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SNPMiner SNPMiner Trials (Home Page)


Report for Mutation P4503A

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 12 clinical trials

Clinical Trials


1 A Phase 2a, Randomized, Double-Blind, Placebo- and Active-Controlled, Parallel-Group, Multicenter Study to Assess the Safety and Efficacy of ADL5859 100 mg BID in Subjects With Neuropathic Pain Associated With Diabetic Peripheral Neuropathy

The purpose of this study is to evaluate the effectiveness of ADL5859 in relieving the pain associated with diabetic peripheral neuropathy (DPN) compared with placebo and duloxetine (a marketed drug approved for the treatment of painful DPN). The pain symptoms of DPN are thought to be due to damage to nerves caused by the diabetes.

NCT00603265
Conditions
  1. Peripheral Neuropathy
  2. Neuropathic Pain
Interventions
  1. Drug: ADL5859
  2. Drug: Duloxetine
  3. Drug: Placebo
MeSH:Peripheral Nervous Peripheral Nervous System Diseases Neuralgia
HPO:Abnormal peripheral nervous system morphology Peripheral neuropathy Polyneuropathy

Change from baseline = NPRS at baseline - NPRS at Weeks 1, 2, 3, and 4.. Inclusion Criteria: - Male and female participants between 18 and 75 years of age, inclusive - Body weight of at least 45 kilograms (kg) - Diabetes mellitus (type I or II) that is documented to be under stable glycemic control over a period of at least 3 months, as indicated by a glycosylated hemoglobin (HbgAIC) of less than or equal to 12% and a stable dose of insulin or oral diabetic medication for 90 days prior to starting study medication - No change in diabetic medications is planned for the duration of the study - Evidence of symmetrical, bilateral pain in the lower extremities due to diabetic peripheral neuropathy (DPN) - Presence of daily pain due to DPN for at least 3 months - Score greater than or equal to 3 on the physical examination portion of the Michigan Neuropathy Screening Instrument (MNSI) - Average weekly pain score of greater than or equal to 4 on the numeric pain rating scale (NPRS) for symmetrical neuropathic pain in the feet and legs - For male participants, be surgically sterile or agree to use an appropriate method of contraception - For female participants of childbearing potential, be surgically sterile or using an intrauterine device, or injectable, transdermal, or combination oral contraceptive deemed highly effective by the Food and Drug Administration (FDA) - Be willing and able to comply with the protocol requirements - Be able to understand and willing to provide written informed consent in English Exclusion Criteria: - Presence of pain conditions that cannot be distinguished from DPN - Presence of significant renal disease, as indicated by a serum creatinine greater than or equal to 2.0 milligrams per deciliter (mg/dL), or presence of significant hepatic disease - Have a history of a seizure disorder - Presence of serious or unstable cardiovascular disease, respiratory disease, hematologic illness, or a psychiatric condition - History of evidence of symptomatic orthostatic hypotension - History of a major depressive disorder, generalized anxiety disorder, eating disorder, or substance abuse (including alcohol) within the past year - History or evidence of mania, bipolar disorder, or psychosis - History of allergy to acetaminophen or duloxetine - Score of greater than or equal to 18 on the Beck Depression Inventory II (BDI-II) or score of greater than zero on Item 9 of the BDI-II - Use of any of the following concomitant medications: fluvoxamine; quinolone antimicrobials (ciprofloxacin and enoxacin); selective serotonin reuptake inhibitors (SSRIs); serotonin norepinephrine reuptake inhibitors (SNRIs); tricyclic antidepressants; opioids; nonsteroidal anti-inflammatory drugs (NSAIDS); anticonvulsants; aspirin (with the exception of low-dose aspirin as cardiovascular prophylaxis); or cytochrome P4503A (CYP3A) and P-glycoprotein transporter inhibitors - Pregnant, lactating, or plans to become pregnant during the study - Presence of foot or toe amputation - Participation in another study with an investigational compound within the previous 30 days prior to study medication administration, or concurrent participation in another clinical study Inclusion Criteria: - Male and female participants between 18 and 75 years of age, inclusive - Body weight of at least 45 kilograms (kg) - Diabetes mellitus (type I or II) that is documented to be under stable glycemic control over a period of at least 3 months, as indicated by a glycosylated hemoglobin (HbgAIC) of less than or equal to 12% and a stable dose of insulin or oral diabetic medication for 90 days prior to starting study medication - No change in diabetic medications is planned for the duration of the study - Evidence of symmetrical, bilateral pain in the lower extremities due to diabetic peripheral neuropathy (DPN) - Presence of daily pain due to DPN for at least 3 months - Score greater than or equal to 3 on the physical examination portion of the Michigan Neuropathy Screening Instrument (MNSI) - Average weekly pain score of greater than or equal to 4 on the numeric pain rating scale (NPRS) for symmetrical neuropathic pain in the feet and legs - For male participants, be surgically sterile or agree to use an appropriate method of contraception - For female participants of childbearing potential, be surgically sterile or using an intrauterine device, or injectable, transdermal, or combination oral contraceptive deemed highly effective by the Food and Drug Administration (FDA) - Be willing and able to comply with the protocol requirements - Be able to understand and willing to provide written informed consent in English Exclusion Criteria: - Presence of pain conditions that cannot be distinguished from DPN - Presence of significant renal disease, as indicated by a serum creatinine greater than or equal to 2.0 milligrams per deciliter (mg/dL), or presence of significant hepatic disease - Have a history of a seizure disorder - Presence of serious or unstable cardiovascular disease, respiratory disease, hematologic illness, or a psychiatric condition - History of evidence of symptomatic orthostatic hypotension - History of a major depressive disorder, generalized anxiety disorder, eating disorder, or substance abuse (including alcohol) within the past year - History or evidence of mania, bipolar disorder, or psychosis - History of allergy to acetaminophen or duloxetine - Score of greater than or equal to 18 on the Beck Depression Inventory II (BDI-II) or score of greater than zero on Item 9 of the BDI-II - Use of any of the following concomitant medications: fluvoxamine; quinolone antimicrobials (ciprofloxacin and enoxacin); selective serotonin reuptake inhibitors (SSRIs); serotonin norepinephrine reuptake inhibitors (SNRIs); tricyclic antidepressants; opioids; nonsteroidal anti-inflammatory drugs (NSAIDS); anticonvulsants; aspirin (with the exception of low-dose aspirin as cardiovascular prophylaxis); or cytochrome P4503A (CYP3A) and P-glycoprotein transporter inhibitors - Pregnant, lactating, or plans to become pregnant during the study - Presence of foot or toe amputation - Participation in another study with an investigational compound within the previous 30 days prior to study medication administration, or concurrent participation in another clinical study Peripheral Neuropathy Neuropathic Pain Peripheral Nervous Peripheral Nervous System Diseases Neuralgia Participants were permitted to take acetaminophen 650 to 975 mg every 4 to 6 hours (up to a total of 4 grams in 24 hours) as needed for pain relief. --- P4503A ---

Change from baseline = NPRS at baseline - NPRS at Weeks 1, 2, 3, and 4.. Inclusion Criteria: - Male and female participants between 18 and 75 years of age, inclusive - Body weight of at least 45 kilograms (kg) - Diabetes mellitus (type I or II) that is documented to be under stable glycemic control over a period of at least 3 months, as indicated by a glycosylated hemoglobin (HbgAIC) of less than or equal to 12% and a stable dose of insulin or oral diabetic medication for 90 days prior to starting study medication - No change in diabetic medications is planned for the duration of the study - Evidence of symmetrical, bilateral pain in the lower extremities due to diabetic peripheral neuropathy (DPN) - Presence of daily pain due to DPN for at least 3 months - Score greater than or equal to 3 on the physical examination portion of the Michigan Neuropathy Screening Instrument (MNSI) - Average weekly pain score of greater than or equal to 4 on the numeric pain rating scale (NPRS) for symmetrical neuropathic pain in the feet and legs - For male participants, be surgically sterile or agree to use an appropriate method of contraception - For female participants of childbearing potential, be surgically sterile or using an intrauterine device, or injectable, transdermal, or combination oral contraceptive deemed highly effective by the Food and Drug Administration (FDA) - Be willing and able to comply with the protocol requirements - Be able to understand and willing to provide written informed consent in English Exclusion Criteria: - Presence of pain conditions that cannot be distinguished from DPN - Presence of significant renal disease, as indicated by a serum creatinine greater than or equal to 2.0 milligrams per deciliter (mg/dL), or presence of significant hepatic disease - Have a history of a seizure disorder - Presence of serious or unstable cardiovascular disease, respiratory disease, hematologic illness, or a psychiatric condition - History of evidence of symptomatic orthostatic hypotension - History of a major depressive disorder, generalized anxiety disorder, eating disorder, or substance abuse (including alcohol) within the past year - History or evidence of mania, bipolar disorder, or psychosis - History of allergy to acetaminophen or duloxetine - Score of greater than or equal to 18 on the Beck Depression Inventory II (BDI-II) or score of greater than zero on Item 9 of the BDI-II - Use of any of the following concomitant medications: fluvoxamine; quinolone antimicrobials (ciprofloxacin and enoxacin); selective serotonin reuptake inhibitors (SSRIs); serotonin norepinephrine reuptake inhibitors (SNRIs); tricyclic antidepressants; opioids; nonsteroidal anti-inflammatory drugs (NSAIDS); anticonvulsants; aspirin (with the exception of low-dose aspirin as cardiovascular prophylaxis); or cytochrome P4503A (CYP3A) and P-glycoprotein transporter inhibitors - Pregnant, lactating, or plans to become pregnant during the study - Presence of foot or toe amputation - Participation in another study with an investigational compound within the previous 30 days prior to study medication administration, or concurrent participation in another clinical study Inclusion Criteria: - Male and female participants between 18 and 75 years of age, inclusive - Body weight of at least 45 kilograms (kg) - Diabetes mellitus (type I or II) that is documented to be under stable glycemic control over a period of at least 3 months, as indicated by a glycosylated hemoglobin (HbgAIC) of less than or equal to 12% and a stable dose of insulin or oral diabetic medication for 90 days prior to starting study medication - No change in diabetic medications is planned for the duration of the study - Evidence of symmetrical, bilateral pain in the lower extremities due to diabetic peripheral neuropathy (DPN) - Presence of daily pain due to DPN for at least 3 months - Score greater than or equal to 3 on the physical examination portion of the Michigan Neuropathy Screening Instrument (MNSI) - Average weekly pain score of greater than or equal to 4 on the numeric pain rating scale (NPRS) for symmetrical neuropathic pain in the feet and legs - For male participants, be surgically sterile or agree to use an appropriate method of contraception - For female participants of childbearing potential, be surgically sterile or using an intrauterine device, or injectable, transdermal, or combination oral contraceptive deemed highly effective by the Food and Drug Administration (FDA) - Be willing and able to comply with the protocol requirements - Be able to understand and willing to provide written informed consent in English Exclusion Criteria: - Presence of pain conditions that cannot be distinguished from DPN - Presence of significant renal disease, as indicated by a serum creatinine greater than or equal to 2.0 milligrams per deciliter (mg/dL), or presence of significant hepatic disease - Have a history of a seizure disorder - Presence of serious or unstable cardiovascular disease, respiratory disease, hematologic illness, or a psychiatric condition - History of evidence of symptomatic orthostatic hypotension - History of a major depressive disorder, generalized anxiety disorder, eating disorder, or substance abuse (including alcohol) within the past year - History or evidence of mania, bipolar disorder, or psychosis - History of allergy to acetaminophen or duloxetine - Score of greater than or equal to 18 on the Beck Depression Inventory II (BDI-II) or score of greater than zero on Item 9 of the BDI-II - Use of any of the following concomitant medications: fluvoxamine; quinolone antimicrobials (ciprofloxacin and enoxacin); selective serotonin reuptake inhibitors (SSRIs); serotonin norepinephrine reuptake inhibitors (SNRIs); tricyclic antidepressants; opioids; nonsteroidal anti-inflammatory drugs (NSAIDS); anticonvulsants; aspirin (with the exception of low-dose aspirin as cardiovascular prophylaxis); or cytochrome P4503A (CYP3A) and P-glycoprotein transporter inhibitors - Pregnant, lactating, or plans to become pregnant during the study - Presence of foot or toe amputation - Participation in another study with an investigational compound within the previous 30 days prior to study medication administration, or concurrent participation in another clinical study Peripheral Neuropathy Neuropathic Pain Peripheral Nervous Peripheral Nervous System Diseases Neuralgia Participants were permitted to take acetaminophen 650 to 975 mg every 4 to 6 hours (up to a total of 4 grams in 24 hours) as needed for pain relief. --- P4503A --- --- P4503A ---

Primary Outcomes

Description: The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. The mean of the daily average scores were calculated from the NPRS pain assessments obtained up to 3 times per day over a 7-day period. Least Squares (LS) means were calculated using analysis of covariance (ANCOVA) with treatment group as a main factor and baseline NPRS score as a covariate. Change from Baseline = NPRS at baseline - NPRS at Week 4; a positive number in the LS mean indicates a reduction in pain intensity from baseline.

Measure: Change From Baseline in Mean Numeric Pain Rating Scale (NPRS) Score

Time: Baseline, Week 4

Secondary Outcomes

Description: A responder was defined as a participant who showed a reduction in average pain (as measured by NPRS) of at least 30% from baseline to Week 4. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. The percentage of participants who qualified as responders is presented per treatment arm.

Measure: Percentage of Responders

Time: Baseline, Week 4

Description: PGIC is a participant-rated instrument that measures the change in the participant's overall status for the previous 2 weeks based on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). The number of participants in each category is presented.

Measure: Patient Global Impression of Change (PGIC)

Time: Week 4

Description: Sleep Interference was assessed on an 11-point Numeric Rating Scale where a score of 0 indicated "pain did not interfere with sleep" and a score of 10 indicated "pain completely interfered with sleep". Here, "n" signifies "Number of participants" for Baseline and Month 3 telephone interview whereas "n" signifies "number of observations" for Month 1, 2, and 3 because a participant could have had multiple visits during Month 1, 2, and 3 as this was a non-interventional study with no scheduled study visits, except Baseline visit and the Month 3 telephone interview. LS means were calculated using ANCOVA with treatment group as a main factor and baseline SIS score as a covariate. Change from baseline = SIS score at baseline - SIS score at Week 4.

Measure: Change in Sleep Interference Scale (SIS) From Baseline

Time: Baseline, Week 4

Description: At each of the evening pain assessments, participants assessed their overall pain intensity over the preceding 24 hours using NPRS. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. The mean of the daily average scores were calculated from the NPRS pain assessments obtained at Baseline and Week 4. Change from baseline = NPRS at baseline - NPRS at Week 4.

Measure: Change From Baseline in the Evening Assessment of the 24-hour Overall Mean Pain Intensity Score

Time: Baseline, Week 4

Description: The mean of the daily average scores were calculated from the NPRS pain assessments obtained 1 time per week over a 4-week period. NPRS assessments were taken while the participant was at rest. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. LS means were calculated using ANCOVA with treatment group as a main factor and baseline NPRS score as a covariate. Change from baseline = NPRS at baseline - NPRS at Weeks 1, 2, 3, and 4.

Measure: Change From Baseline in NPRS at Rest in the Clinic

Time: Baseline, Week 1, Week 2, Week 3, Week 4

Description: The mean of the daily average scores were calculated from the NPRS pain assessments obtained 1 time per week over a 4-week period. NPRS assessments were taken after the participant walked 50 feet in the clinic. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. LS means were calculated using ANCOVA with treatment group as a main factor and baseline NPRS score as a covariate. Change from baseline = NPRS at baseline - NPRS at Weeks 1, 2, 3, and 4.

Measure: Change From Baseline in NPRS After Walking 50 Feet in the Clinic

Time: Baseline, Week 1, Week 2, Week 3, Week 4

2 Phase I Study Of Vincristine, Doxorubicin, And Dexamethasone (VXD) Plus Ixazomib In Adults With Relapsed Or Refractory Acute Lymphoblastic Leukemia/Lymphoma, Lymphoblastic Lymphoma Or Mixed Phenotype Acute Leukemia

This is a phase I study of vincristine, doxorubicin and dexamethasone (modified VXD) plus MLN9708 in adults with relapsed or refractory acute lymphoblastic leukemia/lymphoma, lymphoblastic lymphoma or mixed phenotype acute leukemia.

NCT01887587
Conditions
  1. Relapsed or Refractory Acute Lymphoblastic Leukemia
  2. Relapsed or Refractory Lymphoblastic Lymphoma
  3. Mixed Phenotype Acute Leukemia
Interventions
  1. Drug: MLN9708
  2. Drug: Vincristine
  3. Drug: Doxorubicin
  4. Drug: Dexamethasone
MeSH:Lymphoma Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Lymphoma, Non-Hodgkin Acute Disease
HPO:Leukemia Lymphoid leukemia Lymphoma Non-Hodgkin lymphoma

- Systemic treatment, within 7 days before study enrollment, with strong inhibitors of cytochrome P450 1A2 (CYP1A2) (e.g., fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of cytochrome P4503A (CYP3A) (e.g., clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort. --- P4503A ---

Primary Outcomes

Description: Safety, tolerability will be assessed by counting the number of participants experiencing adverse events at 8 weeks post treatment.

Measure: Adverse Events.

Time: Baseline to 30 days post treatment; approximately 8 weeks

Description: This measure will be the maximum tolerated dose (MTD) at which no more than 1 Dose Limiting Toxicity (DLT) is observed. The starting dose of MLN9708 will be 2.3 mg orally on days 1, 8 and 15. If no DLT is seen in the first 3 patients, the dose will be increased to 3 mg and then to 4 mg orally on days 1, 8 and 15 in a classic 3 +3 phase I design. We will not attempt to increase the dose beyond 4 mg orally which, if achieved with acceptable toxicity, would be accepted as the recommended phase 2 dose (RP2D). 0 of 3 DLTs would allow escalation to the next dose level. 1 of 3 DLTs will require expanding to six patients; 1 of 6 DLTs will allow escalation again. 2 DLTs will require dose de-escalation.

Measure: Optimal Dose of MLN9708

Time: 8 Weeks

3 Randomized, Multicenter, Phase III, Open-Label Study of Alectinib Versus Crizotinib in Treatment-Naive Anaplastic Lymphoma Kinase-Positive Advanced Non-Small Cell Lung Cancer

This randomized, active controlled, multicenter phase III open-label study is designed to evaluate the efficacy and safety of alectinib compared with crizotinib treatment in participants with treatment-naive anaplastic lymphoma kinase-positive (ALK-positive) advanced non-small cell lung cancer (NSCLC). Participants will be randomized in a 1:1 ratio to receive either alectinib, 600 milligrams (mg) orally twice daily (BID), or crizotinib, 250 mg orally BID. Participants will receive treatment until disease progression, unacceptable toxicity, consent withdrawal or death. The study is expected to last approximately 84 months.

NCT02075840
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Alectinib
  2. Drug: Crizotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A higher score on the global health and functioning subscales is indicative of better functioning.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive as assessed by the Ventana immunohistochemistry (IHC) test - Life expectancy of at least 12 weeks - Eastern cooperative oncology group performance status (ECOG PS) of 0-2 - Participants with no prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC - Adequate renal, and hematologic function - Participants must have recovered from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment - Measurable disease by response evaluation criteria in solid tumors (RECIST) version 1.1 (v1.1) prior to the administration of study treatment - Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed incidentally at study baseline) - Negative pregnancy test for all females of child bearing potential - Use of highly effective contraception as defined by the study protocol Exclusion Criteria: - Participants with a previous malignancy within the past 3 years - Any gastrointestinal (GI) disorder or liver disease - National cancer institute common terminology criteria for adverse events (NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy (e.g., radiotherapy) (excluding alopecia) - History of organ transplant - Co-administration of anti-cancer therapies other than those administered in this study - Participants with baseline QTc greater than (>) 470 milliseconds or symptomatic bradycardia - Recipient of strong/potent cytochrome P4503A inhibitors or inducers within 14 days prior to the first dose until the end of study treatment - Recipient of any drug with potential QT interval prolonging effects within 14 days prior to the first dose for all participants and while on treatment through the end of the study for crizotinib-treated participants only - History of hypersensitivity to any of the additives in the alectinib and crizotinib drug formulation - Pregnancy or lactation - Any clinically significant disease or condition (or history of) that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the principal investigator, pose an unacceptable risk to the participant in this study - Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the participant before trial entry Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive as assessed by the Ventana immunohistochemistry (IHC) test - Life expectancy of at least 12 weeks - Eastern cooperative oncology group performance status (ECOG PS) of 0-2 - Participants with no prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC - Adequate renal, and hematologic function - Participants must have recovered from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment - Measurable disease by response evaluation criteria in solid tumors (RECIST) version 1.1 (v1.1) prior to the administration of study treatment - Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed incidentally at study baseline) - Negative pregnancy test for all females of child bearing potential - Use of highly effective contraception as defined by the study protocol Exclusion Criteria: - Participants with a previous malignancy within the past 3 years - Any gastrointestinal (GI) disorder or liver disease - National cancer institute common terminology criteria for adverse events (NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy (e.g., radiotherapy) (excluding alopecia) - History of organ transplant - Co-administration of anti-cancer therapies other than those administered in this study - Participants with baseline QTc greater than (>) 470 milliseconds or symptomatic bradycardia - Recipient of strong/potent cytochrome P4503A inhibitors or inducers within 14 days prior to the first dose until the end of study treatment - Recipient of any drug with potential QT interval prolonging effects within 14 days prior to the first dose for all participants and while on treatment through the end of the study for crizotinib-treated participants only - History of hypersensitivity to any of the additives in the alectinib and crizotinib drug formulation - Pregnancy or lactation - Any clinically significant disease or condition (or history of) that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the principal investigator, pose an unacceptable risk to the participant in this study - Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the participant before trial entry Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- P4503A ---

A higher score on the global health and functioning subscales is indicative of better functioning.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive as assessed by the Ventana immunohistochemistry (IHC) test - Life expectancy of at least 12 weeks - Eastern cooperative oncology group performance status (ECOG PS) of 0-2 - Participants with no prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC - Adequate renal, and hematologic function - Participants must have recovered from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment - Measurable disease by response evaluation criteria in solid tumors (RECIST) version 1.1 (v1.1) prior to the administration of study treatment - Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed incidentally at study baseline) - Negative pregnancy test for all females of child bearing potential - Use of highly effective contraception as defined by the study protocol Exclusion Criteria: - Participants with a previous malignancy within the past 3 years - Any gastrointestinal (GI) disorder or liver disease - National cancer institute common terminology criteria for adverse events (NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy (e.g., radiotherapy) (excluding alopecia) - History of organ transplant - Co-administration of anti-cancer therapies other than those administered in this study - Participants with baseline QTc greater than (>) 470 milliseconds or symptomatic bradycardia - Recipient of strong/potent cytochrome P4503A inhibitors or inducers within 14 days prior to the first dose until the end of study treatment - Recipient of any drug with potential QT interval prolonging effects within 14 days prior to the first dose for all participants and while on treatment through the end of the study for crizotinib-treated participants only - History of hypersensitivity to any of the additives in the alectinib and crizotinib drug formulation - Pregnancy or lactation - Any clinically significant disease or condition (or history of) that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the principal investigator, pose an unacceptable risk to the participant in this study - Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the participant before trial entry Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive as assessed by the Ventana immunohistochemistry (IHC) test - Life expectancy of at least 12 weeks - Eastern cooperative oncology group performance status (ECOG PS) of 0-2 - Participants with no prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC - Adequate renal, and hematologic function - Participants must have recovered from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment - Measurable disease by response evaluation criteria in solid tumors (RECIST) version 1.1 (v1.1) prior to the administration of study treatment - Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed incidentally at study baseline) - Negative pregnancy test for all females of child bearing potential - Use of highly effective contraception as defined by the study protocol Exclusion Criteria: - Participants with a previous malignancy within the past 3 years - Any gastrointestinal (GI) disorder or liver disease - National cancer institute common terminology criteria for adverse events (NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy (e.g., radiotherapy) (excluding alopecia) - History of organ transplant - Co-administration of anti-cancer therapies other than those administered in this study - Participants with baseline QTc greater than (>) 470 milliseconds or symptomatic bradycardia - Recipient of strong/potent cytochrome P4503A inhibitors or inducers within 14 days prior to the first dose until the end of study treatment - Recipient of any drug with potential QT interval prolonging effects within 14 days prior to the first dose for all participants and while on treatment through the end of the study for crizotinib-treated participants only - History of hypersensitivity to any of the additives in the alectinib and crizotinib drug formulation - Pregnancy or lactation - Any clinically significant disease or condition (or history of) that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the principal investigator, pose an unacceptable risk to the participant in this study - Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the participant before trial entry Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- P4503A --- --- P4503A ---

Primary Outcomes

Description: PFS was assessed as time to disease progression or death whichever occurred first by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) Criteria. As per RECIST v1.1, disease progression is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 millimeter (mm) and the appearance of new lesions.

Measure: Progression-Free Survival (PFS) by Investigator Assessment

Time: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)

Description: PFS was assessed percentage of participants with disease progression or death whichever occurred first by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) Criteria. As per RECIST v1.1, disease progression is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 millimeter (mm) and the appearance of new lesions.

Measure: Percentage of Participants With PFS Event by Investigator Assessment

Time: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)

Secondary Outcomes

Description: PFS was assessed as time to disease progression or death whichever occurred first by IRC assessment using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) Criteria. As per RECIST v1.1, disease progression is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 mm and the appearance of new lesions.

Measure: PFS Independent Review Committee (IRC)-Assessed

Time: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)

Description: PFS was assessed as percentage of participants with disease progression or death whichever occurred first by IRC assessment using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) Criteria. As per RECIST v1.1, disease progression is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 mm and the appearance of new lesions.

Measure: Percentage of Participants With PFS Event by IRC

Time: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)

Description: CNS progression was assessed as percentage of participants with an event defined as time from randomization until first radiographic evidence of CNS progression by IRC. The risk for a CNS progression without a prior non-CNS progression with alectinib compared with crizotinib.

Measure: Percentage of Participants With Central Nervous System (CNS) Progression as Determined by IRC Using RECIST V1.1 Criteria

Time: Randomization to CNS PD as first occurrence of disease progression (assessed every 8 weeks up to 33 months)

Description: CNS progression was assessed as percentage of participants with event defined as time from randomization until first radiographic evidence of CNS progression by IRC. The risk for a CNS progression without a prior non-CNS progression with alectinib compared with crizotinib.

Measure: Percentage of Participants With Central Nervous System (CNS) Progression as Determined by IRC Using Revised Assessment in Neuro Oncology (RANO) Criteria

Time: Randomization to the first occurrence of disease progression in the CNS (assessed every 8 weeks up to 33 months)

Description: ORR was defined as the percentage of participants who attained CR or PR. As per RECIST v1.1, CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm, PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.

Measure: Percentage of Participants With Objective Response Rate (ORR) of Complete Response (CR) or Partial Response (PR) as Determined by The Investigators According to RECIST V1.1 Criteria

Time: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)

Description: DOR was defined as the time from when response (CR or PR) was first documented to first documented disease progression or death, whichever occurred first. DOR was evaluated for participants who had a best overall response (BOR) of CR or PR.

Measure: Duration of Response (DOR) According to RECIST V1.1 Criteria as Assessed by the Investigators

Time: First occurrence of objective response to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)

Description: Overall survival (OS) was defined as the time from randomization to death from any cause.

Measure: Overall Survival (OS)

Time: From randomization until death (up to 43 months)

Description: Overall survival (OS) was defined as the time from randomization to death from any cause.

Measure: Percentage of Participants With OS Event

Time: From randomization until death (up to 43 months)

Description: CNS ORR was defined as the percentage of participants who attained CR or PR and had measurable/non-measurable CNS lesions at baseline. As per RECIST v1.1, CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm, PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.

Measure: Percentage of Participants With CNS ORR of CR or PR IRC-assessed According to RECIST v1.1 Criteria

Time: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)

Description: CNS DOR was defined as the time from when response (CR or PR) was first documented to first documented disease progression or death, whichever occurred first. DOR was evaluated for participants who had a best overall response (BOR) of CR or PR.

Measure: CNS DOR IRC-assessed According to RECIST v1.1 Criteria

Time: First occurrence of CNS objective response to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)

Description: An adverse event (AE) is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Measure: Percentage of Participants With Adverse Events

Time: Baseline up to 28 months in the crizotinib arm and up to 30 months in the alectinib arm

Measure: Area Under The Concentration-Time Curve (AUC) of Alectinib

Time: Pre-dose (within 2 hours before alectinib) (baseline), 1, 2, 4, 6, and 8 hours post-dose at Visit 0 (first dosing day) and Week 4; Pre-dose (within 2 hours) at Week 8, then every 8 weeks until disease progression or death/withdrawal (up to 33 months)

Measure: Maximum Concentration (Cmax) of Alectinib

Time: Pre-dose (within 2 hours before alectinib), 1, 2, 4, 6, and 8 hours post-dose at baseline and Week 4; Pre-dose (within 2 hours before alectinib) at Week 8, then every 8 weeks until disease progression or death/withdrawal from study (up to 33 months)

Measure: Time to Reach Cmax (Tmax) of Alectinib

Time: Pre-dose (within 2 hours before alectinib), 1, 2, 4, 6, and 8 hours post-dose at baseline and Week 4; Pre-dose (within 2 hours before alectinib) at Week 8, then every 8 weeks until disease progression or death/withdrawal from study (up to 33 months)

Measure: AUC of Alectinib Metabolite

Time: Pre-dose (within 2 hours before alectinib) (baseline), 1, 2, 4, 6, and 8 hours post-dose at Visit 0 (first dosing day) and Week 4; Pre-dose (within 2 hours) at Week 8, then every 8 weeks until disease progression or death/withdrawal (up to 33 months)

Measure: Cmax of Alectinib Metabolite

Time: Pre-dose (within 2 hours before alectinib), 1, 2, 4, 6, and 8 hours post-dose at baseline and Week 4; Pre-dose (within 2 hours before alectinib) at Week 8, then every 8 weeks until disease progression or death/withdrawal from study (up to 33 months)

Measure: Tmax of Alectinib Metabolite

Time: Pre-dose (within 2 hours before alectinib), 1, 2, 4, 6, and 8 hours post-dose at baseline and Week 4; Pre-dose (within 2 hours before alectinib) at Week 8, then every 8 weeks until disease progression or death/withdrawal from study (up to 33 months)

Description: The EORTC QLQ-30 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning. Confirmed clinically meaningful deterioration in global health status or function is defined as a >or=10-point decrease from baseline in a symptom score that must be held for at least two consecutive assessments or an initial >or=10-point decrease from baseline followed by death within 5 weeks from the last assessment.

Measure: Time to Deterioration by European Organization for The Research And Treatment of Cancer (EORTC) Quality Of Life Questionnaire Core 30 (C30)

Time: Baseline, every 4 weeks until disease progression (up to 33 months)

Description: The EORTC QLQ-30 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning. Confirmed clinically meaningful deterioration in global health status or function is defined as a >or=10-point decrease from baseline in a symptom score that must be held for at least two consecutive assessments or an initial >or=10-point decrease from baseline followed by death within 5 weeks from the last assessment.

Measure: Percentage of Participants With Deterioration by EORTC Quality Of Life Questionnaire Core 30 (C30)

Time: Baseline, every 4 weeks until disease progression (up to 33 months)

Description: The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning. Confirmed clinically meaningful deterioration in lung cancer symptoms is defined as a >or=10-point increase from baseline in a symptom score that must be held for at least two consecutive assessments or an initial >or=10-point increase above baseline followed by death within 5 weeks from the last assessment.

Measure: Time to Deterioration by EORTC Quality of Life Questionnaire Lung Cancer Module 13 (LC13)

Time: Baseline, every 4 weeks until disease progression (up to 33 months)

Description: The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning. Confirmed clinically meaningful deterioration in lung cancer symptoms is defined as a >or=10-point increase from baseline in a symptom score that must be held for at least two consecutive assessments or an initial >or=10-point increase above baseline followed by death within 5 weeks from the last assessment.

Measure: Percentage of Participants With Deterioration by EORTC Quality of Life Questionnaire Lung Cancer Module 13 (LC13)

Time: Baseline, every 4 weeks until disease progression (up to 33 months)

Description: The EORTC QLQ-C30 questionnaire consisted of 30 questions generating five functional scores (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale score; three symptom scale scores (fatigue, pain, and nausea and vomiting); and six stand alone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and perceived financial burden. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.

Measure: Health-Related Quality of Life (HRQoL) by EORTC Quality of Life Questionnaire C30 Score

Time: Baseline, every 4 weeks until disease progression (up to 33 months)

Description: The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.

Measure: HRQoL by EORTC Quality of Life Questionnaire LC13 Score Coughing

Time: Baseline, every 4 weeks until disease progression (up to 33 months)

Description: The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.

Measure: HRQoL by EORTC Quality of Life Questionnaire LC13 Score Dyspnoea

Time: Baseline, every 4 weeks until disease progression (up to 33 months)

Description: The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.

Measure: HRQoL by EORTC Quality of Life Questionnaire LC13 Score Pain in Chest

Time: Baseline, every 4 weeks until disease progression (up to 33 months)

Description: The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.

Measure: HRQoL by EORTC Quality of Life Questionnaire LC13 Score Pain in Arm and Shoulder

Time: Baseline, every 4 weeks until disease progression (up to 33 months)

4 A Phase 1 Study of the Safety and Pharmacokinetics of Escalating Doses of ASG-22CE Given as Monotherapy in Subjects With Metastatic Urothelial Cancer and Other Malignant Solid Tumors That Express Nectin-4

The purpose of this study is to evaluate the safety and pharmacokinetics of enfortumab vedotin as well as assess the immunogenicity and antitumor activity in subjects with metastatic urothelial cancer and other malignant solid tumors that express Nectin-4.

NCT02091999
Conditions
  1. Metastatic Urothelial Cancer and Other Malignant Solid Tumors
Interventions
  1. Drug: enfortumab vedotin
MeSH:Neoplasms
HPO:Neoplasm

- Any P-glycoprotein (P-gp) inducers/inhibitors or strong cytochrome P4503A (CYP3A) inhibitors within 14 days prior to the first dose of study drug - Thromboembolic events and/or bleeding disorders ≤ 14 days (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE)) prior to the first dose of study drug - Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms (including congestive heart failure) consistent with New York Heart Association Class III-IV within 6 months prior to the first dose of enfortumab vedotin. --- P4503A ---

Primary Outcomes

Measure: Incidence of adverse events

Time: up to 36 months

Measure: Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Concentration at the end of infusion (CEOI)

Time: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months

Measure: Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Maximum observed concentration (Cmax)

Time: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months

Measure: Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Trough concentration (Ctrough)

Time: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months

Measure: Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Time to maximum concentration (Tmax)

Time: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months

Measure: Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Partial area under the serum concentration-time curve after first dose and as appropriate (AUC0-7)

Time: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months

Measure: Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Terminal or apparent terminal half-life (t1/2)

Time: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months

Measure: Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Systemic clearance (CL)

Time: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months

Measure: Pharmacokinetic parameter for total antibody (TAb), antibody drug conjugate (ADC), and Monomethyl Auristatin E (MMAE): Volume of distribution at steady state (Vss)

Time: Days 1-4, 8, 15-18 of Cycle 1 and Days 1, 8, and 15 of Cycle 2 and Day 1 of subsequent cycles up to an average of 24 months

Secondary Outcomes

Measure: Incidence of Anti-Drug Antibody (ADA)

Time: up to 24 months

Description: Incidence of tumor response defined as either a complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) criteria (version 1.1) that is confirmed ≥ 28 days later

Measure: Tumor response

Time: up to 24 months

Description: Defined as the percentage of subjects who experience a best response of either CR or PR in that cohort. CR and PR must be confirmed ≥ 28 days later.

Measure: Objective response rate

Time: up to 24 months

Description: Defined as the percentage of subjects who experience a best response of CR, PR or stable disease (SD)

Measure: Disease control rate

Time: up to 24 months

Description: Time from the date of first infusion to the earliest date of documented disease progression per radiological evidence or death from any cause

Measure: Progression Free Survival (PFS)

Time: 36 months

Description: Time from the date of first infusion until the date of death from any cause.

Measure: Overall Survival

Time: 36 months

Description: Time from the date of the first response complete response (CRC) or partial response (PR) to the earliest date of disease progression or death from any cause. DOR is only defined for subjects who have best overall response of CR or PR

Measure: Duration of Response

Time: 36 months

5 A Multiarm, Open-label, Phase 1b Study of MLN2480 (an Oral A-, B-, and CRAF Inhibitor) in Combination With MLN0128 (an Oral mTORC 1/2 Inhibitor), or Alisertib (an Oral Aurora A Kinase Inhibitor), or Paclitaxel, or Cetuximab, or Irinotecan, in Adult Patients With Advanced Nonhematologic Malignancies

The primary purpose of this study is to determine the safety profile and the maximum tolerated doses (MTDs)/ potential recommended phase 2 doses (RP2Ds) of the combination treatments of MLN2480 + MLN0128, MLN2480 + alisertib, MLN2480 + paclitaxel, MLN2480 + cetuximab, and MLN2480 + irinotecan in participants with advanced nonhematologic malignancies.

NCT02327169
Conditions
  1. Advanced Nonhematologic Malignancies
Interventions
  1. Drug: MLN2480
  2. Drug: MLN0128
  3. Drug: Alisertib
  4. Drug: Paclitaxel
  5. Drug: Cetuximab
  6. Drug: Irinotecan
MeSH:Neoplasms
HPO:Neoplasm

Additional exclusion criteria for arm 5 only (MLN2480 + irinotecan): 1. Use of strong or moderate Cytochrome P4503A (CYP3A) inhibitors <= days of the first dose of irinotecan. --- P4503A ---

Primary Outcomes

Description: An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An SAE means any untoward medical occurrence that at any dose results in death, is life-threatening, requires in patient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event.

Measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time: From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 13 months)

Description: DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 and included: any drug-related hematologic toxicity ≥Grade 4 with the exception of Grade 4 neutropenia <7 days duration; Grade 3 or 4 neutropenia with fever >38.5 degrees Celsius and/or infection or neutropenia requiring colony-stimulating factor OR non-hematologic DLTs that were any Grade 3, 4, or 5 toxicity with the following exceptions: Grade 3 nausea, vomiting, diarrhea, and dehydration occurring in a setting of inadequate treatment; inadequately treated hypersensitivity reactions; Grade 3 elevated transaminases or urine electrolyte abnormality ≤1 week in duration; Grade 3 serum electrolyte abnormality ≤72 hours in duration. DLTs also included: drug-related adverse experience that lead to a dose modification; unresolved drug-related toxicity resulted in delay in initiation of Cycle 2.

Measure: Number of Participants With Dose-Limiting Toxicities (DLTs)

Time: From Day 1, Cycle 1 through 30 days after the last dose in Cycle 1 (up to 8 weeks)

Measure: Maximum Tolerated Dose (MTD) for MLN2480

Time: Day 1, Cycle 1 up to 28 days

Measure: Recommended Phase 2 Dose (RP2D) of MLN2480

Time: Day 1, Cycle 1 up to 28 days

Secondary Outcomes

Measure: Cmax : Maximum Observed Plasma Concentration for MLN2480

Time: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: Cmax: Maximum Observed Plasma Concentration for MLN0128

Time: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: Cmax: Maximum Observed Plasma Concentration for Alisertib

Time: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN2480

Time: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128

Time: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib

Time: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN2480

Time: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN0128

Time: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Alisertib

Time: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: Cmax: Maximum Observed Plasma Concentration for Paclitaxel

Time: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel

Time: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel

Time: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Measure: Terminal Elimination Half-life (T1/2) for Paclitaxel

Time: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Description: ORR was defined as the percentage of participants with complete response (CR) or partial response (PR) using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.

Measure: Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST)

Time: Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Up to 13 months)

Description: Duration of Response (DOR) was defined as the time in months from the first documented CR or PR per RECIST v. 1.1 to disease recurrence or disease progression (PD) whichever occurs first.

Measure: Duration of Response

Time: From first documented response until disease progression (Up to 13 months)

Description: Time to response was defined as the time in months from the date of first dose of study treatment to the date of the first documentation of a PR or better response.

Measure: Time to Response

Time: From date of enrollment to the date of the first documentation of a confirmed response (Up to 13 months)

Description: PFS is defined as the time in months from the date of first study drug administration to the date of first documented PD or death due to any cause. PD was based on response evaluation criteria in solid tumors (RECIST V1.1), defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Measure: Progression Free Survival (PFS)

Time: Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Approximately up to 13 months)

6 A Phase II Study of Ibrutinib Plus Rituximab With Hyper-CVAD Consolidation in Newly Diagnosed Young Patients With Mantle Cell Lymphoma: A Window Period for Bioimmunotherapy Before Chemotherapy

This phase II trial studies how well ibrutinib, rituximab, and consolidation chemotherapy consisting of cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone, methotrexate, and cytarabine work in treating young patients with newly diagnosed mantle cell lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as rituximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone, methotrexate, and cytarabine, 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 more than one drug (combination chemotherapy) may kill more cancer cells. Giving ibrutinib together with rituximab and consolidation chemotherapy may be a better treatment for mantle cell lymphoma.

NCT02427620
Conditions
  1. Blastoid Variant Mantle Cell Lymphoma
  2. CD20 Positive
  3. Mantle Cell Lymphoma
  4. Pleomorphic Variant Mantle Cell Lymphoma
Interventions
  1. Drug: Cyclophosphamide
  2. Drug: Cytarabine
  3. Drug: Dexamethasone
  4. Drug: Doxorubicin
  5. Drug: Doxorubicin Hydrochloride
  6. Drug: Ibrutinib
  7. Other: Laboratory Biomarker Analysis
  8. Drug: Methotrexate
  9. Biological: Rituximab
  10. Drug: Vincristine
  11. Drug: Vincristine Sulfate
MeSH:Lymphoma Lymphoma, Mantle-Cell
HPO:Lymphoma

Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.. Inclusion Criteria: - Patient has a confirmed diagnosis of mantle cell lymphoma with CD20 positivity in tissue biopsy - Patients with MCL must be symptomatic and need immediate therapy; symptoms and nature of MCL include any of the following: - Blastoid variant - Pleomorphic variant - B symptoms - Mantle Cell International Prognostic Score (MIPI) > 3 - Ki-67 >= 30% - Bulky tumors > 7 cm or in case of >= 2 tumors, each >= 5 cm in diameter - Disease threatening organ function - Elevated lactate dehydrogenase (LDH) - Peripheral blood white blood cell (PB WBC) > 50,000 - Pancytopenia due to bone marrow MCL - Patient's choice due to anxiety - Pain due to lymphoma - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patients with mantle cell lymphoma with any of the following will be considered "high-risk" for the purpose of this protocol: - Blastoid or pleomorphic histology - Ki-67 index larger than 30% - Bulky tumor of larger than 7 cm or in case of multiple tumors, larger than or equal to 5 cm each in diameter - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patient has newly diagnosed disease with no prior therapy - Understand and voluntarily sign an Institutional Review Board (IRB)-approved informed consent form - Patients should have bi-dimensional measurable disease using the Cheson criteria (measurable disease by computed tomography [CT] scan defined as at least 1 lesion that measures >= 1.5 cm in single dimension) - Gastrointestinal or bone marrow or spleen only patients are allowable - Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less - An absolute neutrophil count (ANC) > 1,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their ANC is >= 500/mm^3 [growth factor allowed]; these patients should be discussed with either the principal investigator [PI] or Co-PI of the study for final approval) - Platelet count > 100,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their platelet level is equal to or > than 20,000/mm^3; these patients should be discussed with either the PI or Co-PI of the study for final approval) - Serum bilirubin < 1.5 mg/dl - Creatinine (Cr) clearance >= 30 mL/min - Aspartate transaminase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine transaminase (ALT)/serum glutamic-pyruvate transaminase (SGPT) < 2 x upper limit of normal or < 5 x upper limit of normal if hepatic metastases are present; Gilbert's disease is allowed - Cardiac ejection fraction >= 50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) - Disease free of prior malignancies with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated - Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test (within 30 days of initiation of protocol therapy) and must be willing to use acceptable methods of birth control; men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy - A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) Exclusion Criteria: - Any serious medical condition including but not limited to, uncontrolled hypertension, uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), renal failure, active hemorrhage, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form - Pregnant or breast feeding females - Known human immunodeficiency virus (HIV) infection - Patients with active hepatitis B or C infection (not including patients with prior hepatitis B vaccination); these patients should be cleared by gastrointestinal (GI) consultation for hepatitis B and infectious disease consult for hepatitis C - All patients with central nervous system lymphoma - Significant neuropathy (grades 3 - 4, or grade 2 with pain) within 14 days prior to enrollment - Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis unless due to lymphoma - Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of ibrutinib - Major surgery within 4 weeks of initiation of therapy; clearance letter from primary physician required - Requires anticoagulation with warfarin or equivalent vitamin K antagonist - Requires treatment with strong cytochrome P4503A (CYP3A) inhibitors - Patients with New York Heart Association (NYHA) class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to 2nd degree atrioventricular block (AV block) type II, 3rd degree block, QT prolongation (corrected QT [QTc] > 500 millisecond [msec]), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 beats per minute [bpm]), hypotension, light headedness and syncope; patients with persistent and uncontrolled atrial fibrillation will be excluded; the protocol excludes patients who have recently had a stent and by recommendation of their cardiologist need to stay on anticoagulants such as warfarin or equivalent vitamin K antagonist - Acute infection requiring treatment (IV antibiotics, antivirals, or antifungals) within 14 days prior to initiation of study Inclusion Criteria: - Patient has a confirmed diagnosis of mantle cell lymphoma with CD20 positivity in tissue biopsy - Patients with MCL must be symptomatic and need immediate therapy; symptoms and nature of MCL include any of the following: - Blastoid variant - Pleomorphic variant - B symptoms - Mantle Cell International Prognostic Score (MIPI) > 3 - Ki-67 >= 30% - Bulky tumors > 7 cm or in case of >= 2 tumors, each >= 5 cm in diameter - Disease threatening organ function - Elevated lactate dehydrogenase (LDH) - Peripheral blood white blood cell (PB WBC) > 50,000 - Pancytopenia due to bone marrow MCL - Patient's choice due to anxiety - Pain due to lymphoma - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patients with mantle cell lymphoma with any of the following will be considered "high-risk" for the purpose of this protocol: - Blastoid or pleomorphic histology - Ki-67 index larger than 30% - Bulky tumor of larger than 7 cm or in case of multiple tumors, larger than or equal to 5 cm each in diameter - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patient has newly diagnosed disease with no prior therapy - Understand and voluntarily sign an Institutional Review Board (IRB)-approved informed consent form - Patients should have bi-dimensional measurable disease using the Cheson criteria (measurable disease by computed tomography [CT] scan defined as at least 1 lesion that measures >= 1.5 cm in single dimension) - Gastrointestinal or bone marrow or spleen only patients are allowable - Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less - An absolute neutrophil count (ANC) > 1,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their ANC is >= 500/mm^3 [growth factor allowed]; these patients should be discussed with either the principal investigator [PI] or Co-PI of the study for final approval) - Platelet count > 100,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their platelet level is equal to or > than 20,000/mm^3; these patients should be discussed with either the PI or Co-PI of the study for final approval) - Serum bilirubin < 1.5 mg/dl - Creatinine (Cr) clearance >= 30 mL/min - Aspartate transaminase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine transaminase (ALT)/serum glutamic-pyruvate transaminase (SGPT) < 2 x upper limit of normal or < 5 x upper limit of normal if hepatic metastases are present; Gilbert's disease is allowed - Cardiac ejection fraction >= 50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) - Disease free of prior malignancies with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated - Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test (within 30 days of initiation of protocol therapy) and must be willing to use acceptable methods of birth control; men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy - A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) Exclusion Criteria: - Any serious medical condition including but not limited to, uncontrolled hypertension, uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), renal failure, active hemorrhage, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form - Pregnant or breast feeding females - Known human immunodeficiency virus (HIV) infection - Patients with active hepatitis B or C infection (not including patients with prior hepatitis B vaccination); these patients should be cleared by gastrointestinal (GI) consultation for hepatitis B and infectious disease consult for hepatitis C - All patients with central nervous system lymphoma - Significant neuropathy (grades 3 - 4, or grade 2 with pain) within 14 days prior to enrollment - Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis unless due to lymphoma - Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of ibrutinib - Major surgery within 4 weeks of initiation of therapy; clearance letter from primary physician required - Requires anticoagulation with warfarin or equivalent vitamin K antagonist - Requires treatment with strong cytochrome P4503A (CYP3A) inhibitors - Patients with New York Heart Association (NYHA) class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to 2nd degree atrioventricular block (AV block) type II, 3rd degree block, QT prolongation (corrected QT [QTc] > 500 millisecond [msec]), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 beats per minute [bpm]), hypotension, light headedness and syncope; patients with persistent and uncontrolled atrial fibrillation will be excluded; the protocol excludes patients who have recently had a stent and by recommendation of their cardiologist need to stay on anticoagulants such as warfarin or equivalent vitamin K antagonist - Acute infection requiring treatment (IV antibiotics, antivirals, or antifungals) within 14 days prior to initiation of study Blastoid Variant Mantle Cell Lymphoma CD20 Positive Mantle Cell Lymphoma Pleomorphic Variant Mantle Cell Lymphoma Lymphoma Lymphoma, Mantle-Cell PRIMARY OBJECTIVES: I. To evaluate the response rate of ibrutinib plus rituximab in young newly diagnosed mantle cell lymphoma (MCL) including young high-risk patients. --- P4503A ---

Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.. Inclusion Criteria: - Patient has a confirmed diagnosis of mantle cell lymphoma with CD20 positivity in tissue biopsy - Patients with MCL must be symptomatic and need immediate therapy; symptoms and nature of MCL include any of the following: - Blastoid variant - Pleomorphic variant - B symptoms - Mantle Cell International Prognostic Score (MIPI) > 3 - Ki-67 >= 30% - Bulky tumors > 7 cm or in case of >= 2 tumors, each >= 5 cm in diameter - Disease threatening organ function - Elevated lactate dehydrogenase (LDH) - Peripheral blood white blood cell (PB WBC) > 50,000 - Pancytopenia due to bone marrow MCL - Patient's choice due to anxiety - Pain due to lymphoma - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patients with mantle cell lymphoma with any of the following will be considered "high-risk" for the purpose of this protocol: - Blastoid or pleomorphic histology - Ki-67 index larger than 30% - Bulky tumor of larger than 7 cm or in case of multiple tumors, larger than or equal to 5 cm each in diameter - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patient has newly diagnosed disease with no prior therapy - Understand and voluntarily sign an Institutional Review Board (IRB)-approved informed consent form - Patients should have bi-dimensional measurable disease using the Cheson criteria (measurable disease by computed tomography [CT] scan defined as at least 1 lesion that measures >= 1.5 cm in single dimension) - Gastrointestinal or bone marrow or spleen only patients are allowable - Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less - An absolute neutrophil count (ANC) > 1,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their ANC is >= 500/mm^3 [growth factor allowed]; these patients should be discussed with either the principal investigator [PI] or Co-PI of the study for final approval) - Platelet count > 100,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their platelet level is equal to or > than 20,000/mm^3; these patients should be discussed with either the PI or Co-PI of the study for final approval) - Serum bilirubin < 1.5 mg/dl - Creatinine (Cr) clearance >= 30 mL/min - Aspartate transaminase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine transaminase (ALT)/serum glutamic-pyruvate transaminase (SGPT) < 2 x upper limit of normal or < 5 x upper limit of normal if hepatic metastases are present; Gilbert's disease is allowed - Cardiac ejection fraction >= 50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) - Disease free of prior malignancies with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated - Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test (within 30 days of initiation of protocol therapy) and must be willing to use acceptable methods of birth control; men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy - A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) Exclusion Criteria: - Any serious medical condition including but not limited to, uncontrolled hypertension, uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), renal failure, active hemorrhage, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form - Pregnant or breast feeding females - Known human immunodeficiency virus (HIV) infection - Patients with active hepatitis B or C infection (not including patients with prior hepatitis B vaccination); these patients should be cleared by gastrointestinal (GI) consultation for hepatitis B and infectious disease consult for hepatitis C - All patients with central nervous system lymphoma - Significant neuropathy (grades 3 - 4, or grade 2 with pain) within 14 days prior to enrollment - Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis unless due to lymphoma - Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of ibrutinib - Major surgery within 4 weeks of initiation of therapy; clearance letter from primary physician required - Requires anticoagulation with warfarin or equivalent vitamin K antagonist - Requires treatment with strong cytochrome P4503A (CYP3A) inhibitors - Patients with New York Heart Association (NYHA) class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to 2nd degree atrioventricular block (AV block) type II, 3rd degree block, QT prolongation (corrected QT [QTc] > 500 millisecond [msec]), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 beats per minute [bpm]), hypotension, light headedness and syncope; patients with persistent and uncontrolled atrial fibrillation will be excluded; the protocol excludes patients who have recently had a stent and by recommendation of their cardiologist need to stay on anticoagulants such as warfarin or equivalent vitamin K antagonist - Acute infection requiring treatment (IV antibiotics, antivirals, or antifungals) within 14 days prior to initiation of study Inclusion Criteria: - Patient has a confirmed diagnosis of mantle cell lymphoma with CD20 positivity in tissue biopsy - Patients with MCL must be symptomatic and need immediate therapy; symptoms and nature of MCL include any of the following: - Blastoid variant - Pleomorphic variant - B symptoms - Mantle Cell International Prognostic Score (MIPI) > 3 - Ki-67 >= 30% - Bulky tumors > 7 cm or in case of >= 2 tumors, each >= 5 cm in diameter - Disease threatening organ function - Elevated lactate dehydrogenase (LDH) - Peripheral blood white blood cell (PB WBC) > 50,000 - Pancytopenia due to bone marrow MCL - Patient's choice due to anxiety - Pain due to lymphoma - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patients with mantle cell lymphoma with any of the following will be considered "high-risk" for the purpose of this protocol: - Blastoid or pleomorphic histology - Ki-67 index larger than 30% - Bulky tumor of larger than 7 cm or in case of multiple tumors, larger than or equal to 5 cm each in diameter - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patient has newly diagnosed disease with no prior therapy - Understand and voluntarily sign an Institutional Review Board (IRB)-approved informed consent form - Patients should have bi-dimensional measurable disease using the Cheson criteria (measurable disease by computed tomography [CT] scan defined as at least 1 lesion that measures >= 1.5 cm in single dimension) - Gastrointestinal or bone marrow or spleen only patients are allowable - Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less - An absolute neutrophil count (ANC) > 1,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their ANC is >= 500/mm^3 [growth factor allowed]; these patients should be discussed with either the principal investigator [PI] or Co-PI of the study for final approval) - Platelet count > 100,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their platelet level is equal to or > than 20,000/mm^3; these patients should be discussed with either the PI or Co-PI of the study for final approval) - Serum bilirubin < 1.5 mg/dl - Creatinine (Cr) clearance >= 30 mL/min - Aspartate transaminase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine transaminase (ALT)/serum glutamic-pyruvate transaminase (SGPT) < 2 x upper limit of normal or < 5 x upper limit of normal if hepatic metastases are present; Gilbert's disease is allowed - Cardiac ejection fraction >= 50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) - Disease free of prior malignancies with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated - Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test (within 30 days of initiation of protocol therapy) and must be willing to use acceptable methods of birth control; men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy - A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) Exclusion Criteria: - Any serious medical condition including but not limited to, uncontrolled hypertension, uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), renal failure, active hemorrhage, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form - Pregnant or breast feeding females - Known human immunodeficiency virus (HIV) infection - Patients with active hepatitis B or C infection (not including patients with prior hepatitis B vaccination); these patients should be cleared by gastrointestinal (GI) consultation for hepatitis B and infectious disease consult for hepatitis C - All patients with central nervous system lymphoma - Significant neuropathy (grades 3 - 4, or grade 2 with pain) within 14 days prior to enrollment - Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis unless due to lymphoma - Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of ibrutinib - Major surgery within 4 weeks of initiation of therapy; clearance letter from primary physician required - Requires anticoagulation with warfarin or equivalent vitamin K antagonist - Requires treatment with strong cytochrome P4503A (CYP3A) inhibitors - Patients with New York Heart Association (NYHA) class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to 2nd degree atrioventricular block (AV block) type II, 3rd degree block, QT prolongation (corrected QT [QTc] > 500 millisecond [msec]), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 beats per minute [bpm]), hypotension, light headedness and syncope; patients with persistent and uncontrolled atrial fibrillation will be excluded; the protocol excludes patients who have recently had a stent and by recommendation of their cardiologist need to stay on anticoagulants such as warfarin or equivalent vitamin K antagonist - Acute infection requiring treatment (IV antibiotics, antivirals, or antifungals) within 14 days prior to initiation of study Blastoid Variant Mantle Cell Lymphoma CD20 Positive Mantle Cell Lymphoma Pleomorphic Variant Mantle Cell Lymphoma Lymphoma Lymphoma, Mantle-Cell PRIMARY OBJECTIVES: I. To evaluate the response rate of ibrutinib plus rituximab in young newly diagnosed mantle cell lymphoma (MCL) including young high-risk patients. --- P4503A --- --- P4503A ---

Primary Outcomes

Description: Will be monitored using the Bayesian stopping boundaries calculated based on beta-binomial distribution. Logistic regression will be utilized to assess the effect of patient prognostic factors on the response rate.

Measure: Overall response rate (complete response + partial response)

Time: At 8 weeks

Secondary Outcomes

Description: Will be monitored using the Bayesian stopping boundaries calculated based on beta-binomial distribution. Logistic regression will be utilized to assess the effect of patient prognostic factors on the toxicity rate. Toxicity data by type and severity will be summarized by frequency tables.

Measure: Incidence of adverse events

Time: At 4 weeks

Description: Will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.

Measure: Overall survival

Time: Up to 6 years

Description: Will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.

Measure: Progression free survival

Time: Up to 6 years

7 Randomized, Multicenter, Phase III, Open-Label Study of Alectinib Versus Crizotinib in Asian Patients With Treatment-Naive Anaplastic Lymphoma Kinase-Positive Advanced Non-Small Cell Lung Cancer

This randomized, multicenter, Phase III, open-label study will evaluate the efficacy and safety of alectinib versus crizotinib and to evaluate the pharmacokinetics of alectinib in asian participants with treatment-naive ALK-positive advanced NSCLC. Participants will be randomized 2:1 into one of the two treatment groups to receive either alectinib (600 milligrams [mg] twice daily [BID]) or crizotinib (250 mg BID) orally, respectively.

NCT02838420
Conditions
  1. Anaplastic Lymphoma Kinase-positive Non-small Cell Lung Cancer
Interventions
  1. Drug: Alectinib
  2. Drug: Crizotinib
MeSH:Lymphoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Lymphoma Neoplasm of the lung Non-small cell lung carcinoma

Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception Exclusion Criteria: - A malignancy within the previous 3 years (other than curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is considered to have no impact in progression-free survival (PFS) or overall survival (OS) for the current NSCLC) - Any GI disorder that may affect absorption of oral medications, such as malabsorption syndrome or status post-major bowel resection - Liver disease characterized by: - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than (>) 3× the upper limit of normal (ULN; >=5×ULN for participants with concurrent liver metastases) confirmed on two consecutive measurements; or - Impaired excretory function (e.g., hyperbilirubinemia), synthetic function, or other conditions of decompensated liver disease such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices; or - Acute viral or active autoimmune, alcoholic, or other types of hepatitis - National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 Grade 3 or higher toxicities because of any previous therapy (e.g., radiotherapy) (excluding alopecia), which have not shown improvement and are strictly considered to interfere with current study medication - History of organ transplant - Co-administration of anti-cancer therapies other than those administered in this study - Baseline QTc >470 ms or symptomatic bradycardia - Administration of strong/potent cytochrome P4503A inhibitors or inducers within 14 days prior to the receiving the first dose of study treatment and during treatment with alectinib or crizotinib - Administration of agents with potential QT interval prolonging effects within 14 days prior to receiving the first dose of study drug - History of hypersensitivity to any of the additives in the alectinib or crizotinib drug formulation - Pregnant or lactating - Known human immunodeficiency virus (HIV-positivity or acquired immunodeficiency syndrome (AIDS)-related illness - Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the participant in this study - Any psychological, familial, sociological, or geographical condition that potentially hampers compliance with the study protocol requirements or follow-up procedures; those conditions should be discussed with the participant before study entry Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive as assessed by the Ventana immunohistochemistry (IHC) test. --- P4503A ---

Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception Exclusion Criteria: - A malignancy within the previous 3 years (other than curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is considered to have no impact in progression-free survival (PFS) or overall survival (OS) for the current NSCLC) - Any GI disorder that may affect absorption of oral medications, such as malabsorption syndrome or status post-major bowel resection - Liver disease characterized by: - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than (>) 3× the upper limit of normal (ULN; >=5×ULN for participants with concurrent liver metastases) confirmed on two consecutive measurements; or - Impaired excretory function (e.g., hyperbilirubinemia), synthetic function, or other conditions of decompensated liver disease such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices; or - Acute viral or active autoimmune, alcoholic, or other types of hepatitis - National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 Grade 3 or higher toxicities because of any previous therapy (e.g., radiotherapy) (excluding alopecia), which have not shown improvement and are strictly considered to interfere with current study medication - History of organ transplant - Co-administration of anti-cancer therapies other than those administered in this study - Baseline QTc >470 ms or symptomatic bradycardia - Administration of strong/potent cytochrome P4503A inhibitors or inducers within 14 days prior to the receiving the first dose of study treatment and during treatment with alectinib or crizotinib - Administration of agents with potential QT interval prolonging effects within 14 days prior to receiving the first dose of study drug - History of hypersensitivity to any of the additives in the alectinib or crizotinib drug formulation - Pregnant or lactating - Known human immunodeficiency virus (HIV-positivity or acquired immunodeficiency syndrome (AIDS)-related illness - Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the participant in this study - Any psychological, familial, sociological, or geographical condition that potentially hampers compliance with the study protocol requirements or follow-up procedures; those conditions should be discussed with the participant before study entry Anaplastic Lymphoma Kinase-positive Non-small Cell Lung Cancer Lymphoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- P4503A ---

Primary Outcomes

Description: PFS was defined as the time (in months) from randomization to the first documentation of disease progression, as determined by the investigators, or to death from any cause, whichever occurred first.

Measure: Progression-Free Survival (PFS) as Determined by Investigator Using Response Evaluation Criteria in Solid Tumor (RECIST) v1.1

Time: From the date of randomization to the date of the first documented disease progression or death, whichever occurred first (up to overall period of approximately 40 months)

Secondary Outcomes

Description: PFS was defined as the time (in months) from randomization to the first documentation of disease progression, as determined by an independent review committee, or to death from any cause, whichever occurred first.

Measure: PFS as Determined by Independent Review Committee (IRC) Using RECIST v1.1

Time: Baseline, Week 8, thereafter every 8 weeks until disease progression, death or withdrawal from the study and 4 weeks after permanent discontinuation (up to overall period of approximately 40 months)

Measure: Percentage of Participants With Objective Response of Complete Response (CR) or Partial Response (PR) as Determined by Investigator Using RECIST v1.1

Time: Baseline, Week 8, thereafter every 8 weeks until disease progression, death or withdrawal from the study and 4 weeks after permanent discontinuation (up to overall period of approximately 40 months)

Measure: Time to Progression of Disease in the CNS as Determined by IRC Using RECIST v1.1

Time: Baseline, Week 8, thereafter every 8 weeks until disease progression, death or withdrawal from the study and 4 weeks after permanent discontinuation (up to overall period of approximately 40 months)

Measure: Time to Progression of Disease in the CNS as Determined by IRC Using Response Assessment in Neuro-Oncology (RANO)

Time: Baseline, Week 8, thereafter every 8 weeks until disease progression, death or withdrawal from the study and 4 weeks after permanent discontinuation (up to overall period of approximately 40 months)

Measure: Duration of Response (DOR) Assessed by Investigator Using RECIST v1.1

Time: Baseline, Week 8, thereafter every 8 weeks until disease progression, death or withdrawal from the study and 4 weeks after permanent discontinuation (up to overall period of approximately 40 months)

Measure: Overall Survival Time

Time: Baseline, until death (up to overall period of approximately 40 months)

Description: An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

Measure: Percentage of Participants With Non-serious Adverse Events and Serious Adverse Events

Time: Up to overall period of approximately 40 months

Measure: Time to Deterioration Assessed Using EORTC Quality of Life Questionnaire-Core (QLQ-C30) Score

Time: Baseline, Week 4, thereafter every 4 weeks until disease progression, death or withdrawal from the study and 4 weeks after permanent discontinuation (up to overall period of approximately 40 months)

Measure: Time to Deterioration Assessed Using EORTC Quality of Life Questionnaire-Lung Cancer Module (QLQ-LC13) Score

Time: Baseline, Week 4, thereafter every 4 weeks until disease progression, death or withdrawal from the study and 4 weeks after permanent discontinuation (up to overall period of approximately 40 months)

Description: AUC was collected for both alectinib and its major metabolite, M4, and was based on their concentrations in plasma over time.

Measure: Area Under the Plasma Concentration-time Curve (AUC) of Alectinib and Its Metabolite

Time: Baseline and Week 4 predose (within 2 hours before administration of study drug)

Description: Cmax was collected for both alectinib and its major metabolite, M4, and was based on their concentrations in plasma over time.

Measure: Maximum Plasma Concentration Observed (Cmax) of Alectinib and Its Metabolite

Time: Baseline and Week 4 predose (within 2 hours before administration of study drug)

Description: Tmax was collected for both alectinib and its major metabolite, M4, and was based on their concentrations in plasma over time.

Measure: Time to Cmax (Tmax) of Alectinib and Its Metabolite

Time: Baseline and Week 4 predose (within 2 hours before administration of study drug)

8 A Clinical Trial to Evaluate the Safety and Efficacy of Fycompa in Subjects With Amyotrophic Lateral Sclerosis (ALS)

This is a pilot trial to test perampanel (Fycompa; Eisai, Inc.) in ALS patients. The investigators will focus on safety and preliminary signs of efficacy. Perampanel is approved by the FDA for treatment of seizures in patients with epilepsy. In this study, perampanel will be used off-label for adults with ALS at an oral medication dose on the low end of the recommended dose range for epilepsy. This study will consist of two treatments arms: perampanel and matching placebo randomized at a 1:1 ratio. Subjects will receive medication for 9 months.

NCT03020797
Conditions
  1. Amyotrophic Lateral Sclerosis
Interventions
  1. Drug: Perampanel
  2. Drug: Placebo Oral Tablet
MeSH:Motor Neuron Disease Amyotrophic Lateral Sclerosis Sclerosis
HPO:Abnormal anterior horn cell morphology Amyotrophic lateral sclerosis

Inclusion Criteria: 1. diagnosis of ALS 2. first clinical weakness within past 3 years 3. slow vital capacity >= 60% of predicted within 1 month of treatment 4. may be on stable dose of riluzole for at least 30 days, or otherwise agree to not initiate riluzole for duration of the trial 5. may be on stable dose of edaravone for at least 30 days, otherwise agree to not initiate edaravone for duration of the trial 6. can travel to Stony Brook to receive medical care 7. must have a monitor who can be contacted at regular intervals to report on subject's clinical/psychiatric status Exclusion Criteria: 1. use of tracheostomy or mechanical ventilation within last 3 months 2. hepatic insufficiency or abnormal liver function 3. renal insufficiency 4. clinically significant psychiatric disorder 5. active malignancy 6. history of HIV, clinically significant chronic hepatitis, or other active infection 7. history of stomach or intestinal surgery or condition that could interfere with absorption, distribution, metabolism or secretion of study drug 8. history of alcohol or substance abuse within 3 months prior to entry (subjects will be instructed to refrain from alcohol during the study) 9. use of strong cytochrome P4503A inhibitors or inducers, anticonvulsants or other drugs known to interact strongly with perampanel. --- P4503A ---

10. pregnancy or lactation 11. clinically significant medical condition (other than ALS) that would pose a risk to the subject if they were to participate 12. know hypersensitivity to perampanel 13. currently participating, or has participated in a study with an investigation or marketed compound within 3 months of entry Inclusion Criteria: 1. diagnosis of ALS 2. first clinical weakness within past 3 years 3. slow vital capacity >= 60% of predicted within 1 month of treatment 4. may be on stable dose of riluzole for at least 30 days, or otherwise agree to not initiate riluzole for duration of the trial 5. may be on stable dose of edaravone for at least 30 days, otherwise agree to not initiate edaravone for duration of the trial 6. can travel to Stony Brook to receive medical care 7. must have a monitor who can be contacted at regular intervals to report on subject's clinical/psychiatric status Exclusion Criteria: 1. use of tracheostomy or mechanical ventilation within last 3 months 2. hepatic insufficiency or abnormal liver function 3. renal insufficiency 4. clinically significant psychiatric disorder 5. active malignancy 6. history of HIV, clinically significant chronic hepatitis, or other active infection 7. history of stomach or intestinal surgery or condition that could interfere with absorption, distribution, metabolism or secretion of study drug 8. history of alcohol or substance abuse within 3 months prior to entry (subjects will be instructed to refrain from alcohol during the study) 9. use of strong cytochrome P4503A inhibitors or inducers, anticonvulsants or other drugs known to interact strongly with perampanel. --- P4503A ---

Primary Outcomes

Measure: Incidence of treatment-emergent adverse events

Time: 9 months

Secondary Outcomes

Measure: Efficacy as measured by change in ALSFRS-R score (ALS functional rating scale-revised);

Time: 9 months

9 A Phase II Study of Ibrutinib Plus Rituximab and Lenalidomide in Elderly Patients With Newly Diagnosed MCL

This phase II trial studies how well ibrutinib plus rituximab and lenalidomide work in treating elderly participants with newly diagnosed mantle cell lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as rituximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as lenalidomide, 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 ibrutinib plus rituximab and lenalidomide may work better in treating elderly participants with newly diagnosed mantle cell lymphoma.

NCT03232307
Conditions
  1. CCND1 Positive
  2. CD20-Positive Neoplastic Cells Present
  3. Mantle Cell Lymphoma
Interventions
  1. Drug: Dexamethasone
  2. Drug: Ibrutinib
  3. Drug: Lenalidomide
  4. Biological: Rituximab
MeSH:Lymphoma Lymphoma, Mantle-Cell
HPO:Lymphoma

- Requires treatment with strong cytochrome P4503A (CYP3A) inhibitors. --- P4503A ---

Primary Outcomes

Description: The overall response (complete response + partial response) at four months and toxicity at one month (during course 1) will be monitored simultaneously using the Bayesian approach of Thall, Simon, Estey as extended by Thall and Sung. Independence was assumed between or and toxicity, where toxicity is defined as dose-limiting toxicity (DLT) within cycle 1.

Measure: Overall response rate (ORR) per International Workshop Standardization Response Criteria for non-Hodgkin's lymphoma

Time: At 4 months (each cycle is 28 days)

Secondary Outcomes

Description: Toxicity data by type and severity will be summarized by frequency tables. For the efficacy endpoints, intend-to-treat analysis will be performed. For the toxicity endpoint, per-treated analysis will be performed to include any patient who received the treatment regardless of the eligibility nor the duration or dose of the treatment received.

Measure: Incidence of adverse events per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.03

Time: At 1 month (cycle 1 is 28 days)

Description: Summary statistics will be provided for continuous variables. Frequency tables will be used to summarize categorical variables. The distribution of time-to-event endpoints including overall survival and progression free survival will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test. Cox proportional hazard regression will be employed for multivariate analysis on time-to-event outcomes.

Measure: Overall survival (OS)

Time: Up to 4 years

Description: Summary statistics will be provided for continuous variables. Frequency tables will be used to summarize categorical variables. The distribution of time-to-event endpoints including overall survival and progression free survival will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test. Cox proportional hazard regression will be employed for multivariate analysis on time-to-event outcomes.

Measure: Progression-free survival

Time: Up to 4 years

10 A Phase 1b Study of TAK-659 in Combination With Venetoclax for Adult Patients With Previously Treated Non-Hodgkin Lymphoma

The purpose of this study is to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of TAK-659 and venetoclax when administered in combination in participants with non-Hodgkin lymphoma (NHL) relapsed and/or refractory after at least 1 prior line of therapy and to evaluate safety and tolerability of TAK-659 and venetoclax when administered in combination.

NCT03357627
Conditions
  1. Lymphoma, Non-Hodgkin
  2. Lymphoma, La
  3. Lymphoma, Large B-cell, Diffuse
  4. Lymphoma, Follicular
Interventions
  1. Drug: TAK-659
  2. Drug: Venetoclax
MeSH:Lymphoma Lymphoma, Non-Hodgkin Lymphoma, Large B-Cell, Diffuse Lymphoma, Follicular
HPO:Lymphoma Non-Hodgkin lymphoma

Use or consumption of: - Medications or supplements that are known to be strong or moderate Cytochrome P4503A (CYP3A) inhibitors or strong or moderate CYP3A inducers and/or P-glycoprotein (P-gp) inhibitors or inducers within 7 days or within 5 times the inhibitor or inducer half-life (whichever is longer) before the first dose of study drugs. --- P4503A ---

Primary Outcomes

Description: Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE), Version 5.0 DLT will be defined as any of the events specified in the protocol that are considered by the investigator to be at least possibly related to therapy with study medications and that occur within the first cycle.

Measure: Number of Participants with a Dose Limiting Toxicity (DLT)

Time: Baseline up to 5 weeks

Description: AE Grades will be evaluated as per NCI CTCAE, version 5.0.

Measure: Percentage of Participants Reporting one or More Treatment-emergent Adverse Events (TEAEs), Grade 3 or Higher Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Discontinuation

Time: Baseline up to 13 months

Secondary Outcomes

Measure: Cmax: Maximum Observed Plasma Concentration for TAK-659 and Venetoclax

Time: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length is equal to [=] 35 days)

Measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-659 and Venetoclax

Time: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days)

Measure: AUCτ: Area Under the Plasma Concentration-time Curve from Time 0 to Time Over the Dosing Interval for TAK-659 and Venetoclax

Time: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days)

Measure: Oral Clearance (CL/F) for TAK-659 and Venetoclax

Time: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days)

Measure: Peak-trough Ratio (PTR) for TAK-659 and Venetoclax

Time: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days)

Measure: Accumulation Ratio (Rac) for TAK-659 and Venetoclax

Time: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days)

Measure: Trough Concentration (C trough) for TAK-659 and Venetoclax

Time: Cycle 1 Days 1 and 21 or 28: Pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length =35 days)

Description: ORR is calculated as percentage of participants with complete response (CR) + percentage of participants with partial response (PR) as assessed by International Working Group (IWG) criteria for malignant lymphoma.

Measure: Overall Response Rate (ORR)

Time: Up to 12 months

Measure: Duration of Overall Response

Time: Up to 12 months

Description: CR rate is calculated as percentage of participants with CR as assessed by IWG criteria for malignant lymphoma.

Measure: CR Rate

Time: Up to 12 months

Measure: Duration of CR

Time: Up to 12 months

Description: TTP will be measured as the time in months from the first dose of study treatment to the date of the first documented disease progression as assessed using IWG criteria.

Measure: Time to Progression (TTP)

Time: Up to 13 months

Description: PFS is defined as the time from date of first study drug administration to the day of first documented disease progression or death due to any cause, whichever occurs first.

Measure: Progression-free Survival (PFS)

Time: Up to 18 months

11 Liposomal iRInotecan, Carboplatin or oXaliplatin in the First Line Treatment of Esophagogastric Cancer: a Randomized Phase 2 Study

This is a multi-center, open label, randomized phase II trial for patients with previously untreated metastatic or locally advanced esophagogastric cancer, using a pick the winner design to identify the best combination therapy in terms of progression free survival and neurotoxicity.

NCT03764553
Conditions
  1. Esophageal Cancer
Interventions
  1. Drug: Liposomal Irinotecan
  2. Drug: Carboplatin
  3. Drug: Capecitabine
  4. Drug: Oxaliplatin
  5. Drug: 5-fluorouracil
  6. Drug: Leucovorin

- Current use or any use in last two weeks of strong cytochrome P4503A (CYP3A-enzyme), CYP2C8, and/or strong UDP glucuronosyltransferase (UGT1A) inhibitors/inhibitors - Breast feeding, known pregnancy, positive serum pregnancy test or unwillingness to use a reliable method of birth control, during therapy and for 3 months following the last dose of study treatment. --- P4503A ---

Primary Outcomes

Description: To compare the progression free survival

Measure: Progression free survival

Time: 42 months

Description: Number of participants with treatment-related Neurotoxicity according to CTCAE v4.0

Measure: Number of participants with treatment-related Neurotoxicity

Time: 42 months

Secondary Outcomes

Description: To determine the overall survival of F-Nal-IRI, capecitabine/Carboplatin (CapCar) and capecitabine/oxaliplatin (CapOx)

Measure: Overall survival

Time: 54 months

Description: To determine the response rate of F-Nal-IRI, CapCar and CapOx

Measure: response rate

Time: 42 months

Description: To determine the adverse events of F-Nal-IRI, CapCar and CapOx according to NCI common toxicity criteria (CTC) version 4

Measure: adverse events

Time: 42 months

Description: Overall Quality of life ranging from 0-100 with 100 being best Quality of Life

Measure: Quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ C30))

Time: 42 months

Description: The percentage of patients proceeding to subsequent lines of treatment after progression and describe the types of treatment.

Measure: percentage subsequent treatment lines

Time: 42 months

Description: Reasons for forgoing subsequent treatment after progression on first-line treatment

Measure: the reasons for forgoing subsequent treatment

Time: 42 months

Other Outcomes

Description: Percentage of stroma and tumor immune infiltrate in metastatic tumor tissue as predictor of response to treatment and survival.

Measure: Tumor micro environment

Time: 54 months

Description: Concentration of ADAM12 in blood

Measure: Stromal markers in blood

Time: 54 months

Description: Growth velocity of tumor organoids after treatment measured in days

Measure: Growth velocity of patient derived tumor organoids

Time: 54 months

Description: Concentration circulating tumour DNA (ctDNA) as a marker of response to treatment

Measure: ctDNA

Time: 54 months

Description: Composition of the fecal microbiome as a potential biomarker for response to treatment and toxicity

Measure: Fecal microbiome

Time: 54 months

Description: The cost effectiveness in terms of QUALYs associated with treatment of F-Nal-IRI, CapCar and CapOx

Measure: Costs associated with treatment of F-Nal-IRI, CapCar and CapOx

Time: 54 months

Description: Expression of ADAM12 in metastatic tumor tissue

Measure: Stromal Markers in tumor

Time: 54 months

12 A Phase 2, Open-label Study of Zanubrutinib (BGB-3111) in Patients With Relapsed or Refractory Marginal Zone Lymphoma

This is a single arm study to evaluate the efficacy, safety and tolerability of zanubrutinib (BGB-3111) in participants with relapsed/refractory marginal zone lymphoma (R/R MZL).

NCT03846427
Conditions
  1. Marginal Zone Lymphoma
Interventions
  1. Drug: Zanubrutinib
MeSH:Lymphoma Lymphoma, B-Cell, Marginal Zone
HPO:Lymphoma

Requires ongoing treatment with a strong Cytochrome P4503A (CYP3A) inhibitor or inducer 14. --- P4503A ---

Primary Outcomes

Measure: Overall response rate (ORR) determined by independent central review

Time: Up to 3 years

Secondary Outcomes

Measure: ORR by investigator assessment

Time: Up to 3 years

Measure: Progression-free survival (PFS)

Time: Up to 3 years

Measure: Overall survival (OS)

Time: Up to 3 years

Measure: Duration of response (DOR)

Time: Up to 3 years

Measure: Time to response (TTR)

Time: Up to 3 years

Measure: Participant-reported outcomes (PROs) as measured by the EuroQo EQ-5D-5L questionnaire

Time: Up to 3 years

Measure: PROs as measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)

Time: Up to 3 years

Measure: Occurrence and severity of treatment-emergent adverse events (safety and tolerability)

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