SNPMiner Trials by Shray Alag


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Report for Mutation E255K

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 11 clinical trials

Clinical Trials


1 A Randomized Multi-Center Open Label Study of BMS-354825 vs Imatinib Mesylate (Gleevec®) 800 mg/d in Subjects With Chronic Phase Philadelphia Chromosome-Positive Chronic Myeloid Leukemia Who Have Disease That is Resistant to Iamtinib at a Dose of 400-600 mg/d

RATIONALE: BMS-354825 and imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. PURPOSE: This randomized phase II trial is studying BMS-354825 to see how well it works compared to imatinib mesylate in treating patients with chronic phase chronic myelogenous leukemia that did not respond to previous imatinib mesylate.

NCT00112775 Leukemia Drug: dasatinib Drug: imatinib mesylate
MeSH: Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase
HPO: Chronic myelogenous leukemia Leukemia Myeloid leukemia

DISEASE CHARACTERISTICS: - Diagnosis of chronic phase chronic myelogenous leukemia (CML), meeting all of the following criteria: - Less than 15% blasts in peripheral blood and bone marrow - Less than 20% basophils in peripheral blood - Less than 30% blasts and promyelocytes in peripheral blood and bone marrow - Platelet count ≥ 100,000/mm^3 (unless thrombocytopenia is due to recent therapy) - No extramedullary involvement (other than liver or spleen) - Philadelphia chromosome (Ph)-positive disease by cytogenetic analysis - Must have developed resistant disease during prior treatment with imatinib mesylate* at a dose of 400-600 mg/day**, as defined by 1 of the following: - Loss of major cytogenetic response (MCyR) - Achieved a confirmed MCyR and subsequently no longer meets the MCyR criteria - Documented increase in Ph-positive metaphases by 30% on 2 cytogenetic analyses performed ≥ 4 weeks apart during treatment with imatinib mesylate - Loss of complete hematologic response (CHR) - Achieved a confirmed CHR and subsequently no longer meets the CHR criteria on all asessments over a consecutive 2-week period during treatment with imatinib mesylate - Continuously increasing WBC count on ≥ 2 consecutive evaluations ≥ 2 weeks apart with the final assessment showing a doubling of WBC from the nadir to ≥ 20,000/mm^3 OR an absolute increase in WBC by > 50,000/mm^3 above the lowest count after starting imatinib mesylate - No CHR after 3 months of treatment with imatinib mesylate at a dose of 400-600 mg/day - No cytogenetic response after 6 months of treatment with imatinib mesylate at a dose of 400-600 mg/day - No MCyR after 12 months of treatment with imatinib mesylate at a dose of 400-600 mg/day NOTE: *Imatinib mesylate does not need to be the most recent treatment for CML NOTE: **Imatinib mesylate dose ≤ 600 mg/day - Able to tolerate chronic administration of imatinib mesylate at the highest dose received during prior treatment - No imatinib mesylate-related non-hematologic toxicity ≥ grade 3 - No grade 4 imatinib mesylate-related hematologic toxicity lasting more than 7 days - No imatinib mesylate-related toxicity that led to discontinuation or disruption of dosing for > 4 weeks - No previously identified BCR-ABL mutation of 1 of the following types: - L248V - G250E - Q252H/R - Y253H/F - E255K/V - T315I/D - F317L - H369P/R - No prior diagnosis of accelerated phase or blast crisis CML - Patients who previously met the criteria for accelerated phase or blast crisis CML who achieved CHR during treatment with imatinib mesylate and then subsequently progressed to chronic phase CML are not eligible - Ineligible for or unwilling to undergo hematopoietic stem cell transplantation PATIENT CHARACTERISTICS: Age - 18 and over Performance status - ECOG 0-1 Life expectancy - At least 3 months Hematopoietic - See Disease Characteristics - No history of a significant bleeding disorder unrelated to CML, including any of the following: - Congenital bleeding disorder (e.g., von Willebrand's disease) - Acquired bleeding disorder diagnosed within the past year (e.g. --- L248V --- --- G250E --- --- Q252H --- --- Y253H --- --- E255K ---

acquired anti-factor VIII antibodies) Hepatic - Bilirubin ≤ 2.0 times upper limit of normal (ULN) - ALT and AST ≤ 2.5 times ULN Renal - Creatinine ≤ 1.5 times ULN - Total serum or ionized calcium normal (supplementation allowed) Cardiovascular - Heart rate ≥ 50 beats/minute by EKG - No myocardial infarction within the past 6 months - No uncontrolled angina within the past 3 months - No congestive heart failure within the past 3 months - No diagnosed or suspected congenital long QT syndrome - No history of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or torsades de Pointes) - No prolonged QTc interval (i.e., > 450 msec) by EKG using Bazett's correction - High Bazett's correction (i.e., > 450 msec) allowed provided Fridericia correction is ≤ 450 msec - No history of second or third degree heart block - Pacemaker allowed - No uncontrolled hypertension - No other uncontrolled or significant cardiovascular disease Other - Not pregnant - No nursing during and for ≥ 3 months after study participation - Negative pregnancy test - Fertile patients must use effective contraception for ≥ 1 month before, during, and for ≥ 3 months after study participation - Magnesium and potassium normal (supplementation allowed) - No serious uncontrolled medical disorder or active infection that would preclude study participation - No dementia or altered mental status that would preclude giving informed consent - No significant bleeding from the gastrointestinal tract within the past 6 months - No evidence of organ dysfunction or any clinically significant deviation from normal on physical examination, vital signs, EKG, or clinical laboratory determinations unrelated to CML that would preclude study participation - No prisoners or patients who are involuntarily incarcerated for treatment of either a psychiatric or physical (e.g., infectious disease) illness PRIOR CONCURRENT THERAPY: Biologic therapy - More than 14 days since prior interferon Chemotherapy - More than 14 days since prior cytarabine - Prior or concurrent hydroxyurea for elevated WBC (i.e., WBC > 50,000/mm^3) allowed Endocrine therapy - Not specified Radiotherapy - Not specified Surgery - Not specified Other - More than 7 days since prior imatinib mesylate - At least 7 days since prior and no concurrent low-dose aspirin (≤ 325 mg/day) - At least 14 days since prior and no concurrent high-dose aspirin (> 325 mg/day) - More than 14 days since prior targeted small molecule anticancer agents - More than 28 days since prior investigational or antineoplastic agents except hydroxyurea or anagrelide - At least 5 days or 5 half-lives (whichever is greater) since prior and no concurrent drugs that carry a risk of causing torsades de Pointes, including any of the following: - Quinidine - Procainamide - Disopyramide - Amiodarone - Sotalol - Ibutilide - Dofetilide - Erythromycin - Clarithromycin - Chlorpromazine - Haloperidol - Mesoridazine - Thioridazine - Pimozide - Ziprasidone - Cisapride - Bepridil - Droperidol - Methadone - Arsenic trioxide - Chloroquine - Domperidone - Halofantrine - Levomethadyl - Pentamidine - Sparfloxacin - Lidoflazine - At least 5 days or 5 half-lives (whichever is greater) since prior and no concurrent medication that directly inhibits platelet function (except anagrelide for thrombocytosis due to CML), including any of the following: - Dipyridamole - Epoprostenol - Epitifibatide - Clopidogrel - Cilostazol - Abciximab - Ticlopidine - At least 5 days or 5 half-lives (whichever is greater) since prior and no concurrent anticoagulants (e.g., warfarin, heparin, or low molecular weight heparin [e.g., danaparoid, dalteparin, tinzaparin, or enoxaparin]) - Concurrent prophylactic low-dose warfarin for prevention of catheter thrombosis and heparin-flush for IV lines allowed - No prior BMS-354825 - No concurrent CYP3A4 inhibitors or inducers, including any of the following: - Ketoconazole - Ritonavir - Rifampin - Efavirenz - No other concurrent therapy for CML DISEASE CHARACTERISTICS: - Diagnosis of chronic phase chronic myelogenous leukemia (CML), meeting all of the following criteria: - Less than 15% blasts in peripheral blood and bone marrow - Less than 20% basophils in peripheral blood - Less than 30% blasts and promyelocytes in peripheral blood and bone marrow - Platelet count ≥ 100,000/mm^3 (unless thrombocytopenia is due to recent therapy) - No extramedullary involvement (other than liver or spleen) - Philadelphia chromosome (Ph)-positive disease by cytogenetic analysis - Must have developed resistant disease during prior treatment with imatinib mesylate* at a dose of 400-600 mg/day**, as defined by 1 of the following: - Loss of major cytogenetic response (MCyR) - Achieved a confirmed MCyR and subsequently no longer meets the MCyR criteria - Documented increase in Ph-positive metaphases by 30% on 2 cytogenetic analyses performed ≥ 4 weeks apart during treatment with imatinib mesylate - Loss of complete hematologic response (CHR) - Achieved a confirmed CHR and subsequently no longer meets the CHR criteria on all asessments over a consecutive 2-week period during treatment with imatinib mesylate - Continuously increasing WBC count on ≥ 2 consecutive evaluations ≥ 2 weeks apart with the final assessment showing a doubling of WBC from the nadir to ≥ 20,000/mm^3 OR an absolute increase in WBC by > 50,000/mm^3 above the lowest count after starting imatinib mesylate - No CHR after 3 months of treatment with imatinib mesylate at a dose of 400-600 mg/day - No cytogenetic response after 6 months of treatment with imatinib mesylate at a dose of 400-600 mg/day - No MCyR after 12 months of treatment with imatinib mesylate at a dose of 400-600 mg/day NOTE: *Imatinib mesylate does not need to be the most recent treatment for CML NOTE: **Imatinib mesylate dose ≤ 600 mg/day - Able to tolerate chronic administration of imatinib mesylate at the highest dose received during prior treatment - No imatinib mesylate-related non-hematologic toxicity ≥ grade 3 - No grade 4 imatinib mesylate-related hematologic toxicity lasting more than 7 days - No imatinib mesylate-related toxicity that led to discontinuation or disruption of dosing for > 4 weeks - No previously identified BCR-ABL mutation of 1 of the following types: - L248V - G250E - Q252H/R - Y253H/F - E255K/V - T315I/D - F317L - H369P/R - No prior diagnosis of accelerated phase or blast crisis CML - Patients who previously met the criteria for accelerated phase or blast crisis CML who achieved CHR during treatment with imatinib mesylate and then subsequently progressed to chronic phase CML are not eligible - Ineligible for or unwilling to undergo hematopoietic stem cell transplantation PATIENT CHARACTERISTICS: Age - 18 and over Performance status - ECOG 0-1 Life expectancy - At least 3 months Hematopoietic - See Disease Characteristics - No history of a significant bleeding disorder unrelated to CML, including any of the following: - Congenital bleeding disorder (e.g., von Willebrand's disease) - Acquired bleeding disorder diagnosed within the past year (e.g. --- L248V --- --- G250E --- --- Q252H --- --- Y253H --- --- E255K ---

Primary Outcomes

Measure: Major cytogenic response (MCyR) rate at 12 weeks

Secondary Outcomes

Measure: MCyR at any time

Measure: Duration of MCyR

Measure: Time to MCyR

Measure: Complete hematologic response rate

2 A Single-arm Dose-finding Phase Ib Multicenter Study of the Oral Smoothened Antagonist LDE225 in Combination With Nilotinib in Chronic or Accelerated Phase of Chronic Myeloid Leukemia Patients Who Have Failed Prior Therapy With Other BCR-ABL Tyrosine-kinase Inhibitors

The purpose of this study is to determine the feasibility of administering the combination of nilotinib and LDE225 to patients with chronic or accelerated phase of chronic myeloid leukemia and to establish the maximum tolerated dose (MTD) and/or recommended Phase II dose level (RP2D) of LDE225 in combination with nilotinib.

NCT01456676 Philadelphia Chromosome Positive Chronic Myelogenous Leukemia Drug: Nilotinib + LDE225
MeSH: Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Philadelphia Chromosome
HPO: Chronic myelogenous leukemia Leukemia Myeloid leukemia

Previously documented BCR-ABL Y253H, E255K/V, T315I or F359C/V mutation Other protocol-defined inclusion/exclusion criteria may apply. --- Y253H --- --- E255K ---

Primary Outcomes

Description: Determination of the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of nilotinib in combination with LDE225

Measure: Incidence rate and category of dose limiting toxicities (DLTs) during the first two cycles of therapy

Time: 56 days (2 treatment cycles at 28 days each)

Secondary Outcomes

Description: Assessment of the safety and tolerability profile of nilotinib in combination with LDE225

Measure: No of participants with Adverse drug reactions and serious adverse drug reactions, changes in hematology and blood chemistry values, assessments of physical examinations, vital signs and electrocardiograms

Time: 336 days (12 treatment cycles)

Description: Assessment of the PK characteristics of nilotinib administered in combination with LDE225

Measure: Plasma concentration and basic pharmacokinetics (PK) parameters (as Cmax, Tmax, AUC)

Time: 50 days

Description: Determination of the kinetics of major molecular response

Measure: Major molecular response (MMR) rates at 3, 6 and 12 months

Time: 336 days (12 treatment cycles)

Description: Determination of the kinetics of complete molecular response

Measure: Complete molecular response (CMR) rates at 3, 6 and 12 months

Time: 336 days (12 treatment cycles)

Description: Determination of major cytogenetic response rates

Measure: Major cytogenic response (MCyR) rates by 3, 6 and 12 months

Time: 336 days (12 treatment cycles)

Description: Determination of complete cytogenetic response rates

Measure: Complete cytogenic response (CCyR) rates by 3, 6 and 12 months

Time: 336 days (12 treatment cycles)

3 Dynamics of ABL Mutations in Imatinib Failed Ph Positive or Bcr-Abl Positive CML CP or AP Patients Who Treated With Nilotinib as Second-line TKI Therapy (AMICAN-Prospective)in Asia

The purposes of this study are to investigate expression and frequency of ABL point mutations, a major cause of resistance in imatinib failed CML Asian patients and to find causes of Asian-specific resistance to cancer-targeting therapies through a prospective investigation of dynamics of point mutations and expression of new point mutations during nilotinib treatment.

NCT01562847 Chronic Myeloid Leukemia Drug: Nilotinib
MeSH: Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO: Chronic myelogenous leukemia

With regard to peculiar point mutations, V299L, F317L, and E25K/V show relative resistance to dasatinib, and p-loop mutations including G250E, Q252H, Y253F/H and E255K/V and F359C/V show relative resistance to nilotinib. --- V299L --- --- F317L --- --- E25K --- --- G250E --- --- Q252H --- --- Y253F --- --- E255K ---

Primary Outcomes

Measure: To confirm the patterns of resistance including point mutations which are newly expressed during the nilotinib treatment

Time: 5 years

Secondary Outcomes

Measure: To analyze and evaluate the overall survival and disease free survival in the nilotinib treatment according to progression of the disease and types of point mutations

Time: 5 years

4 A Phase II, Single Arm, Open Label Study of Treatment-free Remission in Chronic Myeloid Leukemia (CML) Chronic Phase (CP) Patients After Achieving Sustained MR4.5 on Nilotinib

A clinical research study to find out if it is safe to stop the drug nilotinib (Tasigna) in chronic myeloid leukemia (CML) patients. Patients who started treatment with imatinib (Gleevec) when they were first diagnosed with CML, then switched to nilotinib (Tasigna) for at least 2 years with the combined time on imatinib (Gleevec) and nilotinib (Tasigna) for at least 3 years and have very small amount of leukemia cells remaining after the nilotinib (Tasigna) treatment will qualify for the study.

NCT01698905 Chronic Myeloid Leukemia Drug: nilotinib
MeSH: Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO: Chronic myelogenous leukemia Leukemia Myeloid leukemia

Written informed consent obtained prior to any screening procedures Exclusion Criteria: 1. Prior AP, BC or allo-transplant 2. Patient has documented MR4.5 at the time when switched from imatinib to nilotinib 3. Patients with known atypical transcript 4. CML treatment resistant mutation(s) (T315I, E255K/V, Y253H, F359C/V) detected if a testing was done in the past (there is no requirement to perform mutation testing at study entry if it was not done in the past) 5. Dose reductions due to neutropenia or thrombocytopenia in the past 6 months 6. --- T315I --- --- E255K ---

Primary Outcomes

Description: TFR is defined as no confirmed loss of MR4 (Molecular response 4.0 log reduction from baseline) or loss of MMR (major molecular response) and no re-starting of nilotinib therapy within 12 months following cessation of nilotinib. Confirmed loss of MR4 is two consecutive BCR-ABL > 0.01% IS. Loss of MMR does not require confirmationTFR is calculated by dividing the number of patients with no documented confirmed loss of MR4, no documented loss of MMR and no re-starting of nilotinib therapy in the first 48 weeks after starting nilotinib TFR phase by the number of patients who entered nilotinib TFR phase.

Measure: Percentage of patients in Treatment Free Remission (TFR) within 48 weeks

Time: First 48 weeks following nilotinib cessation.

Secondary Outcomes

Description: TFR is defined as no confirmed loss of MR4 (molecular response 4.0 log reduction from baseline) or loss of MMR (major molecular response) and no re-starting of nilotinib therapy within 12 months following cessation of nilotinib. Confirmed loss of MR4 is two consecutive BCR-ABL > 0.01% IS. Loss of MMR does not require confirmation.TFR is calculated by dividing the number of patients with no documented confirmed loss of MR4, no documented loss of MMR and no re-starting of nilotinib therapy in the first 96, 144, 192, 264 weeks and within 6,7,8,9 and 10 years after starting nilotinib TFR phase by the number of patients who entered nilotinib TFR phase.

Measure: Percentage of patients in Treatment Free Remission (TFR) within 96, 144, 192, 264 weeks and within 6,7,8,9 and 10 years

Time: 96, 144, 192, 264 weeks and within 6,7,8,9 and 10 years following nilotinib cessation

Description: Kaplan-Meier (KM) estimation of PFS. PFS is measured from the date of start of nilotinib TFR phase (cessation of nilotinib) to the date of the earliest of the event: progression to AP/BC, or death from any cause. Patients not known to have recurred or died on or before the cut-off date for the KM analysis will have their PFS interval right-censored at the earlier of the date of their last assessment (cytogenetic, hematology or extramedullary) for patients who are still on study and at the date of last contact for patients are in follow-up.

Measure: Progression free survival (PFS) to Accelerated phase/Blast crisis (AP/BC) or death

Time: nilotinib cessation up to approximately 580 weeks

Description: TFS is measured from the date of the start of the nilotinib TFR phase to the date of the earliest of the following: loss of MMR, confirmed loss of MR4, re-start of nilotinib treatment, progression to AP/BC or death from any cause. Patients not known to have had any of the events or died on or before the cut-off date for the KM analysis will have their TFS interval right-censored at the earlier of the date of their last assessment (PCR, cytogenetic, hematology or extramedullary) for patients who are still on study and at the date of last contact for patients are in follow-up.

Measure: Treatment free survival (TFS)

Time: nilotinib cessation up to approximately 580 weeks

Description: Kaplan-Meier (KM) estimation of OS. OS is measured from the date of start of nilotinib TFR phase to the date of death from any cause. If a patient is not known to have died, survival will be censored at the date of last contact.

Measure: Overall survival (OS)

Time: nilotinib cessation up to approximately 580 weeks

Description: Descriptive statistics of BCR-ABL over time after re-start of nilotinib therapy. ABL= Abelson leukemia virus and BCR=Break point cluster region

Measure: Change in BCR-ABL (oncoprotein product of BCR-ABL fusion gene) transcripts after re-start of nilotinib therapy

Time: re-start of nilotinib up to approximately 48 weeks

Description: Percentage of patients who are in stable MMR (stable MMR=BCR-ABL ≤ 0.1% IS) at 48, 96, 144, 192, 240,288 ,336, 384, and 432 weeks after achievement of that response in the nilotinib re-initiation phase for 48, 96, 144, 192, 240,288 ,336, 384, and 432 weeks is calculated by dividing the number of patients achieving MMR any time during the nilotinib re-initiation phase and having the same response at 48, 96, 144, 192, 240,288,336, 384, and 432 weeks after the first achievement of MMR, irrespective of whether there is loss of MMR in between, by the number of patients who achieved MMR at any time during the nilotinib re-initiation phase

Measure: Percentage of patients with stable MMR in nilotinib re-initiation phase

Time: start of nilotinib in re-initiation phase up to approximately 432 weeks

Description: Percentage of patients who are in stable MR4 (stable MR4=BCR-ABL ≤ 0.01% IS) at 48, 96, 144, 192, 240,288 ,336, 384, and 432 weeks after achievement of that response in the nilotinib re-initiation phase for 48, 96, 144, 192, 240,288 ,336, 384, and 432 weeks is calculated by dividing the number of patients achieving MR4 any time during the nilotinib re-initiation phase and having the same response at 48, 96, 144, 192, 240,288,336, 384, and 432 weeks after the first achievement of MR4, irrespective of whether there is loss of MR4 in between, by the number of patients who achieved MR4 at any time during the nilotinib re-initiation phase

Measure: Percentage of patients with stable MR4 in nilotinib re-initiation phase

Time: start of nilotinib in re-initiation phase up to approximately 432 weeks

Description: Percentage of patients who are in stable MR4.5 (stable MR4.5=BCR-ABL ≤ 0.0032% IS) at 48, 96, 144, 192, 240,288 ,336, 384, and 432 weeks after achievement of that response in the nilotinib re-initiation phase for 48, 96, 144, 192, 240,288 ,336, 384, and 432 weeks is calculated by dividing the number of patients achieving MR4.5 any time during the nilotinib re-initiation phase and having the same response at 48, 96, 144, 192, 240,288,336, 384, and 432 weeks after the first achievement of MR4.5, irrespective of whether there is loss of MR4.5 in between, by the number of patients who achieved MR4.5 at any time during the nilotinib re-initiation phase

Measure: Percentage of patients with stable MR4.5 in nilotinib re-initiation phase

Time: start of nilotinib in re-initiation phase up to approximately 432 weeks

5 A Single-arm, Multicenter, Nilotinib Treatment-free Remission Study in Patients With BCR-ABL1 Positive Chronic Myelogenous Leukemia in Chronic Phase Who Have Achieved Durable Minimal Residual Disease (MRD) Status on First Line Nilotinib Treatment.

The main purpose of the study is to investigate whether nilotinib treatment can be safely suspended with no recurrence of CML in selected patients who responded optimally on this treatment

NCT01784068 Chronic Myelogenous Leukemia Drug: Nilotinib followed by treatment-free
MeSH: Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO: Chronic myelogenous leukemia Leukemia Myeloid leukemia

Proportion of patients who develop T3151, E255K/V, Y253H, F359V/C/I mutations on study or any other BCR-ABL mutations in patients who lost MMR after nilotinib suspension. --- E255K ---

Proportion will be calculated by dividing the number of patients who developT315I, E255K/V, Y253H, F359V/C/I mutations after nilotinib suspension by the number of patients who lost MMR. --- E255K ---

Primary Outcomes

Description: Primary endpoint is the proportion of patients who are in MMR at 48 weeks after starting the TFR phase and is calculated by dividing the number of patients with MMR at 48 weeks after starting the TFR phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase by the number of patients entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders

Measure: Percentage of patients who are in MMR (major molecular response) at 48 weeks after starting the treatment-free remission (TFR) phase

Time: 48 weeks

Secondary Outcomes

Description: Proportion of patients who are in MR4.5 at 48 weeks after starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 48 weeks after starting the TFR phase with no loss of MR4.5 and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders. MR4.5 = log reductions of the BCR-ABR transcript load in blood as a measurement of deep molecular response of the CML clone to treatment.

Measure: Percentage of patients who are in MR4.5 (BCR-ABL ≤ 0.0032% IS) at 48 weeks after starting the TFR phase

Time: 48 weeks

Description: Proportion of patients who are in MMR at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MMR at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders

Measure: Percentage of patients who are in MMR at 96, 144,192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase

Time: 96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years

Description: Proportion of patients who are in MR4.5 at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 yearsafter starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase with no loss of MR4.5 and no re-initiation of nilotinib therapy in the first 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders

Measure: Percentage of patients who are in MR4.5 at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 yearsafter starting the TFR phase

Time: 96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years

Description: Proportion of patients who are in MMR at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MMR at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who are re-initiated with nilotinib but have less than 12 weeks of re-initiation of treatment will be excluded from the analysis

Measure: Percentage of patients in MMR at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase of nilotinib

Time: 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years

Description: Proportion of patients who are in MR4.5 at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who are re-initiated with nilotinib but have less than 12 weeks of re-initiation of treatment will be excluded from the analysis

Measure: Percentage of patients in MR4.5 at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase of nilotinib

Time: 48, 96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years

Description: Proportion of patients who achieve MMR within 12 weeks of re-initiation of nilotinib is calculated by dividing the number of patients who are in MMR at least at one assessment within 12 weeks after re-start of nilotinib treatment by the number of patients who are re-initiated for at least 12 weeks

Measure: Percentage of patients who achieve MMR within 12 weeks of re-treatment with nilotinib

Time: 12 weeks

Description: Descriptive statistics of BCR-ABL levels (IS) over time after re-start of nilotinib therapy up to 528 weks after the last patient has entered TFR

Measure: Kinetics of BCR-ABL transcript after re-start of nilotinib therapy

Time: Every 4 weeks up to week 24 and every 12 weeks thereafter up to 528 after last patient has entered the TFR

Description: Defined as time from date of start of re-initiation of treatment after loss of MMR to the date of first achievement of MMR. Patients who do not regain MMR after re-initiation of treatment on or before the cut-off date, duration will be censored at the date of last PCR assessment

Measure: Duration of re-initiated treatment required to regain MMR after loss of MMR

Time: Every 4 weeks up to week 24 and every 12 weeks therefater up to 528 weks after the last patient has entered TFR

Description: Defined as the time from start of re-initiation of treatment after loss of MMR to the first achievement of MR4.5. Patients who do not regain MR4.5 after re-initiation of treatment on or before the cut-off date, duration will be censored at the date of last PCR assessment

Measure: Duration of re-initiated treatment required to regain MR4.5 after loss of MMR

Time: Every 4 weeks up to week 24 and every 12 weeks thereafter up to 528 weks after the last patient has entered TFR

Description: TFS is defined as the time from the start of the TFR phase to the earliest occurrence of loss of MMR, re-initiation of treatment due to any cause, progression of AP/BC or death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment (PCR, cytogenetic, hematologic or extramedullary). A TFS sensitivity analysis will be conducted to consider discontinuation from TFR phase due to any reason as a TFS event, in addition to the TFS events as defined above.

Measure: Treatment-free survival (TFS) after the start of the TFR phase

Time: Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks in TFR and every 12 weeks in the last period of 432 weeks of the TFR

Description: PFS is defined as the time from the start of the TFR phase to the earliest occurrence of progression to AP/BC or death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment (cytogenetic, hematologic or extramedullary) for patients who are still on study and at the date of last contact for patients who are in follow-up

Measure: Progression-free survival (PFS) after the start of the TFR phase

Time: Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks of TFR and every 12 weeks in the last period of 432 weeks of the TFR

Description: OS is defined as the time from start of the TFR phase to death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment for patients who are still on study and at the date of last contact for patients who are in follow-up

Measure: Overall survival (OS) after the start of the TFR phase

Time: Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks of TFR and every 12 weeks in the last period of 432 weeks of the TFR

Description: Safety profile includes type, frequency and severity of adverse events, laboratory abnormalities and clinically notable ECG and other safety parameters during the nilotinib treatment consolidation phase, during the TFR phase and during re-initiation of treatment with nilotinib

Measure: Safety profile during the nilotinib treatment consolidation phase, during the TFR phase and during re-initiation treatment with nilotinib

Time: Every 4 weeks in the treatment consolidation and during the first 24 weeks of the re-initaion phase, every 12 weeks thereafter. Every 4, 6 and 12 weeks respectively in the first and second period of 48 weeks and in the last period of 432 weeks of the TFR

Description: Proportion will be calculated by dividing the number of patients who developT315I, E255K/V, Y253H, F359V/C/I mutations after nilotinib suspension by the number of patients who lost MMR

Measure: Proportion of patients who develop T3151, E255K/V, Y253H, F359V/C/I mutations on study or any other BCR-ABL mutations in patients who lost MMR after nilotinib suspension

Time: Every 3 months in patients who lost MMR until the result is negative or up to 528 weeks after the last patient entered TFR. On average 3 analyses (every 3 months or up to 264 weeks after the last patient has entered TFR.)

Description: Proportion of patients who are in stable MMR/MR4.5 after achievement of that response in the nilotinib re-initiation phase for 48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks, based on availability of appropriate data, is calculated by dividing the number of patients achieving MMR/MR4.5 any time during the nilotinib re-initiation phase and having the same response 48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks after the first achievement of MMR/MR4.5, irrespective of whether there is loss of MMR in between, by the number of patients who achieved MMR/MR4.5 at any time during the nilotinib re-initiation phase

Measure: Percentage of patients who are in stable response (MMR and MR4.5) after achievement of that response in nilotinib re-initiation phase for 48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks, based on availability of appropriate data

Time: 48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks

6 Prospective, Phase I/II, Non-randomized, Open Label, Multicenter Study to Determine Safety and Efficacy of Nilotinib in a Population With Steroid-refractory/or Steroid-dependent cGVHD.

Chronic Graft versus Host Disease (cGvHD) has been identified as the leading cause of late non-relapse mortality in Hemopoietic Stem Cell Transplant (HSCT) survivors. Up to now a standard satisfactory treatment for these patients does not exist. cGVHD is an immune-mediated disease, resulting from a complex interaction between donor and recipient adaptive immunity, but its exact pathogenesis is still incompletely defined. The purpose of this study is to determine safety and efficacy of Nilotinib in a population with steroid-refractory/or steroid-dependent cGvHD with a phase I study. In phase II the MTD will be used to define the efficacy of Nilotinib in a cGvHD steroid- refractory or steroid dependent population, with the same characteristics of the previously Imatinib-treated population.

NCT01810718 Chronic Graft Versus Host Disease Drug: nilotinib
MeSH: Graft vs Host Disease

It has to be noticed that in all the proliferation assays the concentration at which 50% of effect is inhibited of Nilotinib is lower than 50 nM, apart from the two BCR-ABL mutants (E255K and E255V) where the IC50 is 600 to 700 nM. --- E255K ---

Primary Outcomes

Description: Primary is DLT - occurrence of any grade >3 toxicity after at least one month of treatment.

Measure: Dose Limiting Toxicity (DLT)

Time: within 6 months since the start of treatment

Description: Overall Response Rate (ORR)is defined as an Objective improvement at sixth month, and includes at least 1 of the following criteria: At least 50% reduction of body surface area involved; Reduction (at least 20%) of skin sclerosis, measured by Rodnan score Improvement>1 point in functional pulmonary tests, evaluated by LFS score; >50% steroid reduction (for at least 4 weeks)

Measure: Overall Response Rate (ORR)

Time: 6 months after date of start of Nilotinib

Secondary Outcomes

Description: Number of patients experiencing failure, from date of registration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months after the enrolment.

Measure: Time to treatment Failure (TTF)

Time: participants will be followed for the duration of the 6 months of treatment, and for the follow-up for expected average of 12 months

Description: Number of patients alive from date of registration until the date of death from any cause, assessed up to 24 months after the enrolment

Measure: Overall Survival (OS)

Time: participants will be followed for the duration of the 6 months of treatment, and for the follow-up for expected average of 12 months

Other Outcomes

Description: To assess how Nilotinib could interact with the putative pathogenetic pathways of the cGvHD: Presence and activity of auto-antibodies stimulating PDGF-R baseline and during treatment; Modifications of fibroblast (from skin biopsies from patients with skin involvement) characteristics (in terms of: ROS output, modification of both the PDGF-R and the TGFΒ downstream and collagen production)before and after treatment. Quantitative and qualitative modifications of the immune cell populations. Plasma levels of Nilotinib in order to find relationship between clinical improvement and plasma Nilotinib dosage.

Measure: BIOLOGICAL TASKS

Time: Every 6 months starting from baseline (at enrolment), along the duration of the 6 months of treatment, and for the follow-up for expected average of 12 months

7 A PHASE I/II, MULTI-CENTRE, TRIAL OF RUXOLITINIB THERAPY IN COMBINATION WITH NILOTINIB IN PATIENTS WITH PHILADELPHIA POSITIVE CHRONIC MYELOID LEUKEMIA OR ACUTE LYMPHOBLASTIC LEUKEMIA WHO HAVE FAILED TYROSINE KINASE INHIBITOR THERAPY

This is the study to test combination regimen of Nilotinib and Ruxolitinib therapy for the treatment of patients with Philadelphia positive chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) who is resistant to multiple tyrosine kinase inhibitor therapies with BCR-ABL kinase inhibition activity. Ruxolitinib is a tyrosine kinase inhibitor blocking alternative pathway independent of BCR-ABL mediated pathway, thus having a potential to overcome tyrosine kinase inhibitor resistance in Philadelphia positive CML or ALL patients. Phase I study will be conducted to define a recommended phase II dose (RPTD) and phase II study will examine the hypothesis that combinational approach will increase response rate of resistant CML/ALL patients, thus evaluating efficacy of the combination regimen.

NCT01914484 Chronic Phase Chronic Myeloid Leukemia Accelerated Phase Chronic Myeloid Leukemia Blastic Phase Chronic Myeloid Leukemia Philadelphia Positive Acute Lymphoblastic Leukemia Resistant to Tyrosine Kinase Inhibitor Therapy Drug: Nilotinib Drug: Ruxolitinib
MeSH: Leukemia Leukemia, Myeloid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Blast Crisis Leukemia, Myeloid, Chronic-Phase Leukemia, Myeloid, Accelerated Phase
HPO: Chronic myelogenous leukemia Leukemia Lymphoid leukemia Myeloid leukemia

Developed the T315I, T315A Y253H, E255K/V or F359C/V mutation after any TKI therapy. --- T315I --- --- T315A --- --- Y253H --- --- E255K ---

Primary Outcomes

Description: Maximum Tolerated Dose (MTD) of Ruxolitinib with fixed dose of Nilotinib. Dose escalation will follow a 3+3 study design. The CTCAE v4.03 criteria will be used. Grade 4 toxicity will be accounted as dose limiting toxicity (DLT).

Measure: Phase I: Maximum Tolerated Dose (MTD)

Time: Average of 6 months

Description: Major cytogenetic response defined by 35% or less of Philadelphia chromosomes by metaphase cytogenetics in marrow from CML and ALL patients

Measure: Phase II: Major cytogenetic response

Time: Average of 6 months

Secondary Outcomes

Description: Complete hematologic response defined by CBC differential without any evidence of leukemia. It will be evaluated in CML patients in AP or BP, and patients with Ph+ ALL.

Measure: Phase I: complete hematologic response

Time: Average of 3 months

Description: Major cytogenetic response defined by 35% or less of Philadelphia chromosomes by metaphase cytogenetics in marrow taken at 6 months.

Measure: Phase I: major cytogenetic response

Time: Average of 6 months

Description: It will be defined by NCI Common Terminology Criteria for Adverse Events (CTCAE)version 4.03 for adverse event reporting.

Measure: Phase I: Safety and tolerability

Time: Average of 6 months

Description: Complete hematologic response defined by CBC differential without any evidence of leukemia. It will be evaluated in the CML patients in AP or BP and in patients with Ph+ ALL.

Measure: Phase II: complete hematologic response

Time: Average of 3 months

Other Outcomes

Description: Cmax will be measured for the maximum plasma concentration of nilotinib after oral administration.

Measure: Phase II (exploratory): pharmacokinetic profile of combination of Nilotinib with Ruxolitinib

Time: During first 24 hours of first dose

8 Multicenter, PhaseⅣ, Open Label Trial of Nilotinib in Adult Patients Diagnosed Philadelphia Chromosome Positive(Ph+) Chronic Myeloid Leukemia in CP/AP Intolerant to Dasatinib

Describe the purpose of the study: This study aims to evaluate the improvement of Dasatinib-related adverse events and to evaluate the treatment effect and safety by measuring the genetic response of nilotinib with nilotinib 400mg BID for 12 months in Philadelphia chromosome-positive chronic myeloid leukemia patients intolerant to Dasatinib.

NCT02389920 Leukemia, Chronic Myeloid Drug: Nilotinib
MeSH: Leukemia Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO: Chronic myelogenous leukemia Leukemia

- Potassium ≥ LLN- Magnesium ≥ LLN- Phosphorus ≥ LLN 7. Voluntary, signed and dated informed consent prior to any study procedures being performed Exclusion Criteria: 1. Subjects with the T315I mutation 2. Mutation known to be associated with low sensitivity to nilotinib(e.g., Y253H, E255K, E255V, F359V), 3. Cardiac function abnormalities as follows are found. --- T315I --- --- Y253H --- --- E255K ---

Primary Outcomes

Measure: The rate of improvement of Dasatinib-related adverse events

Time: at 3 months of nilotinib treatment

9 Phase I Trial Adding Ruxolitinib to a Combination of Dasatinib Plus Dexamethasone in Remission Induction Therapy in Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Patients Aged 40 Years or Older.

The purpose of this study is to test the safety of a new combination of three oral drugs in Ph+ ALL. These drugs are dexamethasone, dasatinib, and ruxolitinib. All three drugs have been studied before in humans. This is a phase I study in which ruxolitinib dose will start low for the first patient together with dexamethasone plus dasatinib. If this dose does not cause a bad side effect, the ruxolitinib dose will slowly be made higher as new patients take part in the study. This will help the investigators find the right dose of ruxolitinib to give together with dexamethasone and dasatinib that will be used in future studies

NCT02494882 Acute Lymphoblastic Leukemia Drug: Ruxolitinib Drug: Dasatinib Drug: Dexamethasone
MeSH: Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Philadelphia Chromosome
HPO: Leukemia Lymphoid leukemia

L248R, L248V, Q252H, E255K, V299L, T315A, T315I, F317C, F317L, F317S, F317V) - Relapsed or refractory Ph-like ALL without prior exposure to dasatibin and with mutations or rearrangements of genes conferring sensitivity to dasatibin (ABL, CSF1R, PDGFRB) or ruxolitinib (CRLF2, JAK3, EPOR, TSLP) - Newly diagnosed or relapsed CML in lymphoid blast crisis - Confirmation of Philadelphia chromosome positivity by cytogenetics (karyotype/FISH) and/or molecular tests (BCR-ABL1 transcripts) - Acceptable end-organ function, except for documented exclusions for organ function compromise due to ALL itself - ECOG performance status ≤ 2 - Men and women of childbearing potential must be willing to practice an effective method of birth control during treatment and for at least 4 months following treatment on study Exclusion Criteria: - Ph-negative ALL - Patients with dominant leukemic clone bearing documented bcr-abl mutations enabling bcr-abl TKI resistance at diagnosis - Mature B-cell (Burkitt's) ALL - Serum creatinine > 1.5x ULN and calculated creatinine clearance, based on a 24-hour urine collection, < 30 mL/min--unless related to ALL/tumor lysis syndrome and able to be corrected - Direct Bilirubin > 2x ULN; AST/ALT > 10x ULN, unless related to ALL liver infiltration. --- L248R --- --- L248V --- --- Q252H --- --- E255K ---

Primary Outcomes

Description: is to be evaluated by using a combination of criteria. Molecular remissions will be defined by standard criteria for BCR-ABL1 and IGH qRT-PCR. Flow cytometric assessment of MRD will be defined by standard flow cytometry criteria

Measure: Clinical response

Time: 2 years

Secondary Outcomes

Description: Molecular remission status will be defined by undetectable BCR-ABL1 transcripts and/or IGH clonal gene rearrangement in bone marrow aspirate (BMA) examination as determined by qRT-PCR in CLIA laboratory.

Measure: Complete Molecular Remission (CMR) rate

Time: 2 years

10 A Phase II, Single-arm, Multicenter Study of Full Treatment-free Remission in Patients With Chronic Myeloid Leukemia in Chronic Phase Treated With Nilotinib in First-line Therapy Who Have Achieved a Sustained, Deep Molecular Response for at Least 1 Year

This is a prospective, single arm, phase II study to assess the effect of nilotinib reduced to half the standard dose for 12 months on treatment-free remission in patients with CML-CP treated with first-line nilotinib who reached a sustained deep molecular response before entering the study.

NCT03874858 Chronic Myeloid Leukemia Drug: Nilotinib
MeSH: Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO: Chronic myelogenous leukemia Leukemia Myeloid leukemia

2. CML treatment resistant mutation(s) (T315I, E255K/V, Y253H, F359C/V) detected if testing was done in the past (there is no requirement to perform mutation testing at study entry if it was not done in the past). --- T315I --- --- E255K ---

Primary Outcomes

Description: Percentage of patients in full treatment-free remission 96 weeks after the start of the consolidation phase is calculated by dividing the number of patients with no loss of MMR-Major Molecular Response (BCR-ABL ≤ 0.1% (IS) after 96 weeks by the number of patients who entered the consolidation phase.

Measure: Percentage of patients in full treatment-free remission 96 weeks after the start of the consolidation phase.

Time: Baseline of consolidation phase up to 96 weeks

Secondary Outcomes

Description: The percentage of patients in sustained DMR at the end of the consolidation phase (week 48). Sustained DMR: Molecular Response (MR) 4.5 (IS) or undetectable MR4.0 with assay sensitivity of 4.0 log in 3 of the 4 BCR-ABL qPCR monthly assessments performed every 4 months, and with the last assessment in MR4.5 or undetectable MR4 before entering the TFR phase.

Measure: Percentage of patients who remain in sustained Deep Molecular Response (DMR) at the end of the consolidation phase (week 48).

Time: Baseline of consolidation phase up to 48 weeks

Description: The percentage of patients in deep molecular response is calculated by dividing the number of patients in DMR (MR4.5 or undetectable MR4.0) 48, 96 and 144 weeks after the start of the consolidation phase by the number of patients who entered the consolidation phase.

Measure: Percentage of patients who remain in DMR at the end of the consolidation phase (week 48), at 96 weeks and at 144 weeks after the start of the consolidation phase.

Time: Baseline of consolidation phase at week 48, 96 and 144

Description: The percentage of patients in full treatment-free remission at week 144 is calculated by dividing the number of patients with no loss of MMR (BCR-ABL ≤ 0.1% (IS)) 144 weeks after the start of the consolidation phase by the number of patients who entered the consolidation phase.

Measure: Percentage of patients in full treatment-free remission 144 weeks after the start of the consolidation phase.

Time: Baseline of consolidation phase at week 144

Description: The percentage of patients with MMR at week 48, 96 and 144 is calculated by dividing the number of patients with MMR at week 48, 96 and 144, regardless of whether they required re-initiation of treatment after the start the study, by the number of patients who entered the consolidation phase.

Measure: Percentage of patients with MMR or better at 48, 96, 144 weeks after starting the consolidation phase

Time: Baseline of consolidation phase at week 48, 96 and 144

Description: Descriptive statistics of BCR-ABL levels (International scale), measured by quantitative Polymerase Chain Reaction (PCR), over time after re-start of nilotinib therapy up to 144 weeks in patient who failed Treatment Free Remission Phase.

Measure: Change in Polymerase Chain Reaction (PCR) of BCR-ABL transcript after re-start of nilotinib therapy in patients who failed Treatment Free Remission Phase.

Time: Every 3 months after restart of nilotinib therapy up to approximately 144 weeks

Description: Descriptive statistics of BCR-ABL levels (IS), measured by quantitative PCR, over time after discontinuation of nilotinib therapy in Treatment Free Remission Phase up to 144 weeks.

Measure: Change in Polymerase Chain Reaction (PCR) of BCR-ABL transcript after discontinuation of nilotinib therapy in Treatment Free Remission Phase.

Time: Monthly up to week 96, every 12 weeks up to approximately week 144 after discontinuation of nilotinib therapy .

Description: Descriptive statistics of BCR-ABL levels (IS), measured by quantitative PCR, over time during the consolidation period to 48 weeks.

Measure: Change in Polymerase Chain Reaction (PCR) of BCR-ABL transcript during the consolidation period.

Time: Baseline of consolidation phase up to 48 weeks

Description: FTFS: time from the start of the consolidation phase to the earliest occurrence of any of the following events: loss of MMR, reinitiation of treatment due to any cause, progression to accelerated phase (AP)/blast crisis (BC), or death due to any cause.

Measure: Full Treatment-Free Survival (FTFS)

Time: Baseline of consolidation phase up to 144 weeks

Description: TFS: time from the start of the TFR phase to the earliest occurrence of any of the following events: loss of MMR, reinitiation of treatment due to any cause, progression to AP/BC or death due to any cause.

Measure: Treatment-free survival (TFS)

Time: From the start of the TFR phase up to Week 144.

Description: PFS: time from the start of the consolidation phase to progression to AP/BC or death due to any cause, whichever occurs first.

Measure: Progression-free survival (PFS) after the start of consolidation phase

Time: Baseline of consolidation phase up to 144 weeks

Description: PFS: time from the start of the TFR phase to progression to AP/BC or death due to any cause, whichever occurs first.

Measure: Progression Free Survival (PFS) after the start of TFR phase

Time: From the start of the TFR phase up to week 144.

Description: OS: time from start of the study to death due to any cause.

Measure: Overall Survival (OS)

Time: Baseline of consolidation phase up to 144 weeks

Description: To assess safety during the nilotinib treatment consolidation phase, TFR phase and during reinitiation of treatment with nilotinib.

Measure: The number of patients with Adverse Events as measure of safety and tolerability

Time: From screening up to approximately week 144

Description: Statistical correlation between clinical and laboratory correlates at diagnosis (e.g. Sokal Risk scale, demography, type of BCR-ABL transcript) or during previous treatment (e.g. Early Molecular Response=BCR-ABL transcript measured by quantitative PCR <10% after 3 months of first-line treatment with nilotinib at the dose of 300 mg BID) and the achievement of Full Treatment Free Remission and Treatment Free Remission at 96 weeks

Measure: Correlation between clinical and laboratory factors and clinical outcome

Time: Baseline of consolidation phase up to 96 weeks

Description: To characterize the kinetics of BCR-ABL transcripts after restart of nilotinib therapy in patients who failed Treatment Free Remission (TFR) phase.

Measure: Change in Polymerase Chain Reaction (PCR) of BCR-ABL transcripts after restart of nilotinib therapy in patients who failed TFR phase.

Time: Restart of nilotinib therapy in Follow Up Phase up to approximately 144 weeks

Description: To characterize the kinetics of BCR-ABL transcripts after discontinuation of nilotinib therapy in TFR Phase.

Measure: Change in Polymerase Chain Reaction (PCR) of BCR-ABL transcripts after discontinuation of nilotinib therapy in TFR Phase

Time: Discontinuation of nilotinib therapy in patients in TFR phase up to approximately 144 weeks

Description: To characterize the kinetics of BCR-ABL transcripts during the consolidation period.

Measure: Change in Polymerase Chain Reaction (PCR) of BCR-ABL transcripts during the consolidation period.

Time: Baseline of consolidation phase up to 48 weeks

Description: Identify which factors are associated with the successful of FTFR and TFR (no loss of MMR and no reinitiation of nilotinib therapy)in the first 96 weeks following the study start. Possible factors: patient demography, Sokal risk category, Early Molecular Response (EMR), type of transcript)

Measure: Correlation of factors associated with the successful clinical outcome to the treatment up to 96 weeks

Time: Baseline of consolidation phase up to approximately 96 weeks

Description: To characterize the kinetics of BCR-ABL transcripts after restart of nilotinib therapy in patients who failed Treatment Free Remission (TFR) phase.

Measure: The change of the kinetics of BCR-ABL transcripts after restart of nilotinib therapy in patients who failed TFR phase.

Time: Restart of nilotinib therapy in Follow Up Phase until week 144.

Description: To characterize the kinetics of BCR-ABL transcripts after discontinuation of nilotinib therapy in TFR Phase.

Measure: The change of the kinetics of BCR-ABL transcripts after discontinuation of nilotinib therapy in TFR Phase

Time: Discontinuation of nilotinib therapy in patients in TFR phase until week 144.

Description: To characterize the kinetics of BCR-ABL transcripts during the consolidation period.

Measure: The change of the kinetics of BCR-ABL transcripts during the consolidation period.

Time: Baseline of consolidation phase up to 48 weeks

Description: Identify the factors correlated to the successful of FTFR and TFR (no loss of MMR and no reinitiation of nilotinib therapy)in the first 96 weeks following the study start.

Measure: Identification of factors related to the clinical outcome to the treatment

Time: Baseline of consolidation phase up to approximately 96 weeks

11 Multicenter, Open-Label, Single Arm, Phase II Exploratory Study to Evaluate the Reinduction and Second Stop of TKI With Ponatinib in CML in Molecular Response (ResToP)

The purpose of the present study is to determine the rate of successful treatment-free remission (TFR) within the first 52 weeks following cessation of ponatinib treatment in patients who achieved MR4. Eligible patients had been previously treated with TKI and when patients achieved an optimal molecular response, TKI treatment was discontinued. After loss of response, patients were treated again with a TKI treatment and have documented MR4 for one year at the time of switch to ponatinib to study entry. MR4 is defined as BCR-ABL transcript level ≤ 0.01% IS or undetectable BCR-ABL levels with sample sensitivity of at least 4 log.

NCT04160546 Chronic Myeloid Leukemia, Chronic Phase Drug: Ponatinib 15 MG Drug: Acetylsalicylic acid 100 MG
MeSH: Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO: Chronic myelogenous leukemia Myeloid leukemia

3. CML treatment resistant mutation(s) (T315I, E255K/V, Y253H, F359C/V) detected if a testing was done in the past (there is no requirement to perform mutation testing at study entry if it was not done in the past). --- T315I --- --- E255K ---

Primary Outcomes

Description: This variable is defined as the number of patients who have a maintained MMR and have not restarted TKI therapy in the first 52 weeks after starting ponatinib TFR phase divided by the number of patients who entered ponatinib TFR phase.

Measure: Proportion of patients with a maintained MMR within 52 weeks following ponatinib Treatment-Free Remission (TFR)

Time: 52 weeks

Secondary Outcomes

Description: The number and percentage of patients with treatment-emergent adverse events (new or worsening from baseline) will be summarized by system organ class (SOC) and/or preferred term (PT), severity (based on CTCAE grades), type of adverse event and relation to study treatment.

Measure: Evaluate the toxicity and safety profile of 15 mg/24h dose treatment of ponatinib combined with ASA.

Time: 104 weeks

Description: The number and percentage of patients with thromboembolic events will be summarized by preferred term, severity (based on CTCAE grades), type of adverse event, relation to study treatment by the phases or subsets previously described.

Measure: Evaluate thromboembolic events for study period.

Time: 104 weeks

Description: The number and percentage of patients with hemorrhagic events will be summarized by preferred term, severity (based on CTCAE grades), type of adverse event, relation to study treatment by the phases or subsets previously described.

Measure: Evaluate hemorrhagic events for study period.

Time: 104 weeks

Description: The number and percentage of patients with hemolytic events will be summarized by preferred term, severity (based on CTCAE grades), type of adverse event, relation to study treatment by the phases or subsets previously described.

Measure: Evaluate hemolytic events for study period.

Time: 104 weeks

Description: The number and percentage of patients with gastrointestinal events will be summarized by preferred term, severity (based on CTCAE grades), type of adverse event, relation to study treatment by the phases or subsets previously described.

Measure: Evaluate gastrointestinal events for study period.

Time: 104 weeks

Description: Number of patients still in MR4 and have not restarted TKI therapy in the first 52 weeks after starting ponatinib TFR phase divided by the number of patients who entered ponatinib TFR phase.

Measure: Evaluate the proportion of patients still in MR4 (BCR-ABL ≤ 0.01%) within 52 weeks following ponatinib therapy cessation.

Time: 52 weeks

Description: The number of patients who still have a MMR and have not restarted TKI therapy in the first 24 weeks after starting ponatinib TFR phase divided by the number of patients who entered ponatinib TFR phase.

Measure: Evaluate the proportion of patients still in MMR within 24 weeks following ponatinib therapy cessation.

Time: 24 weeks

Description: Number of patients with each clinical response obtained after stop Ponatinib treatment classified with subject´s physical activity frequency during 52 weeks

Measure: Evaluate the effects of physical activity on treatment response

Time: 52 weeks

Description: Time from start ponatinib treatment to the occurrence of progression to AP/BC, loss of MMR or death from any cause, the earliest of these events.

Measure: To estimate progression-free survival (PFS)

Time: 4 years

Description: time from ponatinib cessation to the occurrence of loss of MMR, restart of TKI treatment, progression of AP/BC, or death from any cause, the earliest of these events.

Measure: Treatment-free survival (TFS)

Time: 104 weeks

Other Outcomes

Description: The number of patients who achieve a MR 5 at ponatinib therapy cessation divided by the number of patients who entered ponatinib TFR phase.

Measure: Evaluate the proportion of patients who achieve a MR 5 at ponatinib therapy cessation.

Time: 104 weeks


HPO Nodes


Chronic myelogenous leukemia
Genes 9
KIT MPL ASXL1 TET2 ABL1 JAK2 THPO BCR SRSF2
Leukemia
Genes 190
ATM KRAS KIT RPS15A NF1 MPL RPL35A RPL11 RPL18 DDX41 SBDS LPP ETV6 BUB1B F13A1 DNMT3A JAK2 NUP214 FANCD2 MSH6 FANCA PIGL NRAS TCIRG1 BUB1 TET2 FLT3 TAL1 ATRX TREX1 PDGFRA SRP54 RPS29 PTPN11 CALR FANCE WIPF1 SF3B1 GATA2 GLI1 STS SH3GL1 XRCC4 MPL SH2B3 EFL1 PIGA TREM2 CBL MPL RUNX1 MPL PIGL THPO FANCG NSD1 BRD4 NSUN2 SH2B3 RARA GATA2 NPM1 CBL CHIC2 ERBB3 GFI1 TERT KIT BCR ARHGAP26 DYNC2LI1 EVC SCN10A GATA1 ELANE RNASEH2B RPS14 SH2B3 JAK2 RPL15 SBDS NRAS RPL26 RPL27 ADA2 RPS7 TYROBP F13B MSH2 BCR WAS TERC TP53 TRIP13 MYD88 NUTM1 RPS24 GNB1 TP53 DNMT3A TERT NUMA1 NUP214 RPL5 SAMD9L TET2 CFTR POT1 FANCC RPS10 EP300 EVC2 BUB1B CEBPA BRCA2 DNAJC21 CALR SCN9A LIG4 ADAR BLM TET2 JAK2 SMPD1 RNASEH2C SCN11A GATA2 BUB3 PRSS1 KIF11 BCR RPL35 TAL2 SRP54 IFIH1 ABL1 PDGFRB KRAS RNASEH2A TET2 MLLT10 SRP54 DNAJC21 DKC1 RUNX1 APC LIG4 CBFB BLM THPO CALR NBN JAK2 MLH1 RPS19 ELANE SAMD9L RPL31 PMS2 ASXL1 TSR2 MLF1 PIK3CA DNAJC21 RUNX1 GFI1 SRSF2 SETBP1 HAX1 RPS26 RPS17 FLT3 RPS27 PIK3R1 KRAS CEP57 PICALM CREBBP GATA2 CTRC MYD88 TET2 RPS28 ABL1 RB1 SPINK1 GATA1 NBN JAK2 SAMHD1
Myeloid leukemia
Genes 20
KIT SETBP1 NF1 ARHGAP26 CBL TET2 KRAS PTPN11 F13A1 SAMD9L SAMD9L GATA2 CBL ASXL1 DNMT3A F13B NRAS SRSF2 TERC TERT
Lymphoid leukemia