaluate changes in concomitant medications

Time: Through study completion, an average of 1 year

Description: Investigators will report any clinically significant changes from baseline in the RR interval (sec) as noted by a 12 lead electrocardiogram (ECG)

Measure: To evaluate change in electrical activity of the heartbeat, RR interval

Time: Through study completion, an average of 1 year

Description: Investigators will report any clinically significant changes from baseline in the PR interval (sec) as noted by a 12 lead electrocardiogram (ECG)

Measure: To evaluate change in electrical activity of the heartbeat, PR interval

Time: Through study completion, an average of 1 year

Description: Investigators will report any clinically significant changes from baseline in the QRS complex (sec) as noted by a 12 lead electrocardiogram (ECG)

Measure: To evaluate change in electrical activity of the heartbeat, QRS complex

Time: Through study completion, an average of 1 year

Description: Investigators will report any clinically significant changes from baseline in the QT interval (sec) as noted by a 12 lead electrocardiogram (ECG)

Measure: To evaluate change in electrical activity of the heartbeat, QT interval

Time: Through study completion, an average of 1 year

Description: Investigators will note any clinically significant changes in hematological clinical laboratory values from baseline in all subjects with at least 1 dose or partial dose of tazemetostat using laboratory reference ranges

Measure: To evaluate changes in clinical laboratory values, hematology

Time: Through study completion, an average of 1 year

Description: Investigators will note any clinically significant changes in serum chemistry clinical laboratory values from baseline in all subjects with at least 1 dose or partial dose of tazemetostat using laboratory reference ranges

Measure: To evaluate changes in clinical laboratory values, serum chemistry

Time: Through study completion, an average of 1 year

Description: Investigators will note any clinically significant changes in urinalysis clinical laboratory values from baseline in all subjects with at least 1 dose or partial dose of tazemetostat using laboratory reference ranges

Measure: To evaluate changes in clinical laboratory values, urinalysis

Time: Through study completion, an average of 1 year

49 Efficacy and Safety of Dabigatran in Patients With Cirrhosis and Portal Vein Thrombosis-A Randomized Placebo Controlled Trial

A randomized controlled trial to study the efficacy and safety of Dabigatran in Cirrhotic patients who develop PVT.In this study the patients who meet the inclusion criteria will be randomized to either receive Dabigatran or placebo [multivitamin tablet]. Blood samples will be taken &Imaging will be done accordingly to notice progression or recanalization of PVT.The patients are followed up every 2 months up to 18 month .Then statistical analysis will be done to find whether the Dabigatran is efficacious in cirrhotic patients for recanalization of PVT.

NCT04433481
Conditions
  1. Liver Cirrhosis
  2. Portal Vein Thrombosis
Interventions
  1. Drug: Dabigatran
  2. Other: Placebo
MeSH:Liver Cirrhosis Thrombosis Venous Thrombosis Fibrosis
HPO:Cirrhosis Deep venous thrombosis Hepatic fibrosis Venous thrombosis

All included patients will be evaluated with - 1. Etiology of cirrhosis 2. Upper GI endoscopy 3. Haemogram (including reticulocyte count) 4. Coagulogram- PT/INR,APTT,TEG 5. Prothrombotic profile- protein c/protein-s/AT-III/Factor V Leiden mutation/ MTHFR C677T/PROTHROMBIN G20210A/ JAK2 V617F MUTATION / Anticardiolipin Ab. 6. Liver function tests, Renal function tests 7. Alpha fetoprotein/PIVKA II 8. USG abdomen with Doppler study 9. CECT-TP or CEMRI-TP to R/O HCC or angiography when PVT diagnosis doubtful. --- C677T --- --- G20210A --- --- V617F ---

Primary Outcomes

Measure: Number of participants with complete recanalization of thrombus in both groups.

Time: 1 year

Secondary Outcomes

Measure: Number of participants with partial recanalization of thrombus in both groups.

Time: 1 Year

Measure: Number of participants with improvements in Child-Turcotte-Pugh (CTP) in both groups.

Time: 6 months

Measure: Number of participants with improvements in Child-Turcotte-Pugh (CTP) in both groups.

Time: 1 year

Description: MELD score ranges from 6 to 40.

Measure: Improvements in Model for End Stage Liver Disease (MELD) Score in both groups

Time: 6 months

Description: MELD score ranges from 6 to 40.

Measure: Improvements in Model for End Stage Liver Disease (MELD) Score in both groups

Time: 1 Year

Measure: Number of participants with prevention of secondary decompensation in both groups

Time: 1 Year

Measure: Adverse Events in both groups

Time: 1 year

Measure: To study the changes in coagulation parameters by ROTEM(Rotational Thrombo Elastometry) analysis which includes CFT(clot formation time).

Time: 6 Months

Measure: To study the changes in coagulation parameters by ROTEM(Rotational Thrombo Elastometry) analysis which includes CFT(clot formation time).

Time: 12 Months

Measure: Number of participants with reduction in clinical complications in patients with PVT in both groups

Time: 3 Months

Measure: Number of participants with reduction in clinical complications in patients with PVT in both groups

Time: 6 Months

Measure: Number of participants with reduction in clinical complications in patients with PVT in both groups

Time: 12 Months

Measure: To study the number of participants developing reoccurrence of PVT after treatment with Dabigatran for 12 months by Ultrasound Doppler of splenoportal venous system.

Time: 12 months

50 Characteristic of Patients With Gastroesophageal Varices and Portal Cavernoma

Myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, may lead to gastroesophageal varices. The quality of life, morbidity, and mortality of MPN patients mainly depend on disease-related symptoms, thromboembolic and hemorrhagic complications. Previous studies have shown that JAK2 V617F has a prominent role in vascular risk and MPN-associated gastroesophageal varices. Portal vein thrombosis and portal cavernoma frequently occur in the MPN population and the management of gastroesophageal varices in these patients are sometimes technically difficult. The aim of this study is to investigate the the characteristics of patients with gastroesophageal varices and portal caver cavernoma with or without JAK2 mutation.

NCT04525768
Conditions
  1. Gastroesophageal Varices
  2. Myeloproliferative Neoplasm
  3. Portal Caver Cavernoma
  4. Portal Hypertension
Interventions
  1. Diagnostic Test: JAK2 mutation test
MeSH:Hemangioma, Cavernous Hypertension, Portal Esophageal and Gastric Varices Hypertension Varicose Veins Myeloproliferative Disorders
HPO:Cavernous hemangioma Esophageal varix Gastric varix Hypertension Myeloproliferative disorder Portal hypertension Varicose veins

Previous studies have shown that JAK2 V617F has a prominent role in vascular risk and MPN-associated gastroesophageal varices. --- V617F ---

Primary Outcomes

Description: Have a history of the occurrence of gastroesophageal variceal bleeding

Measure: History of variceal bleeding

Time: 1 day (the same time as diagnosis)

Secondary Outcomes

Description: 1-year death rate

Measure: 1-year death rate

Time: 1 year

Description: The concurrence of complications of portal hypertension (ascites, infections, variceal bleeding, et al)

Measure: Complications of portal hypertension

Time: 1 year

51 Anticoagulation Treatment of Patients With Gastroesophageal Varices and JAK2 V617 Mutation

Myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, may lead to gastroesophageal varices. The quality of life, morbidity, and mortality of MPN patients mainly depend on disease-related symptoms, thromboembolic and hemorrhagic complications. Previous studies have shown that JAK2 V617F has a prominent role in vascular risk and MPN-associated gastroesophageal varices. The aim of this study is to evaluate the efficacy of anticoagulation in patients with JAK2 mutation and gastroesophageal varices.

NCT04527666
Conditions
  1. Gastroesophageal Varices
  2. JAK2 Mutation
  3. Myeloproliferative Neoplasm
Interventions
  1. Drug: Anticoagulation Agents
MeSH:Esophageal and Gastric Varices Varicose Veins Myeloproliferative Disorders
HPO:Esophageal varix Gastric varix Myeloproliferative disorder Varicose veins

Previous studies have shown that JAK2 V617F has a prominent role in vascular risk and MPN-associated gastroesophageal varices. --- V617F ---

Primary Outcomes

Description: The changes of portal vein thrombosis including progression, disappear or unchanged.

Measure: Changes of portal vein thrombosis

Time: 1 year

Secondary Outcomes

Description: The occurrence of variceal bleeding including haematemesis and melena

Measure: The occurrence of variceal bleeding

Time: 1 year

Description: Overall survival rate

Measure: Overall survival

Time: 1 year

52 A Phase I, Open-label Multi-dose Two-part Study to Characterize the Effects of a Strong CYP3A4 Inhibitor and a Strong CYP3A4 Inducer on the Steady-State Pharmacokinetics of Tazemetostat (EPZ-6438) in Subjects With Advanced Malignancies

This is a phase I, multi-center, open-label, multi-dose, two-part PK and safety study to characterize the DDI potential of oral Tazemetostat.

NCT04537715
Conditions
  1. All Malignancies
  2. Advanced Malignancies
  3. Hematologic Malignancy
  4. Solid Tumor
  5. Follicular Lymphoma (FL)
  6. Non-Hodgkin Lymphoma (NHL)
  7. Diffuse Large B-Cell Lymphoma (DLBCL)
  8. Epithelioid Sarcoma (ES)
  9. Synovial Sarcoma
  10. Renal Medullary Carcinoma
  11. Mesothelioma
  12. Rhabdoid Tumor
Interventions
  1. Drug: Tazemetostat
  2. Drug: Itraconazole
  3. Drug: Rifampin
MeSH:Lymphoma Neoplasms Sarcoma Lymphoma, Non-Hodgkin Lymphoma, Large B-Cell, Diffuse Mesothelioma Hematologic Neoplasms Sarcoma, Synovial Rhabdoid Tumor Carcinoma, Medullary
HPO:Hematological neoplasm Leukemia Lymphoma Neoplasm Non-Hodgkin lymphoma Sarcoma Soft tissue sarcoma Synovial sarcoma

Has abnormalities known to be associated with MDS (e.g., del 5q, chr 7 abn) and myeloproliferative neoplasms (MPN) (e.g., JAK2 V617F) observed in cytogenetic testing and DNA sequencing. --- V617F ---

Primary Outcomes

Description: AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration

Measure: Part 1: To evaluate the effect of CYP3A4 inhibition by itraconazole on the steady-state pharmacokinetics (PK) of Tazemetostat when administered as a single and twice daily oral dose in subjects with advanced malignancies, AUC0-t.

Time: 0 to 48 hours post-dose on Days 1 - 3. 0 to 72 hours post-dose on Days 15 - 18 and 36 - 39. 0 to 24 hours post-dose on Days 21 - 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34.

Description: AUC0-72: area under the plasma concentration-time curve from time 0 to 72 hours post dose

Measure: Part 1: To evaluate the effect of CYP3A4 inhibition by itraconazole on the steady-state pharmacokinetics (PK) of Tazemetostat when administered as a single and twice daily oral dose in subjects with advanced malignancies, AUC0-72.

Time: 0 to 48 hours post-dose on Days 1 - 3. 0 to 72 hours post-dose on Days 15 - 18 and 36 - 39. 0 to 24 hours post-dose on Days 21 - 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34.

Description: Cmax: observed maximum plasma concentration

Measure: Part 1: To evaluate the effect of CYP3A4 inhibition by itraconazole on the steady-state pharmacokinetics (PK) of Tazemetostat when administered as a single and twice daily oral dose in subjects with advanced malignancies, Cmax.

Time: 0 to 48 hours post-dose on Days 1 - 3. 0 to 72 hours post-dose on Days 15 - 18 and 36 - 39. 0 to 24 hours post-dose on Days 21 - 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34.

Description: AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration

Measure: Part 2: To evaluate the effect of CYP3A4 induction by rifampin on the steady-state PK of Tazemetostat when administered as a single and twice daily oral dose in subjects with advanced malignancies, AUC0-t.

Time: 0 to 48 hours post-dose on Days 1 - 3, 15 - 17 and 24 - 26. 0 and 2 hours post-dose on Days 19 and 21.

Description: AUC0-48: area under the plasma concentration-time curve from time 0 to 48 hours post dose

Measure: Part 2: To evaluate the effect of CYP3A4 induction by rifampin on the steady-state PK of Tazemetostat when administered as a single and twice daily oral dose in subjects with advanced malignancies, AUC0-48.

Time: 0 to 48 hours post-dose on Days 1 - 3, 15 - 17 and 24 - 26. 0 and 2 hours post-dose on Days 19 and 21.

Description: Cmax: observed maximum plasma concentration

Measure: Part 2: To evaluate the effect of CYP3A4 induction by rifampin on the steady-state PK of Tazemetostat when administered as a single and twice daily oral dose in subjects with advanced malignancies, Cmax.

Time: 0 to 48 hours post-dose on Days 1 - 3, 15 - 17 and 24 - 26. 0 and 2 hours post-dose on Days 19 and 21.

Secondary Outcomes

Description: AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration

Measure: Part 1: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with itraconazole, and to evaluate the effect of itraconazole on PK of a single 400 mg oral dose of Tazemetostat, AUC0-t.

Time: 0 to 48 hours post-dose on Days 1 - 3. 0 to 72 hours post-dose on Days 15 - 18 and 36 - 39. 0 to 24 hours post-dose on Days 21 - 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34.

Description: Cmax: observed maximum plasma concentration

Measure: Part 1: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with itraconazole, and to evaluate the effect of itraconazole on PK of a single 400 mg oral dose of Tazemetostat, Cmax.

Time: 0 to 48 hours post-dose on Days 1 - 3. 0 to 72 hours post-dose on Days 15 - 18 and 36 - 39. 0 to 24 hours post-dose on Days 21 - 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34.

Description: Tmax: observed time at Cmax

Measure: Part 1: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with itraconazole, and to evaluate the effect of itraconazole on PK of a single 400 mg oral dose of Tazemetostat, Tmax.

Time: 0 to 48 hours post-dose on Days 1 - 3. 0 to 72 hours post-dose on Days 15 - 18 and 36 - 39. 0 to 24 hours post-dose on Days 21 - 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34.

Description: λz: terminal phase elimination rate constant

Measure: Part 1: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with itraconazole, and to evaluate the effect of itraconazole on PK of a single 400 mg oral dose of Tazemetostat, λz.

Time: 0 to 48 hours post-dose on Days 1 - 3. 0 to 72 hours post-dose on Days 15 - 18 and 36 - 39. 0 to 24 hours post-dose on Days 21 - 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34.

Description: t1/2: terminal elimination half-life

Measure: Part 1: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with itraconazole, and to evaluate the effect of itraconazole on PK of a single 400 mg oral dose of Tazemetostat, t1/2.

Time: 0 to 48 hours post-dose on Days 1 - 3. 0 to 72 hours post-dose on Days 15 - 18 and 36 - 39. 0 to 24 hours post-dose on Days 21 - 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34.

Description: AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration

Measure: Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin, AUC0-t.

Time: 0 to 48 hours post-dose on Days 1 - 3, 15 - 17 and 24 - 26. 0 and 2 hours post-dose on Days 19 and 21.

Description: Cmax: observed maximum plasma concentration

Measure: Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin, Cmax.

Time: 0 to 48 hours post-dose on Days 1 - 3, 15 - 17 and 24 - 26. 0 and 2 hours post-dose on Days 19 and 21.

Description: Tmax: observed time at Cmax

Measure: Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin, Tmax.

Time: 0 to 48 hours post-dose on Days 1 - 3, 15 - 17 and 24 - 26. 0 and 2 hours post-dose on Days 19 and 21.

Description: λz: terminal phase elimination rate constant

Measure: Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin, λz.

Time: 0 to 48 hours post-dose on Days 1 - 3, 15 - 17 and 24 - 26. 0 and 2 hours post-dose on Days 19 and 21.

Description: t1/2: terminal elimination half-life

Measure: Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin, t1/2.

Time: 0 to 48 hours post-dose on Days 1 - 3, 15 - 17 and 24 - 26. 0 and 2 hours post-dose on Days 19 and 21.

Description: Severity of adverse events experienced by all subjects with at least 1 dose or partial dose of tazemetostat will be evaluated by the Investigator based on the CTCAE, version 5.0.

Measure: To evaluate the number of participants with treatment-emergent adverse events as assessed by CTCAE v5.0.

Time: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1.

Description: Investigators will note any new clinically significant findings (e.g., not noted at screening) or changes in intensity of conditions that occurred after the initial tazemetostat administration.

Measure: To evaluate the number of abnormalities or changes in intensity of conditions noted during the physical exam.

Time: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1.

Description: Investigators will note any clinically significant changes from baseline in systolic and diastolic blood pressure measured in units of millimeters of mercury (mmHg).

Measure: To evaluate change in blood pressure.

Time: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1.

Description: Investigators will note any clinically significant changes from baseline in heart rate measured in units of beats per minute (BPM).

Measure: To evaluate change in heart rate

Time: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1.

Description: Investigators will note any clinically significant changes from baseline in body temperature measured in degrees Fahrenheit or Celsius.

Measure: To evaluate change in body temperature.

Time: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1.

Description: Investigators will note any changes in concomitant medications from baseline in all subjects with at least 1 dose or partial dose of tazemetostat.

Measure: To evaluate changes in concomitant medications.

Time: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1.

Description: Investigators will report any clinically significant changes from baseline in the RR interval (sec) as noted by a 12 lead electrocardiogram (ECG).

Measure: To evaluate change in electrical activity of the heartbeat, RR interval.

Time: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1.

Description: Investigators will report any clinically significant changes from baseline in the PR interval (sec) as noted by a 12 lead electrocardiogram (ECG).

Measure: To evaluate change in electrical activity of the heartbeat, PR interval.

Time: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1.

Description: Investigators will report any clinically significant changes from baseline in the QRS complex (sec) as noted by a 12 lead electrocardiogram (ECG).

Measure: To evaluate change in electrical activity of the heartbeat, QRS complex.

Time: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1.

Description: Investigators will report any clinically significant changes from baseline in the QT interval (sec) as noted by a 12 lead electrocardiogram (ECG).

Measure: To evaluate change in electrical activity of the heartbeat, QT interval.

Time: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1.

Description: Investigators will note any clinically significant changes in hematological clinical laboratory values from baseline in all subjects with at least 1 dose or partial dose of tazemetostat using laboratory reference ranges.

Measure: To evaluate changes in clinical laboratory values, hematology.

Time: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1.

Description: Investigators will note any clinically significant changes in serum chemistry clinical laboratory values from baseline in all subjects with at least 1 dose or partial dose of tazemetostat using laboratory reference ranges.

Measure: To evaluate changes in clinical laboratory values, serum chemistry.

Time: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1.

Description: Investigators will note any clinically significant changes in urinalysis clinical laboratory values from baseline in all subjects with at least 1 dose or partial dose of tazemetostat using laboratory reference ranges.

Measure: To evaluate changes in clinical laboratory values, urinalysis.

Time: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1.

53 Retrospective and Prospective Multicenter Study Evaluating the Impact of Treatment With Cytoreducing Agents on the Recurrence of Thrombosis in Thrombotic Patients With a Diagnosis of Myeloproliferative Neoplasia and Normal Blood Counts - a FIM Study

Among the etiologies of thrombosis, myeloproliferative neoplasia (MPN) is quite rare but should be investigated in case of thrombosis of atypical localization (digestive or cerebral) or in the context of recurrent idiopathic thrombosis in a young subject. Thrombosis could reveal an underlying MPN through the identification of a JAK2 V617F mutation. Rarely, MPN with thrombotic complications present with normal complete blood count(CBC). In case of a MPN with a thrombotic event but without CBC abnormality, anti-thrombotic treatment is recommended. But there is no recommendation for the indication of cytoreductive therapy and the clinician's decision is often empirical. One of the major complications of for essential thrombocythemia (ET) or polycythemia vera (PV) is thrombosis and an age over 60 is a major risk factor. The treatment of thrombosis associated with TE or PV is based on recommendations the main therapeutic objective of which is to reduce the thrombotic risk. The combination of a cytoreducing agent and antithrombotic treatment is thus proposed in high-risk patients. The efficacy of this management is monitored by assessing CBC with the objective of normalization at <400 G/L of platelets for ET patients and <45% hematocrit in case of PV. The absence of abnormal CBC makes it difficult to justify cytoreduction. The benefit of such a therapy in this context has not been clinically demonstrated. If a cytoreductive therapy is initiated, no biological parameters are available to assess the response to treatment. The objective of this observational study is to evaluate the incidence of recurrence of thrombosis in patients whose thrombotic event revealed an underlying MPN with normal CBC. A comparison of groups treated or not with cytoreductive agents will be performed. Longitudinal monitoring of the patients will provide a better understanding of the nature and kinetics of hematological changes in these patients.

NCT04539678
Conditions
  1. Thrombotic Patient
  2. Thrombotic Patients
  3. Diagnosis of Myeloproliferative Neoplasia
  4. Impact of Treatment With Cytoreducing Agent
MeSH:Neoplasms
HPO:Neoplasm

Thrombosis could reveal an underlying MPN through the identification of a JAK2 V617F mutation. --- V617F ---

Primary Outcomes

Description: The diagnosis of thromboembolic events must be confirmed by imaging

Measure: Cumulative incidence of recurrence of thromboembolic events after the initial thrombosis leading to the diagnosis of MPN

Time: 24 months follow-up

Secondary Outcomes

Description: Hematological progression criteria will be based on the WHO classification

Measure: Cumulative incidence of hematological progression to essential thrombocythemia, polycythemia vera, secondary myelofibrosis or acute transformation

Time: 24 months follow-up

Description: The diagnosis of thromboembolic event must be confirmed by imaging

Measure: Cumulative incidence of recurrence of thromboembolic events according to the type and duration of anticoagulant or anti-aggregant treatment

Time: 24 months follow-up

54 Phase 1/2 Study of an EZH2 Inhibitor (Tazemetostat) in Combination With Dual BRAF/MEK Inhibition in Patients With BRAF- Mutated Metastatic Melanoma Who Progressed on Prior BRAF/MEK Inhibitor Therapy

This phase I/II trial investigates the best dose and side effects of tazemetostat and how well it works in combination with dabrafenib and trametinib in treating patients with melanoma that has a specific mutation in the BRAF gene (BRAFV600) and that has spread to other places in the body (metastatic). Tazemetostat, dabrafenib, and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving tazemetostat with dabrafenib and trametinib may help treat patients with BRAFV600 mutated melanoma.

NCT04557956
Conditions
  1. Clinical Stage IV Cutaneous Melanoma AJCC v8
  2. Metastatic Malignant Neoplasm in the Central Nervous System
  3. Metastatic Melanoma
  4. Pathologic Stage IV Cutaneous Melanoma AJCC v8
Interventions
  1. Drug: Dabrafenib Mesylate
  2. Drug: Tazemetostat Hydrobromide
  3. Drug: Trametinib Dimethyl Sulfoxide
MeSH:Melanoma Neoplasms Skin Neoplasms
HPO:Cutaneous melanoma Melanoma Neoplasm Neoplasm of the skin

JAK2 V617F) observed in cytogenetic testing and DNA sequencing - History of T-lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia (T-ALL) - Patients with history of RAS mutation-positive tumors are not eligible regardless of interval from the current study. --- V617F ---

Primary Outcomes

Description: Data analysis will be descriptive in nature, and will be determined using the standard 3+3 algorithm. Toxicities by grade, number of cycles administered, and response to treatment will be listed for each dose level.

Measure: Recommended phase 2 dose (R2PD) (Phase 1)

Time: Up to 3 years

Description: Median PFS in each arm will be assessed using Kaplan-Meier product limit methods and the randomized arms will be compared using log-rank test (at 0.15 one-sided significance level) when 36 PFS events are observed.

Measure: Median progression-free survival (PFS) in Arm 1 and 2 (Phase 2)

Time: At 6 and 12 months

Secondary Outcomes

Description: Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, and 95% confidence intervals will be calculated.

Measure: Overall response rates (complete response [CR], partial response [PR])

Time: Up to 3 years

Description: Will be estimated in each arm using Kaplan-Meier product limit methods, and its 95% confidence interval will be calculated.

Measure: Overall survival

Time: Up to 3 years

Description: Toxicity evaluation will be descriptive, and standard toxicity definitions and criteria will be used as outlined in the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The number and percentage of subjects experiencing each type of adverse event will be tabulated by severity. If appropriate, confidence intervals will be used to characterize the precision of the estimate. A complete listing of adverse events will also be tabulated, and will provide details including severity, relationship to treatment, onset, duration, and outcome. Laboratory data measured on a continuous scale will be characterized by summary statistics (mean and standard deviation).

Measure: Incidence of adverse events

Time: Up to 3 years


HPO Nodes


HP:0002664: Neoplasm
Genes 1537
H19 RPS19 WT1 GPR101 CHEK2 MYD88 VEGFC PGM3 CTNNB1 PDGFRA IRF1 RHBDF2 PICALM FANCC GDNF RET PRKAR1A NELFA BCL10 KRT10 BLK TINF2 SMARCD2 NSD2 BRCA1 KRAS TRIP13 KCNH1 PERP CDH23 IKBKG MCC JAK2 MET GTF2E2 FOXC2 NF1 RAD51 TP53 ERCC4 WNT10A ASXL1 CTLA4 FLT4 DVL3 BRCA1 MLH3 NSD1 ERCC2 TSC2 FANCL RPS14 CDC73 TNFRSF4 STAG3 MSTO1 AIP EVC RET PLCD1 SDHB NEK1 POLH ASXL1 BRAF IL7 MAP2K1 ARSA BRAF COL4A5 CYLD KRT14 MLLT10 RASGRP1 H19 XIAP NTHL1 FGFR2 IGH DNAJC21 LETM1 MCM4 MYF6 CD70 FAM149B1 FGFR3 TERF2IP TNFRSF13C GLI3 DDX41 RPL26 PRLR SBDS LIG4 MGMT RERE KLLN FANCM WT1 PHB AXIN2 KIT PTEN TGFBR2 GJA1 PDGFRL STAT6 TYR CPLANE1 IFNG SIX6 JAG1 PALB2 SSX1 FANCG KIT MYO1H ELANE RPS19 H19-ICR KRT6B IDH2 PLCB4 FGFR1 BAP1 MINPP1 MST1 SMARCB1 PDGFRB RB1 FAT4 NF1 HFE SDHD WT1 TET2 BMPR1A RAF1 POLR1D CBFB SKIV2L IRF1 COL18A1 HMBS RET MMEL1 IGF2R JAK2 SEC23A BUB1B XPC ING1 AXIN2 KIT PALB2 MAGT1 STAC3 ALK SLC25A13 TMEM231 SHOX TDGF1 REST SMO SMARCA4 DNM2 TSR2 LIN28B GNAS WT1 CDKN1A DNAJC21 DKC1 BAP1 SRGAP1 ALX1 PTPN11 CBL APC SCN11A MAP3K1 RPL10 KLF6 PAX7 APC C1S NRTN BUB3 KRT5 LIG4 CARD14 GNAS MLH1 CDKN2A GNA11 TMEM127 ESR1 IL2RG KRT1 MET NF2 SDHAF2 SDHD WT1 MAP3K8 STAT1 PHOX2B PTPRJ PTCH2 CHD7 TERT LMNA ERCC6 EDNRB XPA PDGFRA OFD1 VHL SAMD9L SF3B1 FERMT1 BRCA1 GDF2 CASP8 TP53 LAMC2 GFI1B FANCD2 PYGL CR2 AR REST APPL1 APC CYP2A6 SEMA3C WT1 CDKN2A CTSA LRRC8A PHOX2B SMARCB1 NAGS FLI1 SOX2 RAD21 TMEM127 APC FGF3 BAP1 BUB1 RAD51 DKC1 RAD54B VHL EPCAM ASXL1 SRC HRAS BMP2 SLC25A11 PTH1R KRAS MYD88 NPM1 PTEN SH3GL1 PHOX2B TP53 SMAD4 XPA GATA4 MLH1 PMS2 STK11 FANCC DHCR7 PTCH1 CDC73 CYLD MEN1 CLCNKB CHEK2 RNF139 HABP2 POLE H19-ICR MMP1 RPL27 CC2D2A PIK3CA GPC3 ABL1 PALLD WASHC5 INTU ERCC5 DYNC2LI1 SLC22A18 TP53 CDH1 SHH MPL AKT1 NFKB2 NRAS PIGL CASP8 MYC KCNE3 DLST TAF15 TNFRSF13B GDNF EYA1 APC2 TNFRSF1B TCTN3 PPOX PNP PKHD1 BLM ODC1 IL12A TERT STK11 KRT17 IDH1 CIB1 RPL18 DVL1 ARHGAP26 PHOX2B CASP8 RPGRIP1L KRT6A SDHB FGFR2 VAMP7 JAK2 SRY DNMT3A EPAS1 KCNQ1OT1 MSH6 KRAS SDHB WNT5A DNMT3A RUNX1 TRIM28 DHCR24 USB1 VANGL2 GCM2 LIG4 KRAS SDHB ENG SEMA3D TRNS2 MINPP1 CASP10 NTHL1 LMOD1 SUFU FOXH1 CD81 ALX4 F13B BMPR1B RB1 CACNA1S CHIC2 VHL HRAS KIF11 KCNJ11 WRN SLC37A4 GNAQ LZTR1 CCND1 CPLX1 NR4A3 RYR1 NBEAL2 GATA2 TP63 APC KRAS HNF1B SUFU GNB1 MSX2 GPC3 CEL TCTN3 OCA2 MDM4 RB1 TMC6 ASCL1 AR BRIP1 CHEK2 AAGAB TSC1 TXNRD2 POLD1 CARMIL2 APC PIK3CA AKT1 POLE FAN1 RAD21 G6PC BRD4 PTCH2 MSH2 DHH EWSR1 SPRTN SDHC PTCH1 ALX3 CD79A TMEM67 INPP5E CCBE1 KRT6B BRCA2 ITK GINS1 HLA-DRB1 SNAI2 NBN PHOX2B BRAF CDH1 FANCE TYR GPC4 NF1 CD19 MVD AIP AR NBN TMEM107 BRIP1 ATRX BCHE MITF WRN BCR BCR NF2 SERPINA1 SDHB RABL3 PARN ANTXR2 TERT DPM1 IFIH1 GDF5 ZAP70 MEN1 TP53 GNAS BRCA2 TMC8 NODAL LETM1 VANGL1 TBXT BRCA1 FIBP FLT4 IL1B CCL2 FGFR3 SUFU MTAP ELANE CD19 HNF4A SAMD9 BUB1B KLHDC8B SLC26A2 FGFR3 FOXP1 PUF60 RUNX1 PTCH2 TRNK FLT4 TYROBP MPL KRAS RAD54L PIK3CA FAH CHEK2 CPLANE1 FAM20C CXCR4 DDR2 POU6F2 TMC6 SEC23B RET TRNP TFE3 TP53 NAB2 ANTXR1 MYSM1 SDHAF2 BTK TNFRSF10B DCLRE1C L2HGDH CDKN2A CYP11B2 BRCA2 SDHD TET2 TMEM216 BRAF PTCH2 TCF3 RPL11 NNT FLT3 BAX HAX1 IGF2 AKT1 FGFR3 MLH3 PLA2G2A TCF4 MLH3 NOTCH1 ERCC4 RRAS2 GPC4 DICER1 LZTS1 DOCK8 CASP10 GREM1 HPGD COL1A1 DCLRE1C IDH1 XRCC3 SUFU DNAJC21 PDGFRB TP53 NLRP1 WWOX TSC1 CTSC USP9X PDCD10 MEN1 ASCL1 RNF43 TNFRSF13C ESCO2 ZFPM2 AP2S1 PRCC HMBS ADA2 GANAB WT1 RNF43 HRAS KRAS SETD2 ATP6V1B2 FLT3 TJP2 BMPR1A PDGFB KIAA0753 PTEN STK4 NFKB1 BAP1 PMS1 MSR1 SLC26A2 RECQL4 MSH2 JAK2 ATRX FH RECQL4 FCN3 CD28 ASPSCR1 ADAR WHCR NOTCH3 GATA2 SMARCE1 CDKN2A RET ESCO2 EXT1 ERCC5 TET2 MBTPS2 NF1 OFD1 AGGF1 MVK KIT MUTYH HRAS KRIT1 FGFR1 TRIM28 CHEK2 CD79B GNAS BRCA2 KDSR BAX HACE1 MAP2K2 EDN3 ERCC2 CTNNB1 IL6 IGH PIK3CA MSH3 FZD2 SMPD1 SNAI2 PHOX2B SLC26A2 OFD1 PAX4 RB1 TRIP13 EWSR1 SCN9A PIK3R1 GBA EP300 PIK3CA HMMR KIT PDE6D ZSWIM6 SH3KBP1 SRP54 FUZ USP8 WT1 TERT MAFA FOXO1 GJB3 RAD51D POT1 SDHC PRKAR1A CREB1 SH2D1A WIPF1 WWOX PIK3CA NF2 HNF4A FAS RNASEH2A CD27 ATRX SPRED1 RPS14 FDPS RNR1 PALB2 NF1 MN1 TET2 GPC4 KDR SOX9 RAD51 MAX MYLK EP300 SHOX FOXE1 TCOF1 ESCO2 MYH11 HSPA9 MAD2L2 KRT9 CYP2D6 RFWD3 FANCE KRAS CCND1 LMO1 PTCH1 PORCN EDN3 PDGFRA DICER1 FANCA TERC CTBP1 SDHD ANTXR1 CXCR4 RAD50 BRCA2 MC1R MPL SLC22A18 MMP1 KRT16 F13A1 TSC2 ENG SETBP1 WT1 TET2 SDHC SMAD4 ZFHX3 GFI1 RNF113A STK11 KARS1 FOXE1 CDKN2B WT1 ERBB3 SMARCAD1 PDGFRL DMPK GTF2H5 NF2 CEBPA RPS28 PMS1 AKT1 PRDM16 NBN GCK SPINK1 ERBB2 JAK2 KIT DKC1 EXT1 JAK2 COL7A1 AXIN1 SLC22A18 NRAS ECM1 GNPTAB ABCA5 CDH1 NRAS ERCC6 VANGL1 RAD51C MYCN HBB TP53 SRY FANCI AKT1 MITF LEMD3 TARS1 TET2 NSD2 DAXX DYNC2LI1 OGG1 EXT1 TNFSF15 TERT ERCC6 DMRT3 SLC25A11 CTNNB1 VHL KLLN MLH3 EIF2AK4 GJB6 BARD1 OCRL GPR35 MYC DLST KRAS MSH3 RMRP PRKCD KLF6 NEUROD1 FANCG SLC17A9 BMPER FLCN SDHC SF3B1 STS GNA14 TERC MNX1 CAT TCF4 TUBB TRNQ BRCA2 IL12RB1 PDX1 CDKN2A SLC26A4 SDHC PPM1D NRAS PRKAR1A NRAS TAL1 KIF1B DNMT3A PDGFB MRAP ERCC3 CDC73 PRF1 RFWD3 PMVK RPL15 FGFR1 TP53 BICC1 HNF1A GATA1 RTEL1 RPS15A ERCC4 WRAP53 NR0B1 BCR FGFR2 SEC23A KRT17 NR5A1 VHL BLM BRAF ICOS POLD1 RPS27 FASLG CYSLTR2 PTEN PRKN THPO KIF7 NRAS TAL2 BRAF WDPCP DCC MSH6 NOP10 WNT10A PSAP ERCC2 CALR ACD SLX4 ACAN HABP2 GJB4 TET2 PHF21A ERCC3 MDH2 APC PALB2 RPL10 KRT17 PGM3 IL7R ARL6IP6 APC TCIRG1 NF1 SMAD4 PTPN3 PIK3CA ABCA5 FGFR2 TGFBR2 BRCA2 HNF1A RNASEH2C PAX6 IGH TTC37 DICER1 SRY GPC6 TOP2A KIT OFD1 PALB2 NRAS MC1R SDHD TFAP2A FGFR3 TNFRSF1B REST PTEN MST1R SCN4A BRCA2 CDKN2A FGFR2 ZIC2 EFL1 ECE1 NUP214 DDB2 GPC3 KCNQ1 PTEN HNF1B FN1 ASCC1 SPIB SRP72 PTEN FANCB KCNJ10 AKT1 KRAS KEAP1 INS DISP1 PTEN SASH1 CDKN1C ACTB TNFRSF13B MYH8 EDN1 IVNS1ABP NSUN2 TSC1 RAD51C MSH3 ATP7B RET PTPN12 STIM1 DHCR7 KRAS SFTPC BMPR1A XPC TMC8 KCNJ10 KDM6B STK11 KRAS GNAQ KRAS HFE HOXD13 B3GALT6 RPL5 KAT6B GATA2 MUC5B PIK3CA USP8 GDNF SMAD4 MVK RHBDF2 SSX2 CEP57 RAD51C NEK9 JAK2 PDGFB NRAS KRT1 PIK3CA MFN2 DOCK8 PTEN IL7 SDHC ATM AKT1 BRCA1 RELA GCDH PIK3CA IDH2 HRAS CTLA4 GPR143 ERCC2 GATA2 PTPN11 IGF2 SMAD4 NDUFAF6 CDH23 RPS7 RAD54B TP53 MUTYH GLI3 PTPN11 BRIP1 CDKN1B SF3B1 PTCH1 CIB1 ERCC3 PTPN11 TRPV3 GDNF IGLL1 PRKCD CTNNB1 PIK3CA PTPN11 SLCO2A1 FAH BRCA1 ETV6 BRCA2 EPCAM TP53 EXT1 BCL10 TRPS1 BMPR1A ATM MPL KRT17 MAX SLC12A3 ADA TERT UBE2T TSC2 TCTN3 MSH2 BDNF BTK SKI RPS20 NRAS RUNX1 DCC MSH2 RPS24 WT1 TRNF TFAP2A RPL35 RPS17 SDHA RARA CDC73 SBDS POLH BRAF LAMB3 RNF6 PIEZO2 KCNQ1OT1 CCM2 PHKA2 POU2AF1 TP53 TREM2 ABCC8 EXT2 ALK PHKG2 NUTM1 SLC26A4 PTCH1 MUTYH PALLD NBN FANCA SQSTM1 ELMO2 ACP5 TWIST1 TRIM37 RPL31 HFE RET DLC1 SDHB EP300 TREX1 HSPG2 ATP7A MSH6 C2CD3 CHRNG SRP54 TINF2 BUB1 PSENEN SMAD4 NF1 ERCC3 ARID1B RMRP WAS GATA2 MAPK1 BIN1 COL7A1 EDN3 PIK3CA IGF2 H19-ICR TUBB FH MLH1 TNFSF12 PIK3R1 RASA1 F5 SH2B3 CTNNB1 FOXI1 SUFU TLR2 SRSF2 CDKN1B GJC2 OPCML LEMD3 FIBP TRNS1 HNF1A VHL PTEN PRKAR1A MSH2 CYLD CTHRC1 COL7A1 DDB2 SDHC GJB2 LIG4 MDM2 LAMA3 CHEK2 MTOR CDON SMARCE1 TAF1 GNAQ TP53 RAD54L WWOX BMPR1A CCND1 GFI1 BCL10 PTEN CTNNB1 DHX37 SLX4 FGF8 XRCC4 TRIP13 CDC73 BIRC3 NOTCH3 DIS3L2 PKD2 KIF1B GNA11 ARMC5 CREBBP DIS3L2 HRAS LMX1B BAP1 BRCA2 POT1 ABCB11 AURKA RASA1 SMARCB1 ALX4 GPC3 MGAT2 PAX3 IGHM LMNA TCF4 GATA1 TRNK IDH1 LRP5 CALR FH RET SEC23B APC TET2 SETBP1 WT1 PMS2 POLR1C SIX3 EPHB2 RPL35A RET TINF2 CD28 CYP26C1 MNX1 ALX3 KIT CPOX GJB2 DLL1 MSTO1 RSPO1 TEK EXT2 ABCC6 COL2A1 GNAS FH FASLG BAP1 COL14A1 YY1 RAG2 RB1CC1 MAP2K1 RHOH STAR CREBBP RECQL4 EVC2 HBB ERBB2 ABL1 NDP SUFU NF2 MSH6 ATP7A TSC1 FAS SLC6A17 MS4A1 NQO2 FLCN EXTL3 SOS1 RNASEL NPM1 KIT GNAI3 TRNH RAG1 HRAS BUB1B IGF2 PLAG1 FANCD2 BCL2 NEK1 KIT ATP7A PIK3CA SMARCB1 PCGF2 LIG4 BCL6 NUP214 FLNA IRF5 ACVR1 GAS1 DYNC2H1 RSPRY1 TRAF7 RNASEH2B REST RPS29 TGIF1 TERT PIGA TP53 CDK4 GPR101 ACVRL1 SAMHD1 MSL3 MAPRE2 SLC45A2 CTNNB1 ADA KLF11 NKX2-1 GLI2 PKD1 MAP3K1 SRP54 TNFSF12 ND5 CRKL RASGRP1 BCL10 RPS26 GLI3 TRNL1 AR SDHA RB1 MLH1 MC2R TGFBR1 KIT CYP11B1 AXIN2 EGFR PIK3CA RECQL4 EXOC6B SMO SFTPA2 NRAS CDKN1B TP53 PIK3CA MSH6 ACTG2 POT1 SDHB RNF6 CALR KCNN3 C11ORF95 TSC2 CD96 SOS1 COL2A1 SMAD7 GLI1 FANCF MPL CDH1 BRCA2 BRAF ATR SDHA FLCN DICER1 IL1RN ICOS AIP RSPO1 DICER1 GCM2 XRCC2 DNASE1L3 PPP2R1B TGFBR2 MTM1 CDKN2C SIX1 MEN1 POU6F2 SRD5A3 STAT3 ERCC3 TG ASXL1 CDKN2B CYLD NHP2 CCDC22 TBC1D24 BLNK DIS3L2 SH2B3 MPLKIP AHCY PCNA EXT2 EXT2 MEN1 PARN WRAP53 TP53 HBB GABRD NUMA1 APC ZSWIM6 BRCA1 GJB2 KCNAB2 AIP USF3 RUNX1 H19 HDAC4 SDHD UROD PDGFRB CR2 HRAS CDH1 ERBB2 TNPO3 LPP SDHD IL2RG ATM BARD1 TREX1 POLE C2CD3 ERCC4 SLC25A13 PNP KRAS SRSF2 SDHB FGFR3 CASR CASP10 TET2 CTC1 ENPP1 SOX6 PIK3CA BMPR1A ERCC2 TERC CBL ADAMTS3 PIGL BCR SAMD9L NOD2 CBL TGFBR2 MALT1 SEMA4A ANTXR2 SLC37A4 TBX2 DHH STS SDHB TERT KRT16 DZIP1L RTEL1 SDHD CCND1 AKT1 FOXI1 CDK4 NSD1 MLH1 FLCN DLEC1 FGFRL1 MTMR14 GCGR TBX18 CREBBP MXI1 APC BCL10 COL11A2 TERT MC1R SCN10A RPS10 SMO BRCA2 KIT ATM PRKN MRE11 KIF1B KCNH1 VHL GPR101 GNAS PMS2 ACD WDPCP MAD1L1
HP:0000822: Hypertension
Genes 421
ELN FBN1 SDCCAG8 PRKAR1A ALX4 LIMK1 PDE11A NR3C2 FBN1 KCTD1 VHL GP1BB ANGPTL6 ENPP1 MLXIPL NKX2-5 LEMD3 NOTCH2 SLC37A4 RET SEC24C BBS12 NPHP1 MMP14 EGFR HLA-DPB1 KCTD1 ABCG8 SCNN1A SLC25A11 COX3 CYTB TRAF3IP1 HGD MEF2A VHL PKD1 TRIP13 GANAB RPGRIP1L ITGA8 CDH23 BBS7 ELN DIS3L2 SMARCAL1 GATA5 PKD2 NPHP3 KIF1B JMJD1C UFD1 ARMC5 CCR6 SERPINA6 KLHL3 LMX1B BRCA2 GTF2I YY1AP1 TNFRSF11B LMNA CTLA4 G6PC NOTCH1 MDM2 WDR19 MAFB TRPC6 RET LMNA ERCC4 XYLT2 SDHB CACNA1D TMEM67 LZTFL1 ERCC4 COQ7 MYLK KIF1B PTPN22 COL4A5 NPHP1 DNMT3A SCNN1A CACNA1D BBS9 CDH23 WT1 FGFR2 TGFB2 GLA BICC1 TTC8 ND1 ADA2 WDPCP ARHGAP31 ARL6 AIP FGFR2 ALMS1 INVS FBN1 VHL WT1 IDUA SMAD4 CFHR3 PDE11A WNK1 NPHP1 WRN SLC2A10 SMAD6 OSGEP ABCC6 LRIG2 SDHB PRKACA FLT1 INVS HBB POU3F4 NOTCH3 LMNA MC4R PRKACA HLA-DRB1 TRNK MYH7 HSD11B2 MYH11 VANGL1 EDA2R PHF21A MDH2 MKS1 BBS2 DNAJB11 TSC1 CFB MTRR GNAS MTTP PRKAR1A LMNA NF1 MUC1 ND6 HPSE2 CYP11B1 CUL3 EDA NPHP4 ALMS1 VAC14 TRNK SMAD4 THBD OFD1 STAT2 BBS5 SDHD PRKAR1A HMBS APOB ECE1 KCNJ5 REST RET MKKS FMO3 PRTN3 ERCC6 PKHD1 CFHR1 LRP6 CYP11B2 BBS10 SDHD FN1 PCSK9 CBS ZMPSTE24 SDCCAG8 ERCC8 CDKN1A IRF5 C3 TRNL1 PKD1 FUZ COX1 HLA-DPA1 MGP PLIN1 LDLRAP1 CLCN2 SH2B3 LYZ LOX MFAP5 GNAS CYP17A1 CYP11B1 B2M TMEM127 KCNJ5 PAM16 NR3C1 ACAT1 TRNK CDKN1B MEN1 SDHAF2 WT1 STAT1 BNC2 TGFB3 HMBS USP8 BBIP1 LMX1B GANAB HLA-B PDE8B IFT27 LMNA RREB1 MMP2 CYP11B1 TRNL1 ARVCF MLX GCH1 ABCC6 CLIP2 C8ORF37 OFD1 TBX1 CEP164 JAK2 NFU1 FH GJA1 SDHC BAZ1B CFH CYP21A2 JAK2 CEP290 CD2AP TRNQ TRIM32 STOX1 RFC2 AIP RET CYP11B1 LDLR SPRY2 TMEM70 NDUFAF6 GUCY1A1 WT1 CDKN2C TRNF POU6F2 ADA2 IFT172 ADAMTSL4 TRIM28 GNAS BMPR2 TMEM127 PKD2 CORIN CAV1 PRKG1 ABCB6 VHL SLC25A11 EXT2 MAT2A NFIX XPNPEP3 KCNJ5 GBA SCNN1B MAX CACNA1H ENG AIP ACTA2 TRNW ARMC5 H19 SDHD TRNS2 TSC2 COL4A4 BRCC3 FGA PDE3A USP8 SCNN1B FIG4 COX2 ELP1 WDR35 INF2 GPC3 SDHC ACTN4 ABCC6 SCN2B SLC2A10 TRNV SDHA COMT CYP17A1 WNK4 TBX1 SMAD4 BSCL2 ENPP1 SCNN1G BBS1 SUGCT GTF2IRD1 GLA CFI ACVRL1 MPL NOS3 BBS1 APRT APOA1 FOXE3 MAX TGFBR2 XYLT1 TP53 CCDC28B NOD2 ADA2 PLIN1 DLST CC2D2A FN1 COL4A3 BANF1 TGFBR3 SCNN1G LARS2 GDNF SLC37A4 PPOX PKHD1 CEP290 ACP5 KRT18 DZIP1L CCND1 ERCC8 GUCY1A1 TRNC CCN2 SMAD3 KRT8 SDHB FBN1 TGFBR1 SDHD POR COL4A3 BBS4 SDHB IL12B MYMK FMR1 ELN NF1 CEP19 CPOX ARL6 NR3C1 TET2 EPAS1 ND5 DYRK1B PDE3A ELP1 TRIM28 YY1AP1 CD46 TMEM237 TBL2 ERCC6 THSD1 CDKN2B HIRA ACTA2 WT1 KIF1B VHL NSMCE2 GPR101 COL3A1 ABCG5 HSD11B2 PPARG PPARG TNFRSF11A COL3A1 LEMD3 TRNS1 IQCB1 TRNE
HP:0001873: Thrombocytopenia
Genes 445
DKC1 RBM8A IVD CDC42 RPS19 RNASEH2A MMUT RNASEH2C CD81 COG4 NABP1 GATA1 NUMA1 DLL4 TERC USP18 VWF FANCB FCGR2B GBA GP1BB FANCI FANCC SEC24C NBEAL2 DHFR TINF2 SMARCD2 GATA1 SLX4 MPIG6B KMT2D SMARCAL1 OCRL PRF1 ETV6 JAK2 PRF1 RAD51 JMJD1C VPS33A UFD1 STAT5B GFI1B ERCC4 GP1BA RAG1 PRKCD MAD2L2 SPATA5 LYST HOXA11 FANCG WAS FANCL SF3B1 APOE GNA14 TNFSF11 ITGB3 GATA1 MYORG NRAS ACP5 FIP1L1 ITK BRAF MECOM COL4A5 SLC35A1 CALR MMAA SLC46A1 VPS33A RASGRP1 LYST ANKRD26 HOXA11 XIAP RPL15 DNAJC21 NBN RPL35A GBA RTEL1 PSMB8 RPS15A TINF2 FANCE FCGR2A UROS WRAP53 BCR HLA-B UQCRFS1 TNFRSF13C ARHGEF1 RPL26 SBDS GATA1 CD40LG PDGFRB RPS27 IFNG FANCM FASLG SMARCAL1 ATRX CFHR3 TNFAIP3 FOXP3 MECOM SLC19A2 GP1BA DNASE1 NIPBL FLT1 HLCS PARN MAP2K1 SCARB2 IFIH1 ANKRD11 NOP10 ZAP70 ITGB3 STT3B FANCG ITGA2 HYOU1 GBA SLC19A2 PSMB9 RPS19 PLAU FAS CFB NHP2 ARHGAP31 G6PC3 MS4A1 CD19 FLI1 SRC LMBRD1 CYCS SAMD9 GALC PRKACG PRDX1 HPS5 POMP TMEM165 MMACHC RNASEH2C RBM8A PDGFB DIAPH1 ITGA2B RUNX1 TET2 FANCD2 TBL1XR1 STT3B NFKB2 MPL PEPD OCLN SC5D HELLPAR ADAMTS13 THBD RFX5 STAT2 PALB2 PSMB4 LAT STX11 IRAK1 CD109 ABCD4 LIG4 MTOR CA2 WARS2 RAG2 CTLA4 TERT EFL1 CIITA AP3B1 MYSM1 SARS2 BTK GATA1 RNASEH2B CFHR1 GP1BA BTNL2 FOXP3 NOP10 TBXAS1 RPS29 TET2 FANCB OSTM1 TSR2 RPL11 TCN2 SAMHD1 GP1BB DKC1 TPP2 NSUN2 C3 RRAS2 TERT TNFSF12 PRKCD STIM1 RASGRP1 PTPN22 STIM1 CTC1 KRAS RPS26 RBPJ NHEJ1 LIG4 ZBTB16 CFH DNAJC21 GATA1 SAMHD1 PCCA CDC42 RPL5 ESCO2 STAT1 ADA2 SCARB2 TERT GP9 STAT4 GBA RREB1 RAD51C GP1BA ARVCF NFKB1 UBE2T TBX1 LRBA FANCF RFXAP MYH9 CFH GFI1B ADAR MMUT FLNA GP9 FANCD2 VPS45 FASLG AGK GATA2 STOX1 ICOS BLOC1S6 ERCC6L2 KIF15 XRCC2 TET2 CLCN7 WAS GUCY1A1 RPS7 SPP1 NBEAL2 BRIP1 TALDO1 FCGR2C LBR PTPN11 ACTN1 KDM6A PRKCD NHP2 SLC7A7 JAK2 MYSM1 CORIN CD46 RAG2 DKC1 SPATA5 VWF BCOR SMPD1 DGUOK RARA NLRC4 EOGT FARS2 PARN COG1 FYB1 HLCS NPM1 FANCF SLC20A2 MMAB GBA DGKE ACAD9 BRCA1 ADA SLFN14 FANCC NOTCH1 WFS1 IFIH1 PSAP CR2 IKZF1 UBE2T SRP54 RFXANK MPL SLC35A1 STAT3 RPL27 WDR1 APOE TREX1 PNP ABL1 STAT3 SH2D1A WIPF1 GATA1 MYH9 RPS24 RPL35 CTC1 RPS17 FAS ACAD9 RNASEH2A COMT TBX1 DCLRE1C ASAH1 SBDS CFI MVK NOS3 TET2 NFKB2 COG6 TERC PHGDH FLI1 CD36 SNX10 SAMD9L GP1BB ITGA2B GBA TNFRSF13B ARPC1B LARS2 SP110 FANCA MAD2L2 SBDS PNP PKHD1 NHP2 FAS MPL ACP5 TNFRSF11A RFWD3 FANCE TERT DZIP1L TFRC RPL31 CD81 XPR1 RTEL1 TUBB1 RPL18 PRKAR1A FANCA TERC NFKB1 ABCA1 TREX1 ELANE NPM1 TALDO1 BRCA2 IRF2BP2 SRP54 TINF2 PML RAG1 TREX1 UROS ALG8 ATP7B PCCB WAS MMUT TERT RPS10 CFI RUNX1 SALL4 DOCK6 SLC46A1 CD46 USB1 SLC7A7 HIRA TNFSF12 JAM2 ERBB3 TINF2 IL7R ACD RPS28 WIPF1 CASP10 CTLA4 GP1BB SALL4 EFL1 NBN GBA HLA-DRB1 CASP10
Protein Mutations 2
G20210A V617F
SNP 0
HP:0000708: Behavioral abnormality
Genes 2492
NR2E3 TBC1D24 SH3BP2 PRDM8 SLC1A4 GPR101 NDUFS6 SETBP1 GPHN GUCY2D SNCB COG4 LSS VEGFC PDE11A PRNP CTNNB1 EEF1A2 NR2F1 NTRK1 GJB1 CRADD GP1BB ASS1 MAPT GABRA1 NDUFS1 C12ORF4 SLC25A19 RET SEC24C PROM1 SUCLA2 DKK1 PAH FGFR3 C19ORF12 NOVA2 ATXN2 AP4E1 AFG3L2 ABCA12 DBH FRMPD4 WWOX PRKN FTSJ1 ADH1C ARF1 FOXH1 CDH23 IKBKG SETBP1 MAGEL2 LINS1 GDAP2 SOX5 GTF2E2 FOXC2 NF1 PRF1 RTN4IP1 POLG VCP ZFPM2 HNRNPH2 COASY AHDC1 RHO DGCR8 MLH3 USH2A NECAP1 SIN3A FTSJ1 C12ORF4 RBPJ NSD1 ERCC2 OPN1LW PLA2G6 SATB2 NDUFA1 PRPS1 CAVIN1 FLT4 CRX RBBP8 WDR45 NAGLU KMT2A DLD MSTO1 SHROOM4 EMC1 RET PPP2R1A SIL1 PLCD1 GNAI3 SDHB GRIA4 VCP POLH ARX KIF11 JAM2 MAN2B1 ARSA TIMM8A PROK2 CDH15 PUF60 TP63 SUCLA2 CDHR1 LYST TKT ZNF408 NEUROD2 GATM PRNP APP SPOP CACNA1H CUX2 DPYS GPT2 POMGNT1 CACNA1F SCN2A GJB6 SQSTM1 ABCA2 PON1 APP PANK2 TRIO TTLL5 ZIC1 MAN1B1 RIMS2 COL1A1 KCNV2 HNF4A SBDS DYM NPAP1 RERE GBA TANC2 UNC119 KLLN ARNT2 KDM5B SLC13A5 SNORD116-1 SRPX2 SLC2A1 AP1S2 TGFBR2 IARS1 SVBP GLI2 CACNA1A FLT1 TYR HLCS OPTN IDUA NOTCH3 GAS1 ATXN8OS CAV1 ANKRD11 IFNG HERC2 GFM2 VANGL1 SLC9A6 RGS9BP GNPTAB DGUOK MKRN3 ATN1 TGIF1 VDR PAX8 ND5 CASK SHH TMEM240 PIGH MERTK SPG21 NLGN3 CDON PRPF6 PLCB4 SCN8A SLC18A2 FGFR1 BAP1 PRKAR1A SIX3 SERAC1 CYP27A1 RPGR PIKFYVE MST1 SMARCB1 NKAP RAI1 PHGDH USH1G QDPR PEX14 HPSE2 NDUFA6 VCP NEFH PRODH ZIC2 KMT2E RIC1 ALDH18A1 ST14 PLEC GABRG2 SQSTM1 ALDH3A2 CNNM2 AARS2 ST3GAL3 FGF8 NPHP4 SHH STXBP1 SON GALC HMBS RET RRM2B TH MMEL1 NODAL KCNJ5 RIMS1 PCDH19 SLC26A4 ERAP1 GRIA3 USH1C XPC SMC1A CLN8 CC2D1A LRMDA MTFMT CLRN1 TRHR GAS1 FMO3 SLC25A13 KCNJ2 SEPTIN9 MAPK8IP3 ARX TBX1 NTRK2 RAB11B TRNF NDUFB11 DUOXA2 VCP DYRK1A DNM1 FLCN DPF2 NHLRC1 TMEM231 PIGQ XK IL12A CLRN1 DAO TSHR CDKN1A HCN1 DNAJC21 RORB HLA-DQB1 PDE6C SIX3 NDUFV2 IDH3B MTHFR EPHA4 TSHB COQ2 GABRB3 ZEB2 RPL10 NECTIN1 FRMPD4 ARCN1 C8ORF37 ENTPD1 FXR1 COL13A1 PDE10A ACSL4 SLC22A5 CASR LIG4 LARP7 NTNG1 GNAS GRIK2 RPGRIP1 AIFM1 GRN ALG11 ARL3 TREX1 APP ERF PDGFRB NR3C1 SACS CD96 SDHAF2 SEPSECS PSAT1 DLG4 PRPF3 POLR3B PRNP RDH12 EIF2B5 PRNP NRXN1 GLUD2 HPRT1 CDKL5 CTNS CEP78 PQBP1 NDUFS7 PTS SLC5A2 XPA SIM1 SETD5 SYNGAP1 ZMYND11 DPAGT1 PPP3CA CNTNAP2 ESS2 NFU1 TTC8 SNCA COX7B SCAPER SYNJ1 APC2 HSD17B10 TBK1 MAN2B1 FBXO31 SNCA ACTL6A TBC1D24 TIMM50 LRPPRC GBA PYGL PDGFRB UPF3B PIGV OPN1MW NSDHL SLC33A1 PDCD1 TRNQ RRM2B RFC2 PRCD KIF15 TDGF1 THRB ATR SGSH SLC7A14 PRKCG PDE4D AP3D1 GABRA2 HAL TANGO2 USP7 NLGN4X SEMA3E KRT83 ABCA4 PFN1 VCP SHANK3 ACSF3 GNRHR FGFR1 ZNF711 NAGS MC4R NLRP3 CLCN4 JPH3 TBR1 PEX19 CDK8 TMEM127 SLC7A7 CC2D2A HNF1A MED12 TRNL2 NDUFAF4 CDH23 SYNGAP1 PGK1 FIG4 EPM2A SMG9 SNRPN SLC6A8 CLDN10 VAMP2 FOXH1 NDUFAF5 SLC25A11 RARA VPS13C ND1 GPHN PPARGC1A STS NAXD SRP54 NDUFS4 EIF4G1 TRIP12 PTEN KCNJ5 PHOX2B EIF2B2 PRNP SOX3 PHIP XPA FMN2 REV3L WAC CHRNA2 NTNG2 TOR1A SDHA LTBP2 ARMC5 WFS1 IFIH1 KRAS DHCR7 PEX1 PEX12 ADAMTS2 FBP1 TREM2 MEN1 CLCNKB MAB21L1 COLQ AGBL5 AVPR2 BPTF PIK3CA CLCN4 ATXN10 GAS1 NDUFS1 MAOA GALC ERCC5 ELP2 RERE MAOA PRPH2 KCTD17 AGTPBP1 TARDBP STAG2 NFIX DEAF1 NDUFAF8 DNA2 HADHA PAH PIGL DALRD3 SATB2 TRNS1 CFAP410 DLST TAF1 CFAP410 SQSTM1 NALCN PDE4D PIGW HOXA2 TGIF1 SPAST C9ORF72 MECP2 APC2 CTNS FGFR1 GNAT2 ATAD3A PPOX PNP PKHD1 PET100 MAPT IL1RAPL1 IL12A GLRB TDGF1 MEIS2 SLC24A5 CERKL FARS2 PEX6 SCN9A METTL23 STRADA TRNL1 CERT1 TGIF1 PRKAR1A RHO TBP NOTCH3 EHMT1 INPP5E IGF1 SDHB CLCN2 MEF2C UBE2A INSR PNPLA6 CEP290 LMNB1 PTPN22 ERBB4 ATF6 UBQLN2 SEMA4A WDR26 SRY DNMT3A CEP152 EPAS1 WNT10A DUOX2 TNFSF4 SDHB BSCL2 TREM2 RARS1 CISD2 SGCE OFD1 TACSTD2 TSHR MID2 PRPS1 PSEN1 NTRK2 ANG SVBP PCDH15 TFAP2B COL3A1 NSD1 DLL1 AP4M1 GNB5 CHD2 CNKSR2 CEP57 PDE10A KDM6A TBL1X UNC80 PTPN22 AVP WFS1 ZDHHC9 POGZ TRNL1 PIGP PEX11B TTI2 DYNC1I2 NRXN1 NODAL NR2E3 SPR MECP2 CACNA1A DNAJC13 TBC1D23 RAB39B RPGRIP1 CNNM4 CIC COX10 PRPF4 SCN8A PSEN2 RP2 C12ORF65 TREM2 PPARG USP27X HCRT WDR11 GRIN1 CSGALNACT1 STXBP1 BCOR TOPORS ALG13 MCOLN1 GRIN2B SNCA CHST6 ARL2BP HTT MLXIPL MCCC2 CPS1 CHD2 CYP27B1 ZEB1 AVPR2 NPHP3 CACNA1C NSDHL FGF8 DMD BBS2 TP63 RLIM ERCC8 HCRT CNGB3 UBE3A TFAP2B ZFYVE26 TSHR RAX2 DISP1 CNGA3 GAS1 LRRK2 OCA2 GUCA1A TCF20 MAN1B1 UFD1 C9ORF72 GABRD FRA16E TSC1 DLL1 GPR143 GNB5 NACC1 NHLRC1 GABRB2 FBXO11 DRAM2 ITPR3 FAN1 NDUFA11 FOXG1 LNPK SOBP RORA IMPA1 MSH2 TG HTR2A HERC1 SYN1 SDHC CDON PTCH1 SLC52A2 CHMP2B TBX1 MED12 LHX3 CHMP2B USP9X FIP1L1 ELOVL5 PWAR1 NPHP1 SMARCA2 CHMP2B MECP2 PIK3C2A REEP6 GLRX5 RLIM TCN2 GFM1 PPP2R2B NBN CACNA1B POMT1 COASY VAMP1 SAG FCGR2A HESX1 EBP TYR PMP22 RAD21 DNAJC5 MOG PDGFRB CABP4 TREM2 CP NKX2-1 CSNK2A1 AIP GLI2 CPT1A ALMS1 NFIX HIVEP2 FMR1 WDR26 DISP1 PLCB4 FGD1 AIRE ZBTB11 FGF8 AP4M1 PSAP GABRA5 GRN BCR PSEN1 POLG WDFY3 RNF216 ATAD1 PRPS1 LRIG2 DCX ARSG TRNS2 TK2 DNASE1 NIPBL TSEN54 AP4B1 CHD1 DDX3X SCN1A TULP1 HTT TUBB2B XPR1 IDUA IFIH1 NMNAT1 ELOVL1 RNF135 ATXN1 SYP ND3 GNAS APP BCORL1 ZEB2 CACNA1G GJB2 CLDN16 RAB28 APP APOL2 SPG11 ATXN3 GAMT ATPAF2 TNIK MTPAP TBCK CIZ1 FMR1 MFSD8 OCRL UBAC2 COX1 SORL1 RAI1 ADAM9 GNE NGLY1 TMCO1 SLC35A3 HEXA MAPT EZR GUCA1B LAS1L TGFBI RERE KCNQ3 ALMS1 AQP2 HDAC8 ALDH18A1 EYS JRK ASH1L TWNK PUF60 FLT4 ASAH1 RUSC2 KIAA1549 TYROBP SPR KRAS DGCR2 DOCK3 USP7 PROKR2 CCBE1 MOG PIK3CA ADGRV1 IRAK1 STAG2 SLC6A19 ECE1 HTT POLA1 PPP2CA SEC23B CLTC ASAH1 PIGP EML1 ALG13 HMGCL KCNT1 SLC25A12 HSD17B10 SETD2 RPS6KA3 KCNB1 L2HGDH PRPH2 CYP11B2 SPART FTL CNOT3 TECR NDUFA12 SDHD ATF6 CBS CCNF PRPH2 CDON NKX2-1 NDUFA4 PACS1 PSEN1 ALG12 MAPT KIF14 GRIN2A SLC3A1 DHDDS FRRS1L HAX1 GFM2 CTNNB1 GABBR2 DNAJC12 CKAP2L MKRN3-AS1 CASR CCDC47 TCF4 OPN1LW SLC25A1 USH2A ERCC4 AARS1 ANK3 AIFM1 PDE6H OVOL2 ADCY5 DISC2 CHD7 ABAT DCTN1 SURF1 CNGA1 PTS PTPN22 NDUFA2 THOC2 SMC1A PEX1 AP2M1 CIB2 AIMP1 PSAP KLRC4 TYR DNAJC21 SAMHD1 PCCA C9ORF72 ANOS1 ATP13A2 SMC1A MEN1 ASCL1 NDUFAF6 PINK1 TBC1D7 AP2S1 HMBS TBK1 MAPT B4GALNT1 TKT DHTKD1 BSCL2 DDX11 PSEN1 STAT4 SETD2 ARHGEF18 TMEM216 NDUFS1 BMPR1A PDGFB SYN2 ZNF423 CRX ARVCF GCH1 ATRX PMS1 IQSEC2 PGAP2 HK1 TMLHE POGZ DNMT1 NDUFS2 KCNJ11 FUS EHMT1 POLG FH RPS6KA3 NDUFS8 SIM1 DLG3 HLA-DRB1 SLC25A20 SDHD NDUFS2 HLA-DQB1 ADAR PLXND1 LHX4 ALS2 PITPNM3 FGF17 NLRP3 SHANK3 SLC9A6 FUS SMARCE1 LIAS TUSC3 RGS9 SARS1 AP3B2 CACNA1A CLCC1 UBE2A OVOL2 RTN4R KRT12 PODXL AFF2 ARG1 FAM161A RSPRY1 DRAM2 SLC2A1 HRAS MRPS22 DMXL2 EEF1A2 C9ORF72 ATXN3 PRPS1 DLG3 TRIM8 GNAS RPS6KA3 ALAD GABRA2 FDFT1 PPM1D KIZ GLRA1 ERCC2 HTR2A LRRK2 VCP IL10 COX3 SMPD1 TRIO GRIN2A ATP13A2 ECHS1 EZH2 PEX13 GABBR2 PON2 CST6 MCTP2 FGF8 WASHC4 MAGEL2 SLC19A3 EP300 MTPAP DNA2 MTHFR DNMT1 CLP1 VAC14 CHMP2B PRDM8 SH3KBP1 FOXH1 IMPG2 AP1S2 ATXN3 SDHAF1 GRM7 SLC19A3 TDGF1 HCN1 ERCC6 USP8 SMARCC2 AMER1 TERT ZIC2 SDHC GBA CREBBP DHDDS TRAPPC9 EIF2B4 CRB1 GNA11 PEX3 CHRNA7 NEXMIF NF2 PROP1 HNF4A DNM1 SLC19A3 GNE RNASEH2A AFG3L2 PANK2 TGIF1 SPRED1 GLUD1 SMAD4 BSCL2 GTF2IRD1 NEUROD2 SCN8A NLGN3 SCN11A LAMB2 KLHL7 SLC5A7 NUS1 KCNA2 IQSEC1 COX7B PGAP3 MAX FIG4 TDP2 SLC39A4 KRT86 ADAT3 SMC3 RAC1 STAG1 CUL4B STAT4 IREB2 ADA2 GBA DPYD KLF13 SPOP MEF2C KMT2C VPS13A ALG11 DCAF17 AGTR2 ATP1A1 ALDH5A1 SZT2 EFHC1 CUX2 TACO1 ALG13 CLN3 MPLKIP BCKDHA EP300 CTSF RPGR FANCE HGSNAT SLC6A5 TLR4 ERCC8 APOL4 UPF3B CHMP2B STUB1 PREPL TPO NOP56 MED12 IDH3A SCN1B ADGRV1 IBA57 GATAD2B SDHD PWRN1 TNFRSF1A ADAT3 OPN1LW TBX1 LAS1L ATXN8OS STX16 C4A ERCC1 TREX1 IFT88 SMPD1 NDUFA13 KANSL1 MMP1 FMR1 CHD8 ELN EDC3 PCCB TSC2 PRPF8 SLC9A7 POLA1 ACSL4 VLDLR DRD2 NKX2-1 OPN1MW CTCF PNKP ELP1 DDX3X ERLIN2 POLR2A RNF113A MECP2 SLC46A1 SCN1A DDC KAT8 TMEM237 ARSA TBL2 NOTCH2NLC SLC7A7 MED12 CDKN2B ZC3H14 MRE11 DMPK PEX10 STX1B ZNF81 ZC4H2 OPN1MW RSRC1 GTF2H5 PRDM16 IDS DUSP6 ITPA NBN GBA DPYD DOCK6 DISP1 LMAN2L KCNA2 TRIO NDUFA10 PROKR2 SLC25A22 RBM12 PEX5 COL7A1 SHANK3 MTHFR CNGA3 LIMK1 RPGRIP1 COMT CNKSR2 POLG FGFR1 HLA-DRB1 EXT2 ERCC6 USP27X FGFR3 EEF1A2 HBB SYT1 COX15 TSHR PIGO MMADHC FGFR3 KNL1 SLC2A1 EGF TARS1 POMC SYNJ1 TRNE BMP4 ATP1A3 NPC1 TNFSF15 ZBTB20 CDHR1 FTL WFS1 PIEZO2 SYNE1 VHL ZNF365 TARDBP CHI3L1 SOX2 RPS23 TM4SF20 AUH FOXC2 GJB6 SCN1B DNAJC6 HARS1 NFASC COL1A2 OCRL GPR35 CA4 AFF2 CHCHD10 STAT5B FBXW11 NAT8L CHST6 CHRNA7 KRAS HPRT1 PDE6A LYST KIAA1109 NKX2-5 ASPA TICAM1 MBD5 TUBB3 CNGB3 PDGFB SNX14 ATXN8 LTBP3 ERCC6 CACNA2D4 ATP5F1A PINK1 ECM1 GNAT2 STS CXORF56 NDUFAF4 FOXH1 MECP2 GABRA2 CAT TCF4 RLBP1 LMBRD1 SYN1 NAGA SLC2A1 NOTCH2NLC IL12RB1 HERC2 NLGN1 TRAK1 CSF1R EPG5 TLK2 GAS1 SLC6A4 BCS1L AUTS2 HIBCH TREX1 BCOR KCNJ1 TRNH FBP1 IL6 DNMT3A SLC46A1 HGSNAT ERCC3 GM2A TWIST1 GNAO1 AMT FGFR1 TREM2 RNF13 NODAL RPE65 ADA2 OPN1SW ATP2A2 CLN6 NAGS KMT2A RAC1 DISP1 POU3F3 ATP6AP2 AHSG POU1F1 HCN1 NDUFV1 PPP1R12A PIGG CTSH AP1B1 CYP2R1 CACNA2D4 PTCHD1 ST3GAL5 VHL HCRT SMAD4 DMPK ROM1 SLC6A8 SLC6A17 CARS2 MAP1B KISS1R TDGF1 AMACR PSEN1 MED13L AQP2 GDI1 NDUFA13 RP1 FGF8 STXBP1 PCDH19 PDHA1 NR4A2 PSAP ERCC2 GABRB3 LARGE1 WDR73 MDH2 CA4 HARS1 NIPBL GABBR2 SNORD115-1 POMK TCF12 TARDBP RP9 SRPX2 CRY1 ACADS ACOX1 MBD5 SLC6A1 ATP1A3 RPL10 DBT MTRR WAC STAG2 STXBP1 GNAS PSMD12 DNM1 MYT1L FLI1 ADSL TP63 NF1 ITGB6 CEP250 NSUN2 B3GALNT2 PIK3CA CAMTA1 CSNK1D HLA-B NMNAT1 RNASEH2C STXBP1 TIMMDC1 BCS1L HDAC8 TLR3 DCPS HNRNPA2B1 PAH GRIA3 SHOC2 GJA8 RPIA DRD5 PNKP ABCA7 TMEM231 HLA-A SURF1 ARV1 MC1R SDHD FMR1 HNF1B BCKDHB DHPS DCTN1 PDE6C TIMM8A ATXN2 ZIC2 WARS2 SNRNP200 PRMT7 CTCF SLC2A3 FGFR2 PGAP1 EFL1 GLDC KCNJ10 CACNA1A CEP85L AP3B1 TTC8 DDB2 PDE6H AP3B2 PEX16 AGA PPT1 IQSEC2 PCNT MAPT MFF NDN HNF1B POMC COG5 PCYT1A SPIB BCKDK WHRN DNM1L AKT1 UCHL1 ANXA11 PRPH2 GSS TRAPPC4 PTCH1 APOE ALDH3A2 GLI2 GLI2 PRPH2 GNAT2 SLC6A3 EDN1 ATP1A3 MYO7A NSUN2 TRRAP ATP7B IL23R ALG6 SLC12A6 NDUFA6 PARK7 SLC25A4 DOCK7 DHCR7 ZMIZ1 XPC CLTC SNRPN DPH1 HLA-DQB1 KDM6B PRNP POLR3A CWC27 PRNP TOR1A CHAT TGFBI GNAQ NEK1 SH2B1 TUB TMEM240 TASP1 CDH2 CYP27A1 SLC18A3 CBS NODAL DGCR6 CEP78 ANK3 ACAT1 NDUFB3 SLC39A4 NEK2 USP8 DHX30 CACNA1A RTTN CDK19 MED25 COG4 TRNS2 GJB6 RREB1 KPTN MED25 ABCA4 LRAT PSEN1 YWHAG CILK1 FBLN1 KMT5B PON3 PIGC TBX1 PIGT ALG1 GCH1 DAOA GK ZNF408 MAPT SPG7 SDHC ZSWIM6 DLAT KDM5C RAI1 PRODH STAG2 MED13 NUP88 DRD3 TTC19 AFF4 AP1S2 GPR143 DHX38 SPG21 RUNX2 POLA1 ND1 SCN2A TBP POC1B NDUFS3 PIGL SPP1 SOD1 NDUFAF2 KAT6B TMEM67 ACTL6B SPECC1L CISD2 SLC45A1 GATAD2B LEP ERCC3 MED23 EPM2A PTCH1 POMT1 ATCAY OTUD6B SLC18A3 LRAT DRD4 KRT81 TK2 GUCA1A RAI1 SCN1B PI4KA GNAS MYT1L ARID2 HDAC8 EPCAM CRBN FOXE1 SPATA5 TDGF1 KAT6A TMEM106B BCOR LARP7 GABRG2 RAX2 WDR62 PRNP NFIX FOXP2 PSMD12 ZNF462 RNF168 NKX2-1 SIN3A HLCS NEU1 UBA5 ACADL NAA10 SHROOM4 POLG2 PSAP PTEN SLC12A3 CLTCL1 USP9X GABRG2 TGIF1 PSMD12 SPRY4 RAB39B UBE3A GRIN1 TERT IKZF1 TSC2 LEPR MUSK COG6 KYNU VPS51 HCCS RPGR CARS1 THOC2 GM2A SKI RPS20 HLA-DRB1 STAT3 SCN9A RUNX1 KCNA1 KRT3 ALS2 BPTF AP4S1 FKTN LAMB1 SDHA COMT CHCHD10 PAK3 CDC73 ASAH1 ACY1 GUCA1A POLH MVK TRPV4 PIGV ATRX PRPF31 PCSK1 DEPDC5 MAPT MED13L SLC25A15 GABRG2 ACTB PTCH1 UBA5 GABRA5 MATR3 GJA5 POU2AF1 FOXH1 TP53 TREM2 MAPK10 MBTPS2 FLII NRL PDE6G RBP3 COL1A1 CDKL5 MED13 NDUFAF5 AP2M1 ARSA NEFH PMM2 BRAT1 NLRP1 CLIP1 ALPL POLG PEX26 TRNN TNIK UNC93B1 DLL1 DYRK1A HNRNPA2B1 SHH NDUFAF3 RP1L1 SDHB EP300 TREX1 PER3 DNMT1 HSPG2 MSH6 ALS2 LSS GRIN2A FGFR1 GLT8D1 SIN3A EYS IRF2BP2 SMARCA2 PDZD7 VAPB SRP54 ALDH5A1 PDE10A ARL6 ITM2B ABCC8 CACNA1G AHI1 ATP7B SARS1 ALS2 GABRG2 ALKBH8 PC CPOX ADH1C OTC POMT2 ARID1B NDST1 MAK IQSEC2 MAPK1 TREM2 MICOS13 PROM1 SOX5 ATP6V1A FOXE3 DPP6 SYT2 PDE6C BCAP31 ATP13A2 DLL1 CCR1 COQ2 FSCN2 ATP13A2 HIRA SARDH GSN DSG4 NHLRC2 TBC1D24 TELO2 FGFR3 PRPH UROC1 TBK1 CTLA4 HTR2A MAN1B1 GJC2 KCNT1 ARX PDE4D TYR KDM5C HTRA2 TTI2 NLGN4X IGF1R SH2B1 ZIC2 CDC42 CAMTA1 ITM2B TBP NONO FAT4 MID2 PRRT2 NABP1 NUMA1 LINS1 ZNF41 PNPLA6 AIFM1 PSAT1 LHCGR UBTF ERCC8 COL7A1 DDB2 CACNA1F FTL IGF1 FCGR2B SIX3 SNCA GJB2 ACTL6B PDE6B SLITRK1 CYP27B1 GATA4 KMT2E TIMM50 MTOR HFE ALG3 TAF1 PRKAR1A AVPR2 SLC1A3 SYT1 BMP2 RDH11 ABCC8 C8ORF37 SEMA4A NUS1 RNF125 CRBN C9ORF72 NKX2-5 DLL1 DEAF1 HCFC1 NDP PER2 CDC73 CFAP410 MANBA MECP2 NPHP4 ELN PPP2R5D SYT14 MAPT WARS2 CXORF56 TINF2 JMJD1C ARMC5 ZMIZ1 CREBBP HECW2 BAP1 COX2 SLC25A20 SIX3 SDHA AHDC1 GTF2I TUBB2B MCCC1 TNF SYNGAP1 FGF8 DCTN1 MN1 ACTG1 PCARE SETD5 SLC2A1 TWNK MGAT2 GNB3 GABRD LAMB2 ERCC4 LEP TOMM40 TCF4 VPS53 HPS6 OTX2 DOK7 PEX2 NHS SCN3A OTUD6B FIG4 PRPH FUS GUCY2D VPS33A SLC5A5 GRIA2 CACNA1D RPE65 MBOAT7 TET2 ASL RLBP1 GRN EPG5 CYFIP2 PITPNM3 FKRP GLA CUL4B SLC1A4 NAA15 SHH SEMA4A MECP2 ANTXR1 ABCD1 DDX6 HLA-B DEAF1 MYORG CPOX CDHR1 SLC20A2 RPGR GJB2 HLA-DQB1 TSPYL1 TWNK IDUA NDUFAF3 NDUFS4 ARHGEF6 MSTO1 ZNF513 TYROBP LIPT1 GRIN2A TRNS1 CDON PRKACA YY1 LINGO1 MC4R FGFR1 SNCA CREBBP TBX4 SPATA7 OPA1 HBB MBTPS2 C9ORF72 ADH1B WFS1 ATXN10 MBTPS2 ND4 CDKL5 TMEM126B NDP GBA SUFU NDUFAF1 NAA10 ATP7A TSC1 DEAF1 DCHS1 AASS TSPAN7 GNAS SLC6A17 PSEN2 GRIN2D TAF15 WASF1 EXTL3 CLN8 EIF2B1 SLC25A19 PRODH ZDHHC9 PUS3 MED12 CNGB3 CTNS ZNF365 GNAI3 CDKL5 MYOD1 ATRX EDNRA AUTS2 NFIX TBL1XR1 NDUFS7 TBK1 TWNK CHD2 NPHP1 SMARCB1 CNTNAP2 MYO7A SRPX2 ZC4H2 PCGF2 LEPR KCTD17 SLC1A2 UNC13A TRMT1 IRF5 PTCH1 DLL1 LMX1B NTRK1 CPLX1 CNGB1 NDE1 NDUFS3 TRAPPC9 RSPRY1 TRAF7 TCF4 RNASEH2B GBE1 P2RY11 PIGY HESX1 GPT2 NEXMIF PGAP3 NDUFA9 C9ORF72 SLC1A3 MECP2 ND2 PLA2G6 SCN1A PTCHD1 PRPH2 PARK7 SOD1 MEIS2 GCLC SLC1A2 NUBPL POLG PSEN1 SAMHD1 MSL3 FBXO7 FGF14 PYCR2 SLC45A2 MFRP KPTN MAPT PIGY UCP2 IRF6 SNCAIP YME1L1 PACS1 TAC3 FUZ GABRA1 CRKL COX15 SLC12A3 LHX1 GLI3 TRAPPC14 HS6ST1 PHF21A MLH1 ZBTB16 NALCN AGPAT2 CYP11B1 SPART NFIB GIGYF2 POLR3A FOS DYRK1A IL12A-AS1 UQCC2 HDC COL8A2 SMO CDKN1B GABRA1 SDHA PPP2R2B WDR4 PAK3 TCF20 HNRNPA1 IFT172 FA2H TMEM138 IQSEC1 ADNP NACC1 NDUFV1 MSX1 TBR1 NDST1 PANK2 GALNT2 MCOLN1 CLIP2 BEST1 TACR3 CC2D1A CLP1 GUCY2D ODC1 SH2B1 BAZ1B HNRNPA1 RSRC1 GYS2 BRAF PRSS12 PPOX AP4E1 METTL5 P4HTM ATP6 AIPL1 CSF1R SLC25A1 UGP2 EBP STOX1 AIP DCTN1 SIX3 ARSA BCL11B SASS6 TMEM70 HNF1A VRK1 CDKN2C OPHN1 ATRX FGF12 EP300 HESX1 ATF6 KISS1 PRRT2 ATP13A2 VSX1 GLE1 ATXN7 PDGFB MIR17HG ABCC8 KCNJ13 GLS SLC35C1 CDON ADGRG1 ASXL1 OPHN1 PNKP KMT2A PDHA1 MAGEL2 TBC1D24 NPC2 PARS2 SLITRK1 TAF6 SETD5 JPH3 JRK SGCE HNMT MED12L CORIN MYT1L NDUFS8 ZIC2 DCAF17 GRHL2 FOXRED1 MPLKIP AHCY GLE1 PCNA FXR1 ST3GAL3 ALS2 NONO ITPR1 ASXL3 EXT2 CLCN4 NHS TMEM106B NDUFB10 FGFR3 SNCA VPS35 NDUFS4 HUWE1 C8ORF37 ESR1 NAGA CORO1A GABRD GRN KCNAB2 SNX14 SLC18A2 USF3 ENTPD1 RAPSN GABRB3 HDAC4 PTCH1 FOXRED1 VCP TNPO3 CRYGC ADNP AGRN SDHD MEFV COL17A1 NDUFB11 SNAP25 SHH ELP1 C2CD3 TWNK GLI2 AHR PNP SCN2A SRSF2 CRX FOXG1 PRKAR1B SUOX ESPN NDUFV2 TBX1 IMPDH1 WAC EIF2S3 PACS2 FAS NSMF IYD SLC6A19 SKI ERCC2 FGD1 CBL PIGL SLC45A1 GNRH1 DNAJC6 SCN1A CNGA3 GPC4 YWHAG AGPAT2 APC2 KCNK9 NOD2 MRPL12 ZFYVE26 RAI1 PLA2G6 EIF2B3 BSCL2 SIK1 TSHR CNKSR2 TMEM237 SEMA4A TBX2 IPW VPS13A NGLY1 ASPM SQSTM1 CACNB4 TNFRSF11A INTS1 CACNA2D2 DZIP1L CNNM4 MAPT FGF14 TRNW BCORL1 SLC35A3 TET3 PCNA AKT1 NSD1 NPM1 SLC16A2 PCDH19 TRAF3 FOXP1 ND6 WDR45 COMT MYO9A HCN1 EIF2S3 IL1RAPL1 CFAP43 PML POLG FGFR2 CREBBP HTT NDUFAF2 GCSH PAX8 NADK2 DISP1 PUS7 SLC24A5 HLA-DRB1 NTNG1 FOXP1 NAA10 KDM3B NODAL ERCC6 RGR NDUFB9 SIGMAR1 CHD7 TAT ABCA7 KIF1B RDH5 VHL ARG1 IQSEC2 C19ORF12 MFN2 GPR101 HMGCL PMS2 HSD11B2 COA8 IFT140 TMEM106B MBOAT7 ZEB2 SIM1 TANC2 GNS RNF13 ARFGEF2 GNAO1 FBXW11 SDHB
Protein Mutations 1
V617F
SNP 0
HP:0008069: Neoplasm of the skin
Genes 288
KRT5 MLH1 KIT MLH1 PTEN CDKN2A COL7A1 VEGFC NRAS RECQL4 KRT1 ECM1 PRKAR1A NLRP1 CYLD CTSC NRAS SMO COL7A1 NF2 DDB2 PIK3CA STAT1 GJB2 HRAS LAMA3 TARS1 TERT PRKAR1A LMNA BMPR1A PDGFB STK4 BAP1 PMS1 PTEN XPA MSH2 KRAS CTNNB1 SUFU FERMT1 KLLN FCN3 PERP CD28 NOTCH3 IKBKG OCA2 GJB6 IL7 OCRL TMC6 LAMC2 GTF2E2 NF1 CREBBP WNT10A HRAS HRAS CTLA4 SMARCE1 MSH3 CTLA4 RMRP RSPO1 BAP1 GPR143 ERCC2 TSC1 CARMIL2 ERCC5 SLC17A9 MLH3 TGFBR2 MBTPS2 ERCC2 NF1 FLCN FAN1 RASA1 MVK TNFRSF4 GNA14 BRD4 TP53 PTCH2 MSH2 LRRC8A SDHC ERCC3 PTCH1 IGHM LMNA ALX3 PLCD1 PTCH1 CIB1 CD79A ERCC3 TRPV3 IGLL1 CDKN2A CD79B PRKCD POLH KDSR CTNNB1 KRT6B NRAS IL7 BLNK PDGFB CYLD KRT14 SLCO2A1 RASGRP1 FH ERCC3 SEC23B DKC1 IL6 MPLKIP PMVK NTHL1 EPCAM MSH3 TP53 FGFR1 SNAI2 MEN1 TINF2 CD28 ERCC4 TYR NF1 WRAP53 MVD PTEN EP300 KRT17 KRT17 APC GJB2 BLM PMS2 KLLN GJB2 FASLG KIT USF3 PTEN TGFBR2 MITF WRN HRAS CYLD NRAS FH SDHD GJA1 MSH2 MMP1 DCC TYR MSH6 TERT GJB3 PIK3CA IFNG ERCC4 WNT10A ERCC2 CREBBP RPS20 GNAS NRAS SDHB RECQL4 SLX4 TMC8 ERCC5 GJB4 WWOX MSH2 NF2 FAS SPRED1 FDPS POLH SUFU NF2 MSH6 KRT6B FLT4 FAS BRAF KRT17 AKT1 BMPR1A LAMB3 RNF6 APC BAP1 ERCC2 SMARCB1 PIK3CA PDGFRB NF1 SEMA4A NUTM1 PTCH1 PTCH2 TNFRSF1B FLT4 KRT9 KRAS KIT BLM KRT16 KRAS PIK3CA KRT17 MC1R CIB1 CXCR4 PORCN AKT1 TMC6 DICER1 TERC CDK4 SEC23B TNFRSF1B XPC MLH1 ING1 PTEN MSH6 CXCR4 KIT KRT6A CDKN2A MC1R DDB2 PSENEN TRAF7 MMP1 TNFRSF10B KRT16 DCLRE1C TSC2 NF1 ERCC3 APC SDHC SMO SDHB TCF3 AKT1 KEAP1 KIT COL7A1 RNF113A PIK3CA SASH1 SLC45A2 FH MLH1 PIK3R1 IVNS1ABP DMPK ERCC4 GTF2H5 PMS2 CDKN1B STIM1 APC GJC2 LZTS1 DOCK8 HPGD XPC COL1A1 TMC8 CASP10 KIT NTHL1
Protein Mutations 4
D299G P13K V600E V600K
SNP 0
HP:0002104: Apnea
Genes 406
ZIC2 SH3BP2 SNX10 ND4 POGZ NDUFA10 GPR101 NODAL PRNP CTNNB1 FGFR3 NDUFA2 SIX3 SYT1 FGFR3 NDUFS1 DKK1 FGFR3 SYT1 BMP2 RNF125 TSEN54 TRIP13 DISP1 GAS1 FOXH1 TCTN3 BTD MAGEL2 ASCL1 PTF1A TRNL1 CREBBP TNFSF11 HYLS1 CPLANE1 DLL1 AHDC1 SLC25A20 KIAA0586 SIX3 AHDC1 BTD PLPBP MCCC1 NACC1 SCN5A LTBP3 DCTN1 ATP5F1A PRPS1 FOXH1 ATP6 CDON LAMB2 TOE1 TCF4 GNAI3 HERC2 TMEM67 INPP5E LIFR GAS1 FBP1 PWAR1 SOX9 KIF5A TWIST1 TMEM216 TMEM67 SPOP NODAL PEX13 SCN4A VAMP1 TCTN1 SHH FAM149B1 DISP1 MECP2 ECHS1 ND6 RBM10 SCN2A NDUFV1 AIP GLI2 TMEM107 NPAP1 DISP1 TSPYL1 ACADSB PLCB4 SLC18A3 SNORD116-1 SRPX2 FGF8 KCNQ2 TDGF1 KIF7 NPHP1 NDUFA13 LIPT1 GLI2 FGF8 STXBP1 RPGRIP1L CEP41 OPA1 MYO9A IDUA ARMC9 PDHA1 AHI1 IDUA RARS2 SURF1 MECP2 FGFR1 CREBBP NDUFAF2 ARL13B ND1 GNPTAB ABCA3 GABBR2 MKRN3 SCN4A SNORD115-1 WFS1 SRPX2 ATN1 CSPP1 GBA CDON PLCB4 PLAA STAG2 SIX3 CEP104 GNE NGLY1 DST RAI1 TRNV GNAI3 SCN2A RERE PLAA ZIC2 KCNQ2 NDUFS7 NEK1 USP7 FGF8 TMEM231 STAT2 CSPP1 SHH TSPYL1 SURF1 SLC6A9 RET CPLANE1 STAG2 PCGF2 KCNQ3 NODAL SKI BUB1B PTCH1 ZIC2 PRMT7 MTFMT PIBF1 FGFR2 GAS1 PSAP NDUFS3 HMGCL NDUFA11 NDUFAF3 RPS6KA3 HTRA2 NDN NDUFA12 NDUFA9 FLCN TMEM216 CDON TECPR2 NDUFA4 ARL3 SLC6A5 PTCH1 GABBR2 GLI2 MKRN3-AS1 CRYAB EDN1 CCDC47 TCF4 NDUFV2 SLC25A1 MTHFR COQ2 AHI1 ARCN1 FXR1 COX15 PRRT2 NDUFA2 COL13A1 SNRPN DPH1 BUB3 ND3 SMC1A NALCN LARP7 CHAT PCCA SLC18A3 ASCL1 NDUFAF6 PHOX2B TMEM237 GDNF FBN1 TMEM138 TCIRG1 KCNQ2 CDKL5 SLC5A7 SCO2 AMER1 TMEM216 CEP57 NDUFS1 KIAA0753 ZNF423 GPHN CEP41 PIGT DPAGT1 NDUFS2 KIAA0586 NDUFS8 SIM1 BRAT1 CEP120 BRAF D2HGDH P4HTM KATNIP AFF4 LIAS SIX3 SFTPB TDGF1 KAT6B RUNX2 OFD1 USP7 SOD1 KCNQ3 SLC39A8 SLC2A1 HRAS KIAA0586 CTSD B9D1 CDON ADGRG1 TBR1 PDHA1 MAGEL2 CEP290 AHI1 CC2D2A PIBF1 BCHE CHRNE ZIC2 PI4KA FXR1 HSPD1 NONO FOXH1 NDUFAF5 NFIX FGFR3 ECHS1 NDUFS4 SCN8A FGF8 PHOX2B MAGEL2 ACY1 EP300 GLRA1 DNA2 TGIF1 NDUFB8 SDHA NDUFV1 CSPP1 PDE6D TERT ND5 PTCH1 FBP1 FOXRED1 AGRN TDGF1 VPS51 COLQ SNAP25 SHH CC2D2A C2CD3 GLI2 ARMC9 GAS1 INPP5E NDUFS2 SLC19A3 GNE INPP5E TGIF1 NEB MKS1 LIFR TRPV4 SLC5A7 DNA2 SKI NDUFS8 GABRG2 PTCH1 CHAT FOXH1 GBA TMEM237 TGIF1 CLCN7 TECPR2 IPW TCTN2 NGLY1 NEFH BRAT1 TACO1 GLUL ALPL RPGRIP1L PET100 TDGF1 FARS2 TRNW DLL1 SHH RET TGIF1 EP300 RPGRIP1L TRNK CEP120 HSPG2 INPP5E PWRN1 GRIN2A FGFR1 MYO9A TMEM237 BUB1 ND2 FGFR2 CREBBP PCCB NDUFAF2 CEP290 NADK2 NTNG1 CISD2 NODAL MECP2 SYT2 EDN3 DLL1 COQ2 GSN CPT2 DMPK ZC4H2 PEX5 GPR101 COL3A1 PCK1 DLL1 PRPH IDS CEP57 MKS1 UNC80 DISP1
HP:0001392: Abnormality of the liver
Genes 1396
SNX10 RNASEH2A ND4 GALE MMUT PEX5 NDUFS6 LPIN2 GUCY2D RNASEH2C AXIN1 COG4 GNPTAB LIMK1 HLA-DRB1 LIPA SPTB LBR CD247 PDGFRA RHBDF2 SOS2 HBB ABCD3 COX15 TSHR GP1BB ASS1 IRAK4 FANCI SLC30A10 CLEC7A IL2RG EXTL3 SLC25A19 NSD2 SEC24C ZIC3 DAXX POMC NELFA NPHP3 NPC1 TNFSF15 PIGA APOE HJV COG2 TNFRSF1A DHFR PEX11B PEX11B RINT1 BLK ABCG8 ABCG8 LZTR1 NSD2 TRAF3IP1 UNC13D GPC1 GANAB KCNH1 RNU4ATAC TTC21B INPPL1 PIEZO1 GPR35 TMEM67 JAK2 MET PEX10 EIF2AK3 PRF1 GPI RAD51 ERCC4 MYC CTLA4 LBR FCGR2A PRKCD LYST BTD IL21R NEUROD1 MLH3 BMPER GCDH NSD1 GLB1 LTBP3 ATP8B1 UQCRB CYBA LMNA FANCL ERCC6 SF3B1 NDUFA1 PRPS1 CAVIN1 TERC AGL MECP2 TCF4 NAGLU GUSB DLD NAGA PET100 RNU4ATAC PTPN11 IL12RB1 NEK1 PDX1 UGT1A1 PKLR TMEM67 HBA1 LZTFL1 NRAS BCS1L PLPBP MAN2B1 ARSA HJV TREX1 FBP1 SPTA1 HGSNAT SLC2A1 RASGRP1 LYST TKT IDUA XIAP TSFM DNAJC21 WDR19 BICC1 HNF1A LETM1 TTC8 GBA NCF1 WDPCP MCM4 CD70 SOS1 IL2RB PEX19 WRAP53 PIGM ACADM POU1F1 TMEM70 PEX3 UQCRFS1 PEX1 TNFRSF13C PEX13 G6PD AP1B1 HNF4A SBDS ABCC2 RERE CD40LG ICOS PDGFRB UGT1A1 FANCM FASLG DMPK MPV17 FOXP3 MEFV PEX19 COX14 HBA2 TGFBR2 CIITA UBR1 NR1H4 IARS1 PIEZO1 CYTB ENG PLEKHM1 ATAD3A STAT6 FLT1 NEU1 HBB IDUA MSH6 LMNA CAV1 MRPL44 NOP10 PSAP JAG1 TACO1 GBE1 MET GNPTAB MYBPC3 FANCG HYOU1 APC GALM MKS1 POLG BBS2 LACC1 DNAJB11 ACOX1 DYNC2H1 H19-ICR KCNN4 KIF20A NDUFS7 ARHGAP31 MTRR PEX2 RFT1 IL7R RAF1 GPD1 CYP27A1 ETFA HPD PTPN3 ALG8 MST1 PIK3CA TRNV ADAMTSL2 PEX14 TMEM165 TCIRG1 NDUFA6 HNF1A VCP RNASEH2C SP110 RBM8A TIMMDC1 HFE CIDEC BCS1L SDHD CLDN1 CD55 TET2 TTC37 LPL CLDN1 PEPD SC5D MAGT1 RFX5 OFD1 PALB2 PSMB4 SKIV2L SON HMBS TRNW FGFR2 APOB AP3D1 PEX6 MMEL1 IGF2R RRM2B TNFRSF1B REST SC5D CTCF RAC2 CTLA4 TRHR EFL1 CIITA SLC25A13 AP3B1 GPC3 B9D2 KCNQ1 PEX16 AGA PKHD1 NEUROG3 ZAP70 NDUFB11 BBS10 DUOXA2 FOXP3 HNF1B POMC COG5 VIPAS39 PCSK9 SPIB TRMU FANCB ANKS6 XK OSTM1 KRAS HEXB SEC63 SCNN1G POLG INS ACADVL DCTN4 CDKN1C DKC1 TNFRSF13B TBX19 HAVCR2 DGUOK TSHB EPB42 ATP7B BOLA3 PLIN1 LDLRAP1 PRKCD SLC25A4 C1S APC DHCR7 KRAS SFTPC SLC22A5 HSD17B4 LYZ ANK1 VPS33B CASR WDR35 STK11 MAN2B1 CTNNB1 DDRGK1 SPINK1 IL2RG SPTB HFE DYNC2H1 TMEM216 TREX1 CYP27A1 CBS IFT122 ACAT1 NDUFB3 HOXD13 COA3 CD96 WT1 STAT1 MUC5B MRPS7 BBIP1 SMAD4 SLC4A1 HBG1 ABCG8 MED25 CHD7 PEX10 TERT MVK COG1 COG4 HAMP IFT27 LMNA GBA RREB1 CDAN1 NDUFS7 IDUA RAD51C CTSK DLL4 KLF1 SEC23B FUCA1 PDGFRA TBX1 CEP164 FLNC DPAGT1 JAK2 ALG1 NCF4 DYNC2I2 TPI1 RFXAP PEX12 GPIHBP1 GDF2 CASP8 MFN2 PTRH2 MAN2B1 COX20 PEX26 MMUT LRPPRC TRAF3IP2 PEX3 CEP290 RELA FANCD2 PYGL CR2 APPL1 VPS45 RMND1 GALNS RRM2B TRIM32 APC KRT8 RFC2 ABHD5 CTLA4 NCF1 CD3D STEAP3 PMM2 HNF1B IFT172 SMAD4 CLCN7 ND1 SGSH SERPINA1 HBG2 TFAM CDKN2A IL18BP PTRH2 NDUFS3 TRNS1 SPTB CTSA NDUFAF2 IL17F WDPCP TMEM67 LRRC8A CPT2 NAGS BRIP1 FLI1 CLCN7 XRCC4 IGLL1 MPV17 PEX19 PRKCD PEX12 SLC7A7 NCKAP1L ABHD5 HNF1A HLA-DRB1 SLCO2A1 FAH XIAP CEP83 DKC1 TMEM67 PEX14 NDUFAF4 CYBB CD3E EPCAM VHL DGUOK TTC7A BMP2 TNNI3 EOGT ABCB4 PHKA2 CBL NEU1 MYD88 NPM1 ACADL SLC20A2 SMAD4 MMAB POLG2 MTTP RRAS PSAP TMEM216 CASK ACAD9 PTEN CEP290 CPT1A ADA AIRE PHKG2 POLG2 GAA FANCC CARS2 IFIH1 COA8 PSAP TERT DHCR7 PEX1 PEX12 FBP1 SLCO1B1 UBE2T TSC2 ARSB COG6 RASA2 RHAG APOE CC2D2A EPB42 COX10 CPT2 TTC7A INSR BTK LMNA SKI APOA1 GPC3 RPS20 PLAGL1 PALLD NDUFS1 RUNX1 LYRM4 INTU WT1 DYNC2LI1 MKS1 COMT HYMAI NLRP3 PRKCSH TP53 ASAH1 SBDS ACVRL1 MVK MPL PAX8 LRP5 CLCN7 BBS1 RIPK1 PCSK1 STXBP2 NFKB2 KCNQ1OT1 NDUFAF8 PEX2 DCDC2 SLC25A15 ATP11C HADHA PHKA2 CPOX POU2AF1 IL1RN PSAP CCDC28B PEX12 SNX10 RHAG TGFB1 ABCC8 PEX6 HADH FOXF1 TNFRSF13B TRAPPC11 ALDH7A1 PHKG2 GDF2 CLCN7 SP110 HBG2 CC2D2A NDUFAF5 APC2 HAMP FANCA TNFRSF1B CTNS ARSA PMM2 COX15 UGT1A1 PPOX NLRP1 EARS2 PKHD1 CEP290 ACP5 IL12A KRT18 TRIM37 PEX26 EPB41 PEX6 SLC4A1 TRNW HFE IFT140 HNRNPA2B1 ABCA1 DDRGK1 TREX1 RPGRIP1L TRNK EPB41 ATP7A MSH6 INPP5E TALDO1 CYP7B1 FECH SRP54 TINF2 ATP6AP1 SHPK ATP7B PC CPOX ARL6 IDUA BCS1L RMRP NDUFAF1 PEX6 DUOX2 FGFR2 BSCL2 PSTPIP1 SCNN1B TRIM28 AKR1D1 DOCK6 AP1B1 USB1 IGF2 H19-ICR COX4I2 HIRA TNFSF12 PIK3R1 AKR1D1 PHKB IER3IP1 JAM2 F5 TTC21B TFR2 LIG4 IL7R ABCG5 NHLRC2 CTNNB1 SLC25A13 ALDOB RMRP ACADVL CDKN1B LIPA IFNGR1 SDHB PPARG ENG HLA-DRB1 IQCB1 CASP10 GLIS3 CA2 PSAP PEX11B NOTCH2 DPM2 CD81 ACADM SDCCAG8 PRKAR1A FECH DLL4 COX10 ERCC8 USP18 SLCO1B1 PPARG SDHC GBA LIG4 HADHA ALG13 TYMP KMT2E TMEM199 HMGCS2 KCNJ11 MLXIPL ADK NOTCH2 BLVRA SLC37A4 BBS12 PEX5 DYNC2I1 CPLX1 NPHP1 PCK2 ABCC8 NPHP3 LRP5 CYBB KRT18 WDR35 ERCC8 DYNC2I2 KRAS NKX2-5 SLX4 TUFM PEX13 PKD1 XRCC4 TRIP13 GPC3 RPGRIP1L WDR19 JAM3 BBS7 ELN CFTR CEL DIS3L2 SLC29A3 SLC44A1 KLF1 PKD2 NPHP3 TRNL1 IL17RA JMJD1C IARS1 VPS33A UFD1 FADD TNFSF11 DIS3L2 AGA TSHR RAG1 BRCA2 SLC25A20 EIF2AK3 APC GTF2I ABCB11 CNOT1 MCCC1 ALG9 FAN1 KIF3B NDUFA11 APOE G6PC SLC26A4 RAB27A MSH2 TG CYP7B1 EWSR1 ATP6 SPRTN WDR19 TNFSF11 HK1 IGHM LMNA ERCC4 MOGS HNF4A TBX1 CD79A CFTR TMEM67 LHX3 INPP5E MYORG PEX2 ITK MPI CALR NPHP3 MMAA SLC40A1 VPS33A SLC5A5 SCO1 RPGRIP1L BBS9 APC SPECC1L PEX2 TTC37 TET2 BTK SETBP1 SCNN1A IL7R ASL GFM1 CFTR AP1S1 HBB PSMB8 TINF2 CD28 DHDDS FANCE LMNB2 ANTXR1 GPC4 CD19 ND6 CP ARL6 KIT RFX6 CPT1A ALMS1 INVS B3GLCT TRNE CPOX ITCH MPI PEX26 NSMCE2 RBCK1 TWNK IDUA APOC2 NDUFAF3 NDUFS4 SAA1 HBA2 BCHE NPHP1 AP1S1 NBAS ABCB11 SERPINA1 FH RAG2 TMEM107 MRAS CASR PNPLA6 DPM1 IFIH1 ZAP70 ND3 SCYL1 MYRF GNAS GYPC ND1 BRCA2 RFXANK TARS2 DYNC2LI1 ABCB4 LETM1 GBA HBB GATA6 TMEM126B GBA BRCA1 PSMB9 NDUFAF1 PEX3 ATPAF2 ATP7A F5 TSC1 PCCB FAS NHP2 SLC13A5 GALK1 COX6B1 ALDOA ETFDH G6PC3 MS4A1 HBB CD19 TCIRG1 EXTL3 HNF4A GUSB LBR GNE NGLY1 SLC25A19 PCCA RRAS2 DDOST KIT PEX1 NPHP4 RAG1 ALMS1 PDGFB LIPA TRAPPC11 C4B TRAF3IP1 UGT1A1 SPTA1 ASAH1 PEX12 MPL OCLN KRAS ADAMTS13 DCDC2 LMNA MIF SUMF1 CYBC1 ABCA1 POU1F1 SLC11A2 BBS5 FAH STX11 JAK3 PEX6 TMEM67 SPTB SLC2A1 POLR3A IRF5 CA2 MKKS LIPE RAG2 NAB2 ABCB4 HMGCL BTK ERCC6 RNASEH2B ANK1 NEU1 BTNL2 NOP10 ALAS2 CSPP1 CPT2 ND2 CBS PEPD TERT MARS1 SDCCAG8 TCF3 ERCC8 ICOS PRSS2 KCNN4 GCLC ACVRL1 NUBPL LIPE SAMHD1 SLC40A1 TGFB1 STN1 IGF2 KPTN ADA AUH TPP2 CCDC47 KLF11 FARSB UCP2 GPC4 IL36RN PKD1 PEX14 TNFSF12 RPGRIP1 SURF1 C1QBP RASGRP1 PEX16 CLPB HPGD ATP6AP2 FERMT3 SDHA RBPJ ND3 DCLRE1C PEX1 TRMT5 TRMU MLH1 GLB1 LCAT AGPAT2 BTNL2 TRNN GNMT B2M MRPL3 PSAP TNNT2 DNAJC21 FOS HSD3B7 COG7 CAV1 PCCA SLCO1B3 IFT80 CTSC USP9X SFTPA2 AKT2 ABCA1 CYP7A1 SDHA TNFRSF13C JAK1 HMBS SLC4A1 CAVIN1 GANAB SCARB2 GBA PARS2 RNF43 BSCL2 TCIRG1 KCNN3 SETD2 NDUFV1 PNPLA2 CYP19A1 ATP6V1B2 HMOX1 PKLR C11ORF95 IFT172 IFT140 TJP2 BMPR1A ARVCF NFKB1 PMS1 PEX16 ALDOB CLIP2 C8ORF37 MSH2 PYGL MKS1 RHAG PIGS FANCF KCNJ11 JAK2 ATRX CIDEC RECQL4 NCF2 PRKCSH CD28 LARS1 CASR BAZ1B FUCA1 HNRNPA1 CPA1 SLC25A20 NDUFS2 KRIT1 ADAR WHCR LHX4 ATP8B1 ATP8B1 JAK2 SLC25A1 FASLG HBA1 PEX26 WDR19 GATA2 ETFB IL6 STOX1 ICOS ARSA TMEM231 LDLR XRCC2 DNASE1L3 TET2 CLCA4 STX1A AGGF1 HESX1 MRPS28 ARG1 PLEKHM1 POU6F2 SLC39A8 IFT172 TKFC TALDO1 IL17RC SAR1B ASXL1 TRIM28 TCTN2 CD79B NHP2 AMACR ALG2 FBN1 SLC25A13 INSR NRAS NPC2 GALT POLD1 PKD2 BLNK CORIN RAG2 NDUFS8 PFKM NLRP3 FOXRED1 AHCY CEP290 SLC22A5 DOLK SMPD1 IFT80 HADHB SLC4A1 STEAP3 PARN PAX4 NDUFB10 PEX13 NDUFS4 PRSS1 TP53 PIK3C2A COX8A NAGA HBB GABRD GBA DNAJC19 APC BRCA1 KCNAB2 SNX14 ACOX1 NOTCH1 H19 TRIM37 AMACR UROD ABCC2 ND5 NCF2 CR2 TNPO3 SRP54 SCYL1 RFXANK PEX16 IL2RA POLG2 IL2RG HADH ERCC6 CYBC1 SMPD1 FGA HSD3B7 SLC30A10 CC2D2A TREX1 WDR35 SLC25A13 PRKAR1A TMPRSS6 SRSF2 NPHP3 RIT1 SH2D1A PEX3 GATA6 GLRX5 PIK3CA CCDC115 PROP1 HNF4A CTC1 GNE FAS ACAD9 RNASEH2A CD27 DYNC2I1 NDUFV2 TBX1 RFX5 DCLRE1C BSCL2 MPC1 BBS1 PALB2 GTF2IRD1 PEX14 SLC25A15 FADD APOA1 IYD AKT2 COG6 TERC CBL SLC39A4 AGPAT2 NOD2 SLC29A3 ADA2 PLIN1 BCS1L GBA CC2D2A BSCL2 IFT43 SOX10 ESCO2 SPOP SEMA4A PEX1 SLC37A4 RPGRIP1L VPS13A NGLY1 TF CYBA MAD2L2 NHP2 FAS SEC63 COG8 FDX2 TNFRSF11A CDIN1 SLCO1B3 RFWD3 DZIP1L CCND1 ERCC8 PEX19 XPR1 FAM111B RTEL1 PEX3 CTRC PEX5 TPO KRT8 TERC MYPN CTBP1 MLH1 IFNG ITCH YARS2 PNPLA2 BRCA2 ERCC4 TGFB1 BBS4 FGFRL1 RFXAP SUMF1 ERCC1 GCGR RAG1 SMPD1 ND2 POLG TBX19 UROS ALG8 ELN HADHA PCCB CEP19 A2ML1 SETBP1 TET2 BPGM PEX10 PAX8 MMUT MVK TERT PTPRC SLC17A5 NEK8 CEP120 ALG9 ARSA TBL2 ERCC6 STK11 SLC7A7 NDUFB9 LONP1 RFT1 WT1 ERBB3 SKIV2L PDGFRL CEP55 KCNH1 CPT2 DMPK PEX10 UGT1A1 PEX5 XYLT1 DLD NSMCE2 HMGCL GLB1 PMS2 COA8 PCK1 DNAJC19 B9D1 PGM1 GALT PPARG CASP10 PRDM16 IDS RNU4ATAC EFL1 GCK GNS GBA
HP:0001903: Anemia
Genes 775
DKC1 RPS19 SNX10 NDUFA10 LPIN2 COL7A1 PGM3 PUS1 GATA1 SPTB TERC NTRK1 HBB ABCD3 ZBTB24 FANCI FANCC TARS1 SEC61A1 TGFB1 DAXX STING1 HBB DHFR TINF2 SMARCD2 THRA DBH UNC13D MPIG6B PLEC HELLS PIEZO1 OCRL JAK2 GTF2E2 PTF1A PRF1 GPI RAD51 HBA1 RPS27 STAT5B ERCC4 HPRT1 RMRP PRKCD GSS LYST CUBN FANCG FANCL SF3B1 RPS14 TNFRSF4 GNA14 CAT HBA2 PET100 ITGB3 PKLR HBA1 NRAS MECOM TRNH SPTA1 SLC46A1 CD59 SLC2A1 RASGRP1 LYST XIAP RPL15 IGH DNAJC21 RPS28 RTEL1 RPS15A IL2RB WRAP53 GATB UQCRFS1 NDUFV1 TNFRSF13C DDX41 G6PD RPL26 SBDS GATA1 CD40LG RPS27 IFNG FANCM FASLG CFHR3 TNFAIP3 FOXP3 COX14 HBA2 ALAD NDUFA13 PIEZO1 KRT14 ENG PLEKHM1 COQ2 HBB RPS15A SPTA1 HBA2 NOP10 SURF1 TACO1 SLX4 COL4A1 PHF21A FANCG HYOU1 TBXAS1 HBB ND5 RPS19 KCNN4 CFB ZBTB20 MTRR PGM3 KCNQ1 IL7R NT5C3A SMAD4 MUC1 PRKACG RPL27 PRDX1 TOR1A PHGDH SFXN4 HBD TCIRG1 RBM8A SLC4A1 ITGA2B CD55 TET2 BMPR1A PEPD NPHP4 RFX5 STAT2 PALB2 PSMB4 LYRM7 SURF1 LAT TRNW FTCD ABCD4 RRM2B SLC25A21 CTLA4 MTFMT EFL1 FMO3 CIITA NDUFAF3 GATA1 PCNT TRNF CFHR1 FOXP3 TBXAS1 FANCB DNM1L OSTM1 HBB TSR2 POLG UMPS RPL26 GSS DKC1 TRNT1 NDUFV2 NSUN2 TERT EPB42 ATP7B PRKCD STIM1 STIM1 UMPS CTC1 KRAS ANK1 CASR NHEJ1 LIG4 STK11 AK2 TBCE SPTB CD3G LCAT COA3 RPL5 STAT1 SMAD4 SLC4A1 HBG1 ABCG8 HPRT1 CHD7 TERT GBA CDAN1 RAD51C CTSK MLX KLF1 CLPX UBE2T SEC23B PDGFRA SAMD9L LRBA FERMT1 TPI1 RFXAP GDF2 AMMECR1 LAMC2 COX20 MMUT BRCA1 FANCD2 VPS45 IDH2 TRNQ EPO KIF15 STEAP3 CLCN7 WAS PNPO HBG2 RPS7 HAVCR2 SPP1 TRNS1 SPTB TMEM67 FAM111A BRIP1 FLI1 ERCC3 PRKCD RPL35 SLC7A7 SLCO2A1 CD46 DKC1 PGK1 ABCB6 BCOR TTC7A NDUFAF5 RARA BCL10 PTH1R FARS2 ND1 NDUFS4 MYD88 NPM1 BMPR1A SMAD4 ATRX MMAB MTTP CASK SLC12A3 ADA AIRE UBR1 NDUFB8 SDHA FANCC WFS1 COA8 PSAP TERT IKZF1 UBE2T FAM111A CAD CLCNKB MMP1 RPL27 RHAG EPB42 COX10 TTC7A STIM1 APOA1 STAT3 RUNX1 GATA1 HBA2 RPS24 ACTN4 WT1 NDUFS2 RPL35 RPS17 NLRP3 ASAH1 SBDS GLA ACVRL1 MVK CLCN7 RIPK1 LAMB3 ANK1 REN NFKB2 ATP11C PHKA2 CPOX PHGDH SLC40A1 SNX10 RHAG TGFB1 HBG1 LAMB3 TNFRSF13B PHKG2 CLCN7 LARS2 SP110 HBG2 HAMP XRCC4 FANCA PIGT PPOX NLRP1 PNP ALPL PET100 ACP5 TERT TFRC RPL31 SRD5A3 EPB41 IDH1 RPS26 SLC4A1 RPL18 HBB-LCR PRKAR1A ABCA1 EPB41 TALDO1 FECH DNMT3B IRF2BP2 SPTA1 SRP54 TINF2 SMAD4 SHPK ATP7B CPOX GP1BA GSR RMRP WAS PFKM PSTPIP1 CISD2 COL7A1 USB1 MEFV ELMO2 COX4I2 TNFSF12 TFR2 LIG4 PGK1 GATC NHLRC2 RMRP LIPA IFNGR1 SDHB CTLA4 ENG HLA-DRB1 CASP10 COL7A1 F8 CA2 TRNL1 CD81 NABP1 NUMA1 ALX4 FECH COL7A1 FANCB YARS2 FCGR2B SDHC GBA TYMP LAMA3 AGXT TF HBA1 BMPR1A PTEN MTRR GATA1 SLX4 BIRC3 NPHP4 KMT2D MDM4 ITGB4 SMARCAL1 PRF1 ETV6 EPHB4 KLF1 KIF1B TRNT1 VPS33A TNFSF11 RAG1 COX2 HBB RPS17 MAD2L2 UROD APC ACAD8 EWSR1 TNFSF11 HK1 ERCC4 PUS1 GATA1 FIP1L1 ITK NPHP1 CALR MMAA HBB VPS33A GPX1 SCO1 TET2 RPS29 ISCU TCN2 GLA NBN HBB ALAS2 RPL35A PSMB8 TINF2 FANCE FCGR2A HBB UROS SPTA1 CP HLA-B KIT HBA1 SMARCAL1 ATRX HBA2 TEK RAG1 LIPT1 SLC19A2 TRNS2 DNASE1 TRNS1 RAG2 RPL11 PARN CLCN7 ZAP70 GYPC RECQL4 OPA1 LAMA3 HBB WFS1 ND4 GBA SLC19A2 PSMB9 FAS AASS COX6B1 ALDOA ORAI1 G6PC3 MS4A1 HBB ELANE CD19 TCIRG1 CP COX1 LMBRD1 SAMD9 KIT MMACHC RAG1 FOXP1 FANCD2 SPTA1 TBL1XR1 NDUFS7 MPL HELLPAR ADAMTS13 THBD CYBC1 NPHP1 SLC11A2 STX11 IRAK1 SPTB SLC2A1 RPS7 ADAR CA2 RAG2 NDUFS3 HMGCL MYSM1 IRX5 SARS2 BTK SLC4A1 RPS24 ANK1 FANCL BTNL2 NDUFA12 PLEC NDUFA9 ALAS2 RPS29 KIF23 TET2 MARS1 PIGA RPL11 NDUFA4 KCNN4 GCLC ACVRL1 RPL15 ADA TPP2 FARSB LPIN2 C3 TNFSF12 RASGRP1 COX15 PTPN22 NDUFA2 RPS26 GREM1 HPGD FERMT3 SDHA DCLRE1C ZBTB16 CFH TRNN PNPO CCND1 DNAJC21 GATA1 PCCA ABCA1 NDUFAF6 RPL5 ADA2 SLC4A1 SLC25A10 SCARB2 HLA-B TCIRG1 COL7A1 STAT4 SCO2 HMOX1 PKLR IFT140 NDUFS1 NFKB1 GALNT2 RHAG NDUFS2 FANCF ATRX NDUFS8 LARS1 CFH TP53 FASLG HBA1 ICOS CDCA7 ERCC6L2 LAMC2 XRCC2 TET2 AGGF1 ATRX PLEKHM1 ABCB7 TKFC TALDO1 ASXL1 KCNE1 KDM6A AK1 NHP2 PDHA1 SLC25A13 SRD5A3 MTHFD1 MYSM1 RAG2 TSR2 PFKM NLRP3 ABCB7 MPLKIP COX3 RPL35A EXT2 QRSL1 NLRC4 SLC4A1 STEAP3 PARN ECHS1 COG1 COX8A FANCF HBB TMPRSS6 GBA DNAJC19 DGKE BRCA1 FOXRED1 CR2 COL17A1 SRP54 RFXANK IL2RA MPL IL2RG STAT3 PLA2G4A PNP SRSF2 RPS10 SH2D1A WIPF1 GLRX5 F2 MTR CTC1 SLC19A3 FAS ATRX DCLRE1C RPS14 GCLC CFI PACS2 TET2 BMPR1A CBLIF ERCC2 TERC CBL MMADHC SAMD9L NOD2 SLC29A3 IREB2 ADA2 SLC25A38 ITGB4 GBA MALT1 TF HSPA9 MAD2L2 SBDS