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Report for Mutation T315I

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 100 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 --- --- T315I ---

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 --- --- T315I ---

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 Pilot Phase II Study of PHA-739358 in Patients With Chronic Myeloid Leukemia Relapsing on Gleevec or c-ABL Therapy

RATIONALE: PHA-739358 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. PURPOSE: This phase II trial is studying how well PHA-739358 works in treating patients with chronic myelogenous leukemia that relapsed after imatinib mesylate or c-ABL therapy.

NCT00335868 Leukemia Drug: danusertib Other: laboratory biomarker analysis Other: pharmacological study
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

DISEASE CHARACTERISTICS: - Diagnosis of chronic myelogenous leukemia confirmed by bone marrow biopsy - Chronic, accelerated, or blastic phase disease - May have T315I mutation in BCR-ABL kinase - Relapsed after prior imatinib mesylate or c-ABL therapy - No CNS leukemia PATIENT CHARACTERISTICS: - ECOG performance status 0-2 - Blood pressure ≤ 140/90 mm Hg (with or without hypertension treatment for ≥ 1 week) - Transaminases ≤ 2.5 times upper limit of normal (ULN) - Bilirubin ≤ 1.5 times ULN - Creatinine ≤ 1.5 times ULN - No known history of HIV infection - No active uncontrolled infection - No grade 3 or 4 bleeding - LVEF ≥ 45% by MUGA or ≥ 40% by transthoracic echocardiography - No medical or psychiatric condition or laboratory abnormalities that would limit study compliance or increase risk during study participation - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 90 (female) or 180 (male) days after completion of study treatment - No significant cardiovascular disease (i.e., uncontrolled arrhythmias or unstable angina) within the past 6 months - No major thromboembolic event within the past 6 months, including any of the following: - Myocardial infarction - Stroke - Transient ischemic attack - Pulmonary embolism - Noncatheter-related deep-vein thrombosis PRIOR CONCURRENT THERAPY: - Recovered from all acute toxic effects (excluding alopecia) of prior therapy - More than 2 weeks since prior chemoimmunotherapy - Hydroxyurea must be discontinued 1 day prior to study therapy - More than 4 weeks since prior major surgery - No other concurrent approved or investigational anticancer treatment, including chemotherapy, biologic response modifiers, hormones, or immunotherapy - No other concurrent investigational drugs - No concurrent participation in another treatment clinical trial DISEASE CHARACTERISTICS: - Diagnosis of chronic myelogenous leukemia confirmed by bone marrow biopsy - Chronic, accelerated, or blastic phase disease - May have T315I mutation in BCR-ABL kinase - Relapsed after prior imatinib mesylate or c-ABL therapy - No CNS leukemia PATIENT CHARACTERISTICS: - ECOG performance status 0-2 - Blood pressure ≤ 140/90 mm Hg (with or without hypertension treatment for ≥ 1 week) - Transaminases ≤ 2.5 times upper limit of normal (ULN) - Bilirubin ≤ 1.5 times ULN - Creatinine ≤ 1.5 times ULN - No known history of HIV infection - No active uncontrolled infection - No grade 3 or 4 bleeding - LVEF ≥ 45% by MUGA or ≥ 40% by transthoracic echocardiography - No medical or psychiatric condition or laboratory abnormalities that would limit study compliance or increase risk during study participation - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 90 (female) or 180 (male) days after completion of study treatment - No significant cardiovascular disease (i.e., uncontrolled arrhythmias or unstable angina) within the past 6 months - No major thromboembolic event within the past 6 months, including any of the following: - Myocardial infarction - Stroke - Transient ischemic attack - Pulmonary embolism - Noncatheter-related deep-vein thrombosis PRIOR CONCURRENT THERAPY: - Recovered from all acute toxic effects (excluding alopecia) of prior therapy - More than 2 weeks since prior chemoimmunotherapy - Hydroxyurea must be discontinued 1 day prior to study therapy - More than 4 weeks since prior major surgery - No other concurrent approved or investigational anticancer treatment, including chemotherapy, biologic response modifiers, hormones, or immunotherapy - No other concurrent investigational drugs - No concurrent participation in another treatment clinical trial Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive OBJECTIVES: - Explore the clinical efficacy of PHA-739358, in terms of hematological response lasting ≥ 4 weeks, in patients with chronic myelogenous leukemia that relapsed after imatinib mesylate or c-ABL therapy. --- T315I ---

DISEASE CHARACTERISTICS: - Diagnosis of chronic myelogenous leukemia confirmed by bone marrow biopsy - Chronic, accelerated, or blastic phase disease - May have T315I mutation in BCR-ABL kinase - Relapsed after prior imatinib mesylate or c-ABL therapy - No CNS leukemia PATIENT CHARACTERISTICS: - ECOG performance status 0-2 - Blood pressure ≤ 140/90 mm Hg (with or without hypertension treatment for ≥ 1 week) - Transaminases ≤ 2.5 times upper limit of normal (ULN) - Bilirubin ≤ 1.5 times ULN - Creatinine ≤ 1.5 times ULN - No known history of HIV infection - No active uncontrolled infection - No grade 3 or 4 bleeding - LVEF ≥ 45% by MUGA or ≥ 40% by transthoracic echocardiography - No medical or psychiatric condition or laboratory abnormalities that would limit study compliance or increase risk during study participation - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 90 (female) or 180 (male) days after completion of study treatment - No significant cardiovascular disease (i.e., uncontrolled arrhythmias or unstable angina) within the past 6 months - No major thromboembolic event within the past 6 months, including any of the following: - Myocardial infarction - Stroke - Transient ischemic attack - Pulmonary embolism - Noncatheter-related deep-vein thrombosis PRIOR CONCURRENT THERAPY: - Recovered from all acute toxic effects (excluding alopecia) of prior therapy - More than 2 weeks since prior chemoimmunotherapy - Hydroxyurea must be discontinued 1 day prior to study therapy - More than 4 weeks since prior major surgery - No other concurrent approved or investigational anticancer treatment, including chemotherapy, biologic response modifiers, hormones, or immunotherapy - No other concurrent investigational drugs - No concurrent participation in another treatment clinical trial DISEASE CHARACTERISTICS: - Diagnosis of chronic myelogenous leukemia confirmed by bone marrow biopsy - Chronic, accelerated, or blastic phase disease - May have T315I mutation in BCR-ABL kinase - Relapsed after prior imatinib mesylate or c-ABL therapy - No CNS leukemia PATIENT CHARACTERISTICS: - ECOG performance status 0-2 - Blood pressure ≤ 140/90 mm Hg (with or without hypertension treatment for ≥ 1 week) - Transaminases ≤ 2.5 times upper limit of normal (ULN) - Bilirubin ≤ 1.5 times ULN - Creatinine ≤ 1.5 times ULN - No known history of HIV infection - No active uncontrolled infection - No grade 3 or 4 bleeding - LVEF ≥ 45% by MUGA or ≥ 40% by transthoracic echocardiography - No medical or psychiatric condition or laboratory abnormalities that would limit study compliance or increase risk during study participation - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 90 (female) or 180 (male) days after completion of study treatment - No significant cardiovascular disease (i.e., uncontrolled arrhythmias or unstable angina) within the past 6 months - No major thromboembolic event within the past 6 months, including any of the following: - Myocardial infarction - Stroke - Transient ischemic attack - Pulmonary embolism - Noncatheter-related deep-vein thrombosis PRIOR CONCURRENT THERAPY: - Recovered from all acute toxic effects (excluding alopecia) of prior therapy - More than 2 weeks since prior chemoimmunotherapy - Hydroxyurea must be discontinued 1 day prior to study therapy - More than 4 weeks since prior major surgery - No other concurrent approved or investigational anticancer treatment, including chemotherapy, biologic response modifiers, hormones, or immunotherapy - No other concurrent investigational drugs - No concurrent participation in another treatment clinical trial Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive OBJECTIVES: - Explore the clinical efficacy of PHA-739358, in terms of hematological response lasting ≥ 4 weeks, in patients with chronic myelogenous leukemia that relapsed after imatinib mesylate or c-ABL therapy. --- T315I --- --- T315I ---

- Explore response depending on status of T315I mutation in BCR-ABL kinase. --- T315I ---

Primary Outcomes

Measure: Antileukemic response in terms of complete hematological response, no evidence of leukemia, or return to chronic phase

Measure: Overall safety profile of PHA-739358 by type, severity, timing, and relatedness of adverse events and laboratory abnormalities

Measure: Pharmacokinetics of this drug and its N-oxide metabolite PHA-816359 by measuring their plasma concentration at different times after dosing

Measure: Changes in histone H3 and CRKL phosphorylation

Measure: Correlation between changes in degree of histone H3 and CRKL phosphorylation and concurrent PHA-739358 concentrations and/or hematological response

Measure: Complete, partial, or minor cytogenetic response in bone marrow

3 An Open-Label Randomized Phase III Study of Dasatinib vs. High-Dose (600 mg) Imatinib Mesylate in the Treatment of Subjects With Chronic Phase Philadelphia Chromosome-Positive Chronic Myeloid Leukemia Who Are Imatinib Failures or Who Have Had a Suboptimal Response After 3-18 Months of Therapy With 400 mg Imatinib

The purpose of this clinical research study is to compare the rate of complete cytogenetic response of dasatinib to imatinib therapy at 6 months after randomization in chronic phase CML patients. The safety of this treatment will also be studied.

NCT00362466 Leukemia Drug: Dasatinib Drug: Imatinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Inclusion Criteria: - Men and women ≥18 years diagnosed with Chronic Phase Philadelphia chromosome positive (CP Ph+) CML who have failed to achieve CCyR after 3-18 months of therapy with imatinib 400 mg - Treatment initiation with imatinib 400 mg within 6 months of initial CML diagnosis - Able to tolerate chronic administration of imatinib at the highest dose (400-600 mg) the subject has received in the past - Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2 - Adequate hepatic and renal function Exclusion Criteria: - Eligible and willing to undergo immediate autologous/allogeneic stem cell transplant - Previous diagnosis of accelerated/blast crisis CML - Subjects with clonal evolution in Ph+ cells observed in ≥2 metaphases - Previous documentation of T315I mutation - Uncontrolled or significant cardiovascular disease - Serious uncontrolled medical disorder/active infection - History of significant bleeding disorder unrelated to CML - Intolerance to imatinib ≥400 mg - Concurrent malignancies other than CML Inclusion Criteria: - Men and women ≥18 years diagnosed with Chronic Phase Philadelphia chromosome positive (CP Ph+) CML who have failed to achieve CCyR after 3-18 months of therapy with imatinib 400 mg - Treatment initiation with imatinib 400 mg within 6 months of initial CML diagnosis - Able to tolerate chronic administration of imatinib at the highest dose (400-600 mg) the subject has received in the past - Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2 - Adequate hepatic and renal function Exclusion Criteria: - Eligible and willing to undergo immediate autologous/allogeneic stem cell transplant - Previous diagnosis of accelerated/blast crisis CML - Subjects with clonal evolution in Ph+ cells observed in ≥2 metaphases - Previous documentation of T315I mutation - Uncontrolled or significant cardiovascular disease - Serious uncontrolled medical disorder/active infection - History of significant bleeding disorder unrelated to CML - Intolerance to imatinib ≥400 mg - Concurrent malignancies other than CML Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive null --- T315I ---

Inclusion Criteria: - Men and women ≥18 years diagnosed with Chronic Phase Philadelphia chromosome positive (CP Ph+) CML who have failed to achieve CCyR after 3-18 months of therapy with imatinib 400 mg - Treatment initiation with imatinib 400 mg within 6 months of initial CML diagnosis - Able to tolerate chronic administration of imatinib at the highest dose (400-600 mg) the subject has received in the past - Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2 - Adequate hepatic and renal function Exclusion Criteria: - Eligible and willing to undergo immediate autologous/allogeneic stem cell transplant - Previous diagnosis of accelerated/blast crisis CML - Subjects with clonal evolution in Ph+ cells observed in ≥2 metaphases - Previous documentation of T315I mutation - Uncontrolled or significant cardiovascular disease - Serious uncontrolled medical disorder/active infection - History of significant bleeding disorder unrelated to CML - Intolerance to imatinib ≥400 mg - Concurrent malignancies other than CML Inclusion Criteria: - Men and women ≥18 years diagnosed with Chronic Phase Philadelphia chromosome positive (CP Ph+) CML who have failed to achieve CCyR after 3-18 months of therapy with imatinib 400 mg - Treatment initiation with imatinib 400 mg within 6 months of initial CML diagnosis - Able to tolerate chronic administration of imatinib at the highest dose (400-600 mg) the subject has received in the past - Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2 - Adequate hepatic and renal function Exclusion Criteria: - Eligible and willing to undergo immediate autologous/allogeneic stem cell transplant - Previous diagnosis of accelerated/blast crisis CML - Subjects with clonal evolution in Ph+ cells observed in ≥2 metaphases - Previous documentation of T315I mutation - Uncontrolled or significant cardiovascular disease - Serious uncontrolled medical disorder/active infection - History of significant bleeding disorder unrelated to CML - Intolerance to imatinib ≥400 mg - Concurrent malignancies other than CML Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive null --- T315I --- --- T315I ---

Primary Outcomes

Measure: Complete Cytogenetic Response (CCyR) Rate at Month 6

Time: Month 6

Secondary Outcomes

Measure: Major Molecular Response (MMR) Rates

Time: Month 3, Month 6, Month 12, Month 24 and Month 36

Measure: CCyR Rates

Time: Month 3, Month 12, Month 24 and Month 36

Measure: Estimate Time to MMR and CCyR

Time: throughout the study

Measure: Progression Free Survival (PFS)

Time: at 36 months

Measure: Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Due to AEs

Time: From 2 weeks prior to randomization through Month 36. At least every 4 weeks until all study-related toxicities resolve to baseline, stabilize, or are deemed irreversible.

Measure: Duration of CCyR and MMR

Time: Throughout the study

Measure: Best MMR Rates

Time: throughout study

4 A Phase II Open-Label Study of the Subcutaneous Administration of Homoharringtonine (Omacetaxine Mepesuccinate) in the Treatment of Patients With Chronic Myeloid Leukemia (CML) With the T315I BCR-ABL Gene Mutation

To evaluate the safety and efficacy of subcutaneous administration of omacetaxine mepesuccinate (HHT) in achieving a clinical response in CML patients in chronic, accelerated, or blast phase who have failed prior imatinib therapy and have the T315I kinase domain gene mutation.

NCT00375219 Chronic Myeloid Leukemia Drug: Omacetaxine mepesuccinate
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

A Phase II Open-Label Study of the Subcutaneous Administration of Homoharringtonine (Omacetaxine Mepesuccinate) in the Treatment of Patients With Chronic Myeloid Leukemia (CML) With the T315I BCR-ABL Gene Mutation. --- T315I ---

Homoharringtonine (Omacetaxine Mepesuccinate) in Treating Patients With Chronic Myeloid Leukemia (CML) With the T315I BCR-ABL Gene Mutation To evaluate the safety and efficacy of subcutaneous administration of omacetaxine mepesuccinate (HHT) in achieving a clinical response in CML patients in chronic, accelerated, or blast phase who have failed prior imatinib therapy and have the T315I kinase domain gene mutation. --- T315I ---

Homoharringtonine (Omacetaxine Mepesuccinate) in Treating Patients With Chronic Myeloid Leukemia (CML) With the T315I BCR-ABL Gene Mutation To evaluate the safety and efficacy of subcutaneous administration of omacetaxine mepesuccinate (HHT) in achieving a clinical response in CML patients in chronic, accelerated, or blast phase who have failed prior imatinib therapy and have the T315I kinase domain gene mutation. --- T315I --- --- T315I ---

Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL. --- T315I ---

A quarterly phone survey was conducted to collect survival data for participants who discontinued from the study.. Inclusion Criteria: - Male or female patients, age 18 years or older - Philadelphia chromosome (Ph) positive chronic myelogenous leukemia in either chronic, accelerated, or blast phase - The patient will have the T315I BCR-ABL gene mutation - Patients will have failed prior imatinib therapy - ECOG performance status 0-2 Exclusion Criteria: - NYHA class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia and requiring therapy, uncontrolled hypertension or congestive heart failure - Myocardial infarction in the previous 12 weeks - Lymphoid Ph+ blast crisis Inclusion Criteria: - Male or female patients, age 18 years or older - Philadelphia chromosome (Ph) positive chronic myelogenous leukemia in either chronic, accelerated, or blast phase - The patient will have the T315I BCR-ABL gene mutation - Patients will have failed prior imatinib therapy - ECOG performance status 0-2 Exclusion Criteria: - NYHA class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia and requiring therapy, uncontrolled hypertension or congestive heart failure - Myocardial infarction in the previous 12 weeks - Lymphoid Ph+ blast crisis Chronic Myeloid Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Point mutations within the ABL kinase domain of the BCR-ABL gene are emerging as the most frequent mechanism for resistance to imatinib and resultant reactivation of kinase activity. --- T315I ---

A quarterly phone survey was conducted to collect survival data for participants who discontinued from the study.. Inclusion Criteria: - Male or female patients, age 18 years or older - Philadelphia chromosome (Ph) positive chronic myelogenous leukemia in either chronic, accelerated, or blast phase - The patient will have the T315I BCR-ABL gene mutation - Patients will have failed prior imatinib therapy - ECOG performance status 0-2 Exclusion Criteria: - NYHA class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia and requiring therapy, uncontrolled hypertension or congestive heart failure - Myocardial infarction in the previous 12 weeks - Lymphoid Ph+ blast crisis Inclusion Criteria: - Male or female patients, age 18 years or older - Philadelphia chromosome (Ph) positive chronic myelogenous leukemia in either chronic, accelerated, or blast phase - The patient will have the T315I BCR-ABL gene mutation - Patients will have failed prior imatinib therapy - ECOG performance status 0-2 Exclusion Criteria: - NYHA class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia and requiring therapy, uncontrolled hypertension or congestive heart failure - Myocardial infarction in the previous 12 weeks - Lymphoid Ph+ blast crisis Chronic Myeloid Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Point mutations within the ABL kinase domain of the BCR-ABL gene are emerging as the most frequent mechanism for resistance to imatinib and resultant reactivation of kinase activity. --- T315I --- --- T315I ---

The T315I kinase domain (KD) point mutation has merited particular attention, as T315I expressing CML cells are markedly resistant to imatinib. --- T315I ---

The T315I kinase domain (KD) point mutation has merited particular attention, as T315I expressing CML cells are markedly resistant to imatinib. --- T315I --- --- T315I ---

CML patients with the T315I KD mutation, therefore, do not respond to continued treatment with imatinib, and preliminary clinical data indicate that neither of two newer tyrosine kinase inhibitors will have activity in patients with T315I KD mutation either. --- T315I ---

CML patients with the T315I KD mutation, therefore, do not respond to continued treatment with imatinib, and preliminary clinical data indicate that neither of two newer tyrosine kinase inhibitors will have activity in patients with T315I KD mutation either. --- T315I --- --- T315I ---

HHT works via a different mechanism than imatinib or other tyrosine kinase inhibitors (TKI's), and HHT has been shown to inhibit in vitro CML cell lines which harbor the T315I KD mutation and are highly resistant to imatinib. --- T315I ---

Therefore, CML patients who have the T315I KD mutation may still respond to treatment with HHT. --- T315I ---

HHT may therefore be an attractive therapeutic option for patients with the T315I KD mutation. --- T315I ---

On this basis, a multicenter clinical trial is being conducted of HHT therapy for CML patients who have failed prior imatinib therapy and have the T315I KD mutation. --- T315I ---

Primary Outcomes

Description: Subpopulations reflect chronic myeloid leukemia (CML) phases at the time of enrollment: chronic, accelerated, and blast phase. Primary endpoints as adjudicated by the Data Monitoring Committee were used for the primary analyses. Overall hematologic response for chronic phase participants includes confirmed complete hematologic response (CHR). Overall hematologic response for accelerated or blast phase participants includes confirmed complete hematologic response (CHR), no evidence of leukemia (NEL), or return to chronic phase (RCP). Hematologic response must last >= 8 weeks to be considered meaningful. Response rates by disease phase were examined relative to an a priori value of 2.5% using a one-sided lower 95% exact binomial confidence limit. If the lower limit from the one-sided lower 95% confidence limit exceeds 2.5%, the observed response rate will have exceeded the minimum threshold required to demonstrate efficacy.

Measure: Percentage of Participants Achieving an Overall Hematologic Response by Subpopulation and Total Population

Time: Day 1 up to 6 months

Description: Subpopulations reflect chronic myeloid leukemia (CML) phases at the time of enrollment: chronic, accelerated, and blast phase. Primary endpoints as adjudicated by the Data Monitoring Committee were used for the primary analyses. Major cytogenetic response includes complete or partial response. Both confirmed and unconfirmed major cytogenetic response is considered meaningful. Unconfirmed response is based on a single bone marrow cytogenetic evaluation for participants where a confirmatory evaluation is not available. Complete response shows 0% Philadelphia chromosome positive (Ph+) cells. A partial response shows >0% - 35% Ph+ cells. Response rates by disease phase were examined relative to an a priori value of 2.5% using a one-sided lower 95% exact binomial confidence limit. If the lower limit from the one-sided lower 95% confidence limit exceeds 2.5%, the observed response rate will have exceeded the minimum threshold required to demonstrate efficacy.

Measure: Percentage of Participants Achieving a Major Cytogenetic Response by Subpopulation and Total Population

Time: Day 1 up to 6 months

Description: TEAE are any untoward events that were newly occurring or worsening from Baseline. Treatment related toxicity was considered by the investigator to be unrelated, possibly, probably or unknown related to study drug. Severity was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0 on the following scale: Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, Grade 5 = death. A serious adverse event (SAE) is any untoward medical occurrence that is fatal or life-threatening; results in persistent or significant disability or incapacity; requires or prolongs in-patient hospitalization; is a congenital anomaly/birth defect in the offspring of a patient; and conditions not included in the above that may jeopardize the patient or may require intervention to prevent one of the outcomes listed above. A participant is only counted once in each category (at worst severity or strongest relationship).

Measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total

Time: up to 3 years

Secondary Outcomes

Description: Cytogenetic response categories: Complete: 0% Ph+ cells Partial: >0%-35% Ph+ cells Minor: >35%-65% Ph+ cells Minimal: >65%-95% Ph+ cells No Response: >95% Ph+ cells Unevaluable: <20 metaphases were examined and/or response could not be assigned

Measure: Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+)

Time: Day 1 up to Month 9

Description: MMR is defined as a ratio of BCR-ABL/standard gene of less than 0.1% according to the international scale. BCR-ABL is a fusion gene of the breakpoint cluster region [BCR] gene and Abelson proto-oncogene [ABL] genes). This analysis used the standard gene GUS. Analysis was performed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) of peripheral blood.

Measure: Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene GUS

Time: Day 1 up to Month 6

Description: MMR is defined as a ratio of BCR-ABL/standard gene of less than 0.1% according to the international scale. BCR-ABL is a fusion gene of the breakpoint cluster region [BCR] gene and Abelson proto-oncogene [ABL] genes). This analysis used the standard gene ABL. Analysis was performed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) of peripheral blood.

Measure: Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene ABL

Time: Day 1 up to Month 6

Description: Complete Response (CHR) Chronic phase must last at least 8 weeks: WBC <10*10^9/liter, platelets <450*10^9/liter, myelocytes + metamyelocytes <5% in blood, no blasts or promyelocytes in blood, <20% basophils in peripheral blood, no extramedullary involvement. Accelerated and Blast phase must last at least 4 weeks: absolute neutrophil count 1.5*10^9/liter, platelets 100*10^9/liter, no blood blasts, bone marrow blasts <5%, no extramedullary disease. Partial Response - CHR plus one or more of the following: Persistence of splenomegaly with a reduction of ≥50% from pre-treatment Platelets > 450*10^9/L Presence of immature cells in the peripheral blood 5% to 25% blasts in the bone marrow If extra-medullary disease pre-treatment, reduction by ≥50% Hematologic Improvement - CHR, except allowing persistent thrombocytopenia (<100*10^9/L), and a few immature cells No evidence of leukemia: Morphologic leukemia-free state, defined as <5% bone marrow blasts.

Measure: Percentage of Participants in Each Hematologic Response Category

Time: Day 1 up to Month 6

Description: Clinical response was defined by disease phase and based on evaluations by the independent Data Monitoring Committee (DMC). Chronic Phase subgroup: achieving a complete hematologic response and/or major cytogenetic response (complete cytogenetic response or partial cytogenetic response, confirmed or unconfirmed). Accelerated Phase and Blast Phase subgroups: achieving complete hematologic response, no evidence of leukemia, return to chronic phase, and/or major cytogenetic response (complete cytogenetic response or partial cytogenetic response, confirmed or unconfirmed). The percentage of participants achieving response with extramedullary disease at Baseline was to be summarized, if the sample size was sufficient. This analysis was not done as the sample was ultimately insufficient

Measure: Percentage of Participants With Extramedullary Disease (EMD) at Baseline Achieving a Clinical Response

Time: Day 1 up to Month 9

Description: Summarization is based on the best of the individual response assessments. Not assessable indicates that the participant either had no baseline assessment or the % mutation could not be determined in the post-baseline assessment(s).

Measure: Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL

Time: Day 1 up to Month 9

Description: Induction therapy was administered for 14 consecutive days for each 28 days cycle, for up to 6 cycles. All treatment arms were given omacetaxine mepesuccinate via subcutaneous (SC) administration at 1.25 mg/m^2 twice a day (BID) for the 14 consecutive days.

Measure: Number of Treatment Cycles Needed to Achieve Best Hematologic Response

Time: Day 1 up to Month 6

Measure: Number of Treatment Cycles Needed to Achieve Best Cytogenetic Response

Time: Day 1 up to 22 months

Description: Time to onset was analyzed using Kaplan-Meier estimates. Participants who did not achieve a response are censored at their last visit day. Overall hematologic response for chronic phase participants includes confirmed complete hematologic response (CHR). Overall hematologic response for accelerated or blast phase participants includes confirmed complete hematologic response (CHR), no evidence of leukemia (NEL), or return to chronic phase (RCP). Hematologic response must last >= 8 weeks to be considered meaningful.

Measure: Kaplan-Meier Estimates for Time to Onset of Best Hematologic Response

Time: Day 1 up to Month 6

Description: Time to onset was analyzed using Kaplan-Meier estimates. Participants who did not achieve a response are censored at their last visit day. Major cytogenetic response includes complete or partial response. Both confirmed and unconfirmed major cytogenetic response is considered meaningful. Unconfirmed response is based on a single bone marrow cytogenetic evaluation for participants where a confirmatory evaluation is not available. Complete response shows 0% Philadelphia chromosome positive (Ph+) cells. A partial response shows >0% - 35% Ph+ cells.

Measure: Kaplan-Meier Estimates for Time to Onset of Best Cytogenetic Response

Time: up to 3 years

Description: Duration of response is defined as the time from first reported date of hematologic response until the earliest date of objective evidence of disease progression, relapse or death. Data was censored at the last examination date for participants with ongoing response or participants who discontinued treatment for reasons other than adverse event, disease progression or death.

Measure: Kaplan-Meier Estimates for Duration of Best Hematologic Response

Time: up to 4 years

Description: Duration of response is defined as the time from first reported date of cytogenetic response until the earliest date of objective evidence of disease progression, relapse or death. Data was censored at the last examination date for participants with ongoing response or participants who discontinued treatment for reasons other than adverse event, disease progression or death.

Measure: Kaplan-Meier Estimates for Duration of Best Cytogenetic Response

Time: up to 4 years

Description: Time to disease progression is defined as the time from the initiation of treatment until the onset date of death, the development of CML accelerated phase or blast phase, or the loss of complete hematologic response or major cytogenetic response, whichever came first. Participants were censored only if they did not have progression or if they discontinued treatment for reasons other than AE, progression or death.

Measure: Kaplan-Meier Estimates for Time to Disease Progression

Time: up to 4 years

Description: Overall survival is defined as the time from the initiation of treatment until death from any cause or the last day of participant contact or evaluation for participants that were lost to follow-up. Participants were censored t the last recorded contract or evaluation when a participant was alive at time of analysis. A quarterly phone survey was conducted to collect survival data for participants who discontinued from the study.

Measure: Kaplan-Meier Estimates for Overall Survival

Time: up to 4 years

5 A Phase II Study of MK0457 in Patients With T315I Mutant Chronic Myelogenous Leukemia and Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia

This study will evaluate MK0457 in patients with chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Efficacy and safety will be evaluated.

NCT00405054 Leukemia Drug: MK0457
MeSH:Leukemia
HPO:Leukemia

A Phase II Study of MK0457 in Patients With T315I Mutant Chronic Myelogenous Leukemia and Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia. --- T315I ---

A Phase II Study of MK0457 in Patients With T315I Mutant CML and Ph+All (0457-008) This study will evaluate MK0457 in patients with chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. --- T315I ---

Inclusion Criteria: - This study will evaluate MK0457 in patients with CML (chronic myelogenous leukemia) and Ph+ALL (Philadelphia chromosome-positive acute lymphoblastic leukemia) - Patients must have adequate organ function - Patients must have documented T315I mutation Exclusion Criteria: - Patients within 3 months of allogeneic bone marrow transplant or not fully recovered from previous anti-leukemia therapy - Patients with uncontrolled congestive heart failure - Patients with active or uncontrolled infection or active Hepatitis B or C - Patients with known HIV positivity or AIDS related illness - Patients with currently active second malignancy, other than non-melanoma skin cancer. --- T315I ---

Primary Outcomes

Measure: efficacy

Time: 24 Months

6 A Phase II Open-Label Study of the Subcutaneous Administration of Homoharringtonine (Omacetaxine Mepesuccinate) in the Treatment of Patients With Chronic Myeloid Leukemia (CML) Who Have Failed or Are Intolerant to Tyrosine Kinase Inhibitor Therapy

A Phase II open-label trial of subcutaneous HHT (omacetaxine mepesuccinate) in the treatment of patients who are resistant to or intolerant to Tyrosine Kinase Inhibitors.

NCT00462943 Chronic Myeloid Leukemia Drug: Omacetaxine mepesuccinate
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Accelerated Phase and Blast Phase subgroups: achieving complete hematologic response, no evidence of leukemia, return to chronic phase, and/or major cytogenetic response (complete cytogenetic response or partial cytogenetic response, confirmed or unconfirmed).. Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL. --- T315I ---

Primary Outcomes

Description: Subpopulations reflect chronic myeloid leukemia (CML) phases at the time of enrollment: chronic, accelerated, and blast phase. Primary endpoints as adjudicated by the Data Monitoring Committee were used for the primary analyses. Overall hematologic response for chronic phase participants includes confirmed complete hematologic response (CHR). Overall hematologic response for accelerated or blast phase participants includes confirmed complete hematologic response (CHR), no evidence of leukemia (NEL), or return to chronic phase (RCP). Hematologic response must last >= 8 weeks to be considered meaningful. Response rates by disease phase were examined relative to an a priori value of 2.5% using a one-sided lower 95% exact binomial confidence limit. If the lower limit from the one-sided lower 95% confidence limit exceeds 2.5%, the observed response rate will have exceeded the minimum threshold required to demonstrate efficacy.

Measure: Percentage of Participants Achieving an Overall Hematologic Response by Subpopulation and Total Population

Time: Day 1 up to 6 months

Description: Subpopulations reflect chronic myeloid leukemia (CML) phases at the time of enrollment: chronic, accelerated, and blast phase. Primary endpoints as adjudicated by the Data Monitoring Committee were used for the primary analyses. Major cytogenetic response includes complete or partial response. Both confirmed and unconfirmed major cytogenetic response is considered meaningful. Unconfirmed response is based on a single bone marrow cytogenetic evaluation for participants where a confirmatory evaluation is not available. Complete response shows 0% Philadelphia chromosome positive (Ph+) cells. A partial response shows >0% - 35% Ph+ cells. Response rates by disease phase were examined relative to an a priori value of 2.5% using a one-sided lower 95% exact binomial confidence limit. If the lower limit from the one-sided lower 95% confidence limit exceeds 2.5%, the observed response rate will have exceeded the minimum threshold required to demonstrate efficacy.

Measure: Percentage of Participants Achieving a Major Cytogenetic Response by Subpopulation and Total Population

Time: Day 1 up to 9 months

Description: TEAE are any untoward events that were newly occurring or worsening from Baseline. Treatment related toxicity was considered by the investigator to be unrelated, possibly, probably or unknown related to study drug. Severity was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0 on the following scale: Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, Grade 5 = death. A serious adverse event (SAE) is any untoward medical occurrence that is fatal or life-threatening; results in persistent or significant disability or incapacity; requires or prolongs in-patient hospitalization; is a congenital anomaly/birth defect in the offspring of a patient; and conditions not included in the above that may jeopardize the patient or may require intervention to prevent one of the outcomes listed above. A participant is only counted once in each category (at worst severity or strongest relationship).

Measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total

Time: up to 4 years

Secondary Outcomes

Description: Cytogenetic response categories: Complete: 0% Ph+ cells Partial: >0%-35% Ph+ cells Minor: >35%-65% Ph+ cells Minimal: >65%-95% Ph+ cells No Response: >95% Ph+ cells Unevaluable: <20 metaphases were examined and/or response could not be assigned

Measure: Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+)

Time: Day 1 up to Month 9

Description: MMR is defined as a ratio of BCR-ABL/standard gene of less than 0.1% according to the international scale. BCR-ABL is a fusion gene of the breakpoint cluster region [BCR] gene and Abelson proto-oncogene [ABL] genes). This analysis used the standard gene GUS. Analysis was performed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) of peripheral blood.

Measure: Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene GUS

Time: Day 1 up to Month 6

Description: MMR is defined as a ratio of BCR-ABL/standard gene of less than 0.1% according to the international scale. BCR-ABL is a fusion gene of the breakpoint cluster region [BCR] gene and Abelson proto-oncogene [ABL] genes). This analysis used the standard gene ABL. Analysis was performed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) of peripheral blood.

Measure: Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene ABL

Time: Day 1 up to Month 6

Description: Complete Response (CHR) Chronic phase must last at least 8 weeks: WBC <10*10^9/liter, platelets <450*10^9/liter, myelocytes + metamyelocytes <5% in blood, no blasts or promyelocytes in blood, <20% basophils in peripheral blood, no extramedullary involvement. Accelerated and Blast phase must last at least 4 weeks: absolute neutrophil count 1.5*10^9/liter, platelets 100*10^9/liter, no blood blasts, bone marrow blasts <5%, no extramedullary disease. Partial Response - CHR plus one or more of the following: Persistence of splenomegaly with a reduction of ≥50% from pre-treatment Platelets > 450*10^9/L Presence of immature cells in the peripheral blood 5% to 25% blasts in the bone marrow If extra-medullary disease pre-treatment, reduction by ≥50% Hematologic Improvement - CHR, except allowing persistent thrombocytopenia (<100*10^9/L), and a few immature cells No evidence of leukemia: Morphologic leukemia-free state, defined as <5% bone marrow blasts.

Measure: Percentage of Participants in Each Hematologic Response Category

Time: Day 1 up to Month 6

Description: Clinical response was defined by disease phase and based on evaluations by the independent Data Monitoring Committee (DMC). Chronic Phase subgroup: achieving a complete hematologic response and/or major cytogenetic response (complete cytogenetic response or partial cytogenetic response, confirmed or unconfirmed). Accelerated Phase and Blast Phase subgroups: achieving complete hematologic response, no evidence of leukemia, return to chronic phase, and/or major cytogenetic response (complete cytogenetic response or partial cytogenetic response, confirmed or unconfirmed).

Measure: Percentage of Participants With Extramedullary Disease (EMD) at Baseline Achieving a Clinical Response

Time: Day 1 up to Month 9

Description: Summarization is based on the best of the individual response assessments. Not assessable indicates that the participant either had no baseline assessment or the % mutation could not be determined in the post-baseline assessment(s).

Measure: Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL

Time: Day 1 up to Month 9

Description: Induction therapy was administered for 14 consecutive days for each 28 days cycle, for up to 6 cycles. All treatment arms were given omacetaxine mepesuccinate via subcutaneous (SC) administration at 1.25 mg/m^2 twice a day (BID) for the 14 consecutive days.

Measure: Number of Treatment Cycles Needed to Achieve Best Hematologic Response

Time: Day 1 up to Month 6

Measure: Number of Treatment Cycles Needed to Achieve Best Cytogenetic Response

Time: Day 1 up to Month 9

Description: Time to onset was analyzed using Kaplan-Meier estimates. Participants who did not achieve a response are censored at their last visit day. Overall hematologic response for chronic phase participants includes confirmed complete hematologic response (CHR). Overall hematologic response for accelerated or blast phase participants includes confirmed complete hematologic response (CHR), no evidence of leukemia (NEL), or return to chronic phase (RCP). Hematologic response must last >= 8 weeks to be considered meaningful.

Measure: Kaplan-Meier Estimates for Time to Onset of Best Hematologic Response

Time: Day 1 up to Month 6

Description: Time to onset was analyzed using Kaplan-Meier estimates. Participants who did not achieve a response are censored at their last visit day. Major cytogenetic response includes complete or partial response. Both confirmed and unconfirmed major cytogenetic response is considered meaningful. Unconfirmed response is based on a single bone marrow cytogenetic evaluation for participants where a confirmatory evaluation is not available. Complete response shows 0% Philadelphia chromosome positive (Ph+) cells. A partial response shows >0% - 35% Ph+ cells.

Measure: Kaplan-Meier Estimates for Time to Onset of Best Cytogenetic Response

Time: Day 1 up to Month 9

Description: Duration of response is defined as the time from first reported date of hematologic response until the earliest date of objective evidence of disease progression, relapse or death. Data was censored at the last examination date for participants with ongoing response or participants who discontinued treatment for reasons other than adverse event, disease progression or death.

Measure: Kaplan-Meier Estimates for Duration of Best Hematologic Response

Time: up to four years

Description: Duration of response is defined as the time from first reported date of cytogenetic response until the earliest date of objective evidence of disease progression, relapse or death. Data was censored at the last examination date for participants with ongoing response or participants who discontinued treatment for reasons other than adverse event, disease progression or death.

Measure: Kaplan-Meier Estimates for Duration of Best Cytogenetic Response

Time: up to four years

Description: Time to disease progression is defined as the time from the initiation of treatment until the onset date of death, the development of CML accelerated phase or blast phase, or the loss of complete hematologic response or major cytogenetic response, whichever came first. Participants were censored only if they did not have progression or if they discontinued treatment for reasons other than AE, progression or death.

Measure: Kaplan-Meier Estimates for Time to Disease Progression

Time: up to 4 years

Description: Overall survival is defined as the time from the initiation of treatment until death from any cause or the last day of participant contact or evaluation for participants that were lost to follow-up. Participants were censored t the last recorded contract or evaluation when a participant was alive at time of analysis. A quarterly phone survey was conducted to collect survival data for participants who discontinued from the study.

Measure: Kaplan-Meier Estimates for Overall Survival

Time: up to 4 years

7 A Phase 1 Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of XL228 Administered Intravenously to Subjects With Chronic Myeloid Leukemia (CML) or Philadelphia-Chromosome-Positive Acute Lymphocytic Leukemia (Ph+ ALL)

The purpose of this study is to determine the safest dose of the BCR-ABL inhibitor XL228, how often it should be taken, and how well people with leukemia tolerate XL228.

NCT00464113 Chronic Myeloid Leukemia Leukemia, Lymphoblastic, Acute, Philadelphia-Positive Drug: XL228
MeSH:Leukemia Leukemia, Myeloid Leukemia, Lymphoid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Precursor Cell Lymphoblastic Leukemia-Lymphoma Philadelphia Chromosome
HPO:Chronic myelogenous leukemia Leukemia Lymphoid leukemia Myeloid leukemia

The subject has a confirmed pathologic diagnosis as evidenced by the presence of the BCR-Abl translocation [t(9;22)] by fluorescence in situ hybridization (FISH), cytogenetics, or quantitative polymerase chain reaction (QPCR) of one of the following: 1. CML - Chronic phase (CP) - Accelerated phase (AP) - Blast phase (BP) OR 2. Ph+ ALL 2. The subject has one of the following: - Known T315I Abl mutation - Known resistance to or intolerance of imatinib and dasatinib - At least one prior anti-leukemia therapy, including, but not limited to, interferon, imatinib, or dasatinib 3. The subject is at least 18 years old. --- T315I ---

Primary Outcomes

Measure: Safety, tolerability, and maximum tolerated dose of once-weekly and/or twice-weekly 1-hour intravenous (IV) infusion of XL228

Time: Assessed at periodic visits

Secondary Outcomes

Measure: Evaluate plasma pharmacokinetics and estimate renal elimination of once-weekly and twice-weekly 1-hour IV infusion of XL228

Time: Assessed at periodic visits

Measure: Exploratory Outcomes: Evaluate hematologic and cytogenetic response and pharmacodynamic correlates of XL228 activity

Time: Assessed at periodic visits

8 A Phase III Multi-center, Open-label, Randomized Study of Imatinib Versus Nilotinib in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

In this study, the efficacy and safety of two nilotinib doses, 300 mg twice daily and 400 mg twice daily, will be compared with imatinib 400 mg once daily in newly diagnosed patients with Philadelphia chromosome-positive (Ph+) Chronic Myelogenous Leukemia in the chronic phase (CML-CP). An extension protocol is included in this study design to allow patients who did not show sufficient response to their assigned treatments the opportunity to receive nilotinib therapy at a dose of 400 mg BID, using an abbreviated safety and efficacy assessment schedule. The extension protocol CAMN107A2303E1 (NCT00718263) was registered incorrectly as a separate study. But this study has now been suppressed.

NCT00471497 Myelogenous Leukemia, Chronic Drug: nilotinib Drug: imatinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Philadelphia Chromosome
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

- Diagnosis of chronic myelogenous leukemia in chronic phase with confirmation of Philadelphia chromosome of (9:22) translocations Exclusion criteria: - Previously documented T315I mutation - Treatment with a tyrosine kinase inhibitor prior to study entry is not allowed except for no more than 2 weeks in duration of imatinib - Any medical treatment for CML prior to study entry for longer than 2 weeks with the exception of hydroxyurea and/or anagrelide - Impaired cardiac function. --- T315I ---

Primary Outcomes

Description: Rate of MMR is defined as <= 0.1% BCR-ABL/ABL ratio by international scale (IS), measured by real-time quantitative polymerase chain reaction (RQ-PCR) which corresponds to a ≥ 3 log reduction of BCR-ABL transcript from standardized baseline. BCR-ABL = fusion gene from BCR (breakpoint cluster region gene/BCR gene product) and ABL (Abelson protooncogene)

Measure: Molecular Response Rate (MMR) at 12 Months

Time: Baseline, 12 months

Secondary Outcomes

Measure: Rate of Durable MMR at 24 Months.

Time: Baseline, 24 months

Measure: Rate Reduction in BCR-ABL Transcript Levels in Nilotinib Treatment Arms With Imatinib at 12 Months

Time: Baseline, 12 months

Measure: Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months

Time: Baseline, 12 months

9 A Multi-center, Open-label, Exploratory Study of Bcr-Abl Kinetics in Adult Patients on Nilotinib With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) and a Suboptimal Molecular Response to Imatinib

This exploratory study will evaluate the change in molecular response in chronic myelogenous leukemia - chronic phase patients with a complete cytogenetic response and have a suboptimal molecular response to imatinib

NCT00644878 Chronic Myelogenous Leukemia - Chronic Phase Drug: Nilotinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chroni Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase Philadelphia Chromosome
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Select Inclusion Criteria: - Male or female patients - 18 years of age with a con-firmed diagnosis of Ph+ CML-CP and CCyR - Patients treated with an imatinib dose of 400 mg qd (at least 6 consecutive months for Group 1 patients) - A suboptimal molecular response to imatinib defined as: - Group 1: Treated with 1 year of imatinib, CCyR but no MMR (Bcr-Abl levels >0.1%IS); - Group 2: No specific duration of imatinib required, achieved CCyR but has >1 log increase in Bcr-Abl transcript levels - Adequate end organ function Select Exclusion Criteria: - Prior accelerated phase or blast crisis CML - Patients achieving prior CCyR on imatinib who lost cytogenetic response prior to entering study - Previously documented T315I mutations - Prior therapy with any other tyrosine kinase inhibitor except imatinib - Patients with contraindications to receiving nilotinib, including concomitant medications Select Inclusion Criteria: - Male or female patients - 18 years of age with a con-firmed diagnosis of Ph+ CML-CP and CCyR - Patients treated with an imatinib dose of 400 mg qd (at least 6 consecutive months for Group 1 patients) - A suboptimal molecular response to imatinib defined as: - Group 1: Treated with 1 year of imatinib, CCyR but no MMR (Bcr-Abl levels >0.1%IS); - Group 2: No specific duration of imatinib required, achieved CCyR but has >1 log increase in Bcr-Abl transcript levels - Adequate end organ function Select Exclusion Criteria: - Prior accelerated phase or blast crisis CML - Patients achieving prior CCyR on imatinib who lost cytogenetic response prior to entering study - Previously documented T315I mutations - Prior therapy with any other tyrosine kinase inhibitor except imatinib - Patients with contraindications to receiving nilotinib, including concomitant medications Chronic Myelogenous Leukemia - Chronic Phase Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chroni Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase Philadelphia Chromosome null --- T315I ---

Select Inclusion Criteria: - Male or female patients - 18 years of age with a con-firmed diagnosis of Ph+ CML-CP and CCyR - Patients treated with an imatinib dose of 400 mg qd (at least 6 consecutive months for Group 1 patients) - A suboptimal molecular response to imatinib defined as: - Group 1: Treated with 1 year of imatinib, CCyR but no MMR (Bcr-Abl levels >0.1%IS); - Group 2: No specific duration of imatinib required, achieved CCyR but has >1 log increase in Bcr-Abl transcript levels - Adequate end organ function Select Exclusion Criteria: - Prior accelerated phase or blast crisis CML - Patients achieving prior CCyR on imatinib who lost cytogenetic response prior to entering study - Previously documented T315I mutations - Prior therapy with any other tyrosine kinase inhibitor except imatinib - Patients with contraindications to receiving nilotinib, including concomitant medications Select Inclusion Criteria: - Male or female patients - 18 years of age with a con-firmed diagnosis of Ph+ CML-CP and CCyR - Patients treated with an imatinib dose of 400 mg qd (at least 6 consecutive months for Group 1 patients) - A suboptimal molecular response to imatinib defined as: - Group 1: Treated with 1 year of imatinib, CCyR but no MMR (Bcr-Abl levels >0.1%IS); - Group 2: No specific duration of imatinib required, achieved CCyR but has >1 log increase in Bcr-Abl transcript levels - Adequate end organ function Select Exclusion Criteria: - Prior accelerated phase or blast crisis CML - Patients achieving prior CCyR on imatinib who lost cytogenetic response prior to entering study - Previously documented T315I mutations - Prior therapy with any other tyrosine kinase inhibitor except imatinib - Patients with contraindications to receiving nilotinib, including concomitant medications Chronic Myelogenous Leukemia - Chronic Phase Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chroni Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase Philadelphia Chromosome null --- T315I --- --- T315I ---

Primary Outcomes

Measure: Bcr-Abl levels measured by polymerase chain reaction testing

Time: at 12 months

Secondary Outcomes

Measure: Rate of major molecular response, measured by PCR

Time: yearly

Measure: Rate of log reduction in Bcr-Abl transcripts, measured by PCR

Time: yearly

Measure: Time to and duration of the best molecular response, measured by PCR

Time: at end of study

10 A Multicenter Phase I/II Study of the Prophylactic Inhibition of BCR-ABL Tyrosine Kinase by Tasigna ® (Nilotinib) After Hematopoietic Cell Transplantation for Philadelphia Chromosome-Positive Leukemias.

This phase I/II trial is studying the side effects and best way to give nilotinib when given alone or sequentially after imatinib mesylate after donor stem cell transplant in treating patients with acute lymphoblastic leukemia or chronic myelogenous leukemia. Nilotinib and imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

NCT00702403 Accelerated Phase Chronic Myelogenous Leukemia Adult Acute Lymphoblastic Leukemia in Remission Blastic Phase Chronic Myelogenous Leukemia Childhood Acute Lymphoblastic Leukemia in Remission Childhood Chronic Myelogenous Leukemia Chronic Myelogenous Leukemia, BCR-ABL1 Positive Chronic Phase Chronic Myelogenous Leukemia Philadelphia Positive Adult Acute Lymphoblastic Leukemia Philadelphia Positive Childhood Acute Lymphoblastic Leukemia Recurrent Adult Acute Lymphoblastic Leukemia Recurrent Childhood Acute Lymphoblastic Leukemia Relapsing Chronic Myelogenous Leukemia Untreated Adult Acute Lymphoblastic Leukemia Untreated Childhood Acute Lymphoblastic Leukemia Drug: nilotinib Drug: imatinib mesylate Other: pharmacological study
MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase Blast Crisis Leukemia, Myeloid, Accelerated Phase
HPO:Chronic myelogenous leukemia Leukemia Lymphoid leukemia Myeloid leukemia

Inclusion Criteria: - Body surface area >= 1 m^2 - Allogeneic HCT - Acute lymphocytic leukemia (ALL) or chronic myelogenous leukemia (CML) characterized by the p190 and/or p210 BCR/ABL gene rearrangement - CML in accelerated phase, blast crisis, or blast crisis remission as defined by World Health Organization (WHO) criteria - CML in chronic phase if patient age =< 17 years or a patient of any age with CML in second chronic phase or beyond - Patients with minimal residual disease (MRD) that is not declining in response to tyrosine kinase inhibitor therapy must be screened for the T315I and other mutations - An appropriately matched related or unrelated donor - Signed informed consent - Patient must have a life expectancy of at least 2 months - Stated willingness of the patient to comply with study procedures and reporting requirements - Creatinine =< 2.0 x upper limit normal (ULN) - Platelets > 20 x 10^9 /L - Serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN, conjugated bilirubin < 3 x ULN - Serum potassium phosphorus, magnesium, and calcium >= lower limit normal (LLN) or correctable with supplements prior to first dose of study drug; calcium levels may be corrected for hypoalbuminemia - Serum amylase and lipase < 1.5 x ULN - Female patients of childbearing potential must have negative pregnancy test within 7 days before initiation of study drug dosing; postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential; male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug - Careful rationalization with a view to discontinuing or considering alternatives to any concomitant medications that have potential to prolong the QT interval Exclusion Criteria: - Autologous transplant - Non-myeloablative transplant - Patient age > 17 years with CML in first chronic phase - Aberrant antigen expression on marrow leukemic blasts >= 5% by multidimensional flow cytometric assay immediately before conditioning (CML patients in chronic phase exempt from flow cytometry screening) - Ph+ ALL without complete cytogenetic remission immediately before conditioning - Known T315I mutation - Hypersensitivity to Gleevec or Tasigna - Patients who are Tasigna-resistant or intolerant - Central nervous system (CNS) involvement with leukemia at baseline (pre-imatinib therapy); CML chronic phase (CP), accelerated phase (AP) patients exempt from CNS involvement screening - Female patients who are pregnant, breast-feeding, or of childbearing potential without a negative serum pregnancy test at screening; male or female patients of childbearing potential unwilling to use effective contraceptive precautions throughout the trial; post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential - Life expectancy severely limited by diseases other than leukemia - Myocardial infarction within one year prior to starting nilotinib - Other clinically significant heart disease (e.g. --- T315I ---

Inclusion Criteria: - Body surface area >= 1 m^2 - Allogeneic HCT - Acute lymphocytic leukemia (ALL) or chronic myelogenous leukemia (CML) characterized by the p190 and/or p210 BCR/ABL gene rearrangement - CML in accelerated phase, blast crisis, or blast crisis remission as defined by World Health Organization (WHO) criteria - CML in chronic phase if patient age =< 17 years or a patient of any age with CML in second chronic phase or beyond - Patients with minimal residual disease (MRD) that is not declining in response to tyrosine kinase inhibitor therapy must be screened for the T315I and other mutations - An appropriately matched related or unrelated donor - Signed informed consent - Patient must have a life expectancy of at least 2 months - Stated willingness of the patient to comply with study procedures and reporting requirements - Creatinine =< 2.0 x upper limit normal (ULN) - Platelets > 20 x 10^9 /L - Serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN, conjugated bilirubin < 3 x ULN - Serum potassium phosphorus, magnesium, and calcium >= lower limit normal (LLN) or correctable with supplements prior to first dose of study drug; calcium levels may be corrected for hypoalbuminemia - Serum amylase and lipase < 1.5 x ULN - Female patients of childbearing potential must have negative pregnancy test within 7 days before initiation of study drug dosing; postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential; male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug - Careful rationalization with a view to discontinuing or considering alternatives to any concomitant medications that have potential to prolong the QT interval Exclusion Criteria: - Autologous transplant - Non-myeloablative transplant - Patient age > 17 years with CML in first chronic phase - Aberrant antigen expression on marrow leukemic blasts >= 5% by multidimensional flow cytometric assay immediately before conditioning (CML patients in chronic phase exempt from flow cytometry screening) - Ph+ ALL without complete cytogenetic remission immediately before conditioning - Known T315I mutation - Hypersensitivity to Gleevec or Tasigna - Patients who are Tasigna-resistant or intolerant - Central nervous system (CNS) involvement with leukemia at baseline (pre-imatinib therapy); CML chronic phase (CP), accelerated phase (AP) patients exempt from CNS involvement screening - Female patients who are pregnant, breast-feeding, or of childbearing potential without a negative serum pregnancy test at screening; male or female patients of childbearing potential unwilling to use effective contraceptive precautions throughout the trial; post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential - Life expectancy severely limited by diseases other than leukemia - Myocardial infarction within one year prior to starting nilotinib - Other clinically significant heart disease (e.g. --- T315I --- --- T315I ---

congestive heart failure, uncontrolled hypertension, unstable angina) - Absolute neutrophil count (ANC) less than 1500 per microliter at study entry despite the use of filgrastim (G-CSF) - Impaired cardiac function, including any one of the following: - Complete left bundle branch block or bifascicular block (right bundle branch block plus left anterior hemiblock) or use of ventricular-paced pacemaker - Congenital long QT syndrome or a family history of long QT syndrome - History of or presence of significant ventricular or atrial tachyarrhythmias - Clinically significant resting bradycardia (< 50 beats per minute) - Corrected QT interval (QTc) > 450 milliseconds on screening electrocardiogram (ECG); if QTc > 450 and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient rescreened for QTc Inclusion Criteria: - Body surface area >= 1 m^2 - Allogeneic HCT - Acute lymphocytic leukemia (ALL) or chronic myelogenous leukemia (CML) characterized by the p190 and/or p210 BCR/ABL gene rearrangement - CML in accelerated phase, blast crisis, or blast crisis remission as defined by World Health Organization (WHO) criteria - CML in chronic phase if patient age =< 17 years or a patient of any age with CML in second chronic phase or beyond - Patients with minimal residual disease (MRD) that is not declining in response to tyrosine kinase inhibitor therapy must be screened for the T315I and other mutations - An appropriately matched related or unrelated donor - Signed informed consent - Patient must have a life expectancy of at least 2 months - Stated willingness of the patient to comply with study procedures and reporting requirements - Creatinine =< 2.0 x upper limit normal (ULN) - Platelets > 20 x 10^9 /L - Serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN, conjugated bilirubin < 3 x ULN - Serum potassium phosphorus, magnesium, and calcium >= lower limit normal (LLN) or correctable with supplements prior to first dose of study drug; calcium levels may be corrected for hypoalbuminemia - Serum amylase and lipase < 1.5 x ULN - Female patients of childbearing potential must have negative pregnancy test within 7 days before initiation of study drug dosing; postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential; male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug - Careful rationalization with a view to discontinuing or considering alternatives to any concomitant medications that have potential to prolong the QT interval Exclusion Criteria: - Autologous transplant - Non-myeloablative transplant - Patient age > 17 years with CML in first chronic phase - Aberrant antigen expression on marrow leukemic blasts >= 5% by multidimensional flow cytometric assay immediately before conditioning (CML patients in chronic phase exempt from flow cytometry screening) - Ph+ ALL without complete cytogenetic remission immediately before conditioning - Known T315I mutation - Hypersensitivity to Gleevec or Tasigna - Patients who are Tasigna-resistant or intolerant - Central nervous system (CNS) involvement with leukemia at baseline (pre-imatinib therapy); CML chronic phase (CP), accelerated phase (AP) patients exempt from CNS involvement screening - Female patients who are pregnant, breast-feeding, or of childbearing potential without a negative serum pregnancy test at screening; male or female patients of childbearing potential unwilling to use effective contraceptive precautions throughout the trial; post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential - Life expectancy severely limited by diseases other than leukemia - Myocardial infarction within one year prior to starting nilotinib - Other clinically significant heart disease (e.g. --- T315I ---

congestive heart failure, uncontrolled hypertension, unstable angina) - Absolute neutrophil count (ANC) less than 1500 per microliter at study entry despite the use of filgrastim (G-CSF) - Impaired cardiac function, including any one of the following: - Complete left bundle branch block or bifascicular block (right bundle branch block plus left anterior hemiblock) or use of ventricular-paced pacemaker - Congenital long QT syndrome or a family history of long QT syndrome - History of or presence of significant ventricular or atrial tachyarrhythmias - Clinically significant resting bradycardia (< 50 beats per minute) - Corrected QT interval (QTc) > 450 milliseconds on screening electrocardiogram (ECG); if QTc > 450 and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient rescreened for QTc Inclusion Criteria: - Body surface area >= 1 m^2 - Allogeneic HCT - Acute lymphocytic leukemia (ALL) or chronic myelogenous leukemia (CML) characterized by the p190 and/or p210 BCR/ABL gene rearrangement - CML in accelerated phase, blast crisis, or blast crisis remission as defined by World Health Organization (WHO) criteria - CML in chronic phase if patient age =< 17 years or a patient of any age with CML in second chronic phase or beyond - Patients with minimal residual disease (MRD) that is not declining in response to tyrosine kinase inhibitor therapy must be screened for the T315I and other mutations - An appropriately matched related or unrelated donor - Signed informed consent - Patient must have a life expectancy of at least 2 months - Stated willingness of the patient to comply with study procedures and reporting requirements - Creatinine =< 2.0 x upper limit normal (ULN) - Platelets > 20 x 10^9 /L - Serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN, conjugated bilirubin < 3 x ULN - Serum potassium phosphorus, magnesium, and calcium >= lower limit normal (LLN) or correctable with supplements prior to first dose of study drug; calcium levels may be corrected for hypoalbuminemia - Serum amylase and lipase < 1.5 x ULN - Female patients of childbearing potential must have negative pregnancy test within 7 days before initiation of study drug dosing; postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential; male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug - Careful rationalization with a view to discontinuing or considering alternatives to any concomitant medications that have potential to prolong the QT interval Exclusion Criteria: - Autologous transplant - Non-myeloablative transplant - Patient age > 17 years with CML in first chronic phase - Aberrant antigen expression on marrow leukemic blasts >= 5% by multidimensional flow cytometric assay immediately before conditioning (CML patients in chronic phase exempt from flow cytometry screening) - Ph+ ALL without complete cytogenetic remission immediately before conditioning - Known T315I mutation - Hypersensitivity to Gleevec or Tasigna - Patients who are Tasigna-resistant or intolerant - Central nervous system (CNS) involvement with leukemia at baseline (pre-imatinib therapy); CML chronic phase (CP), accelerated phase (AP) patients exempt from CNS involvement screening - Female patients who are pregnant, breast-feeding, or of childbearing potential without a negative serum pregnancy test at screening; male or female patients of childbearing potential unwilling to use effective contraceptive precautions throughout the trial; post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential - Life expectancy severely limited by diseases other than leukemia - Myocardial infarction within one year prior to starting nilotinib - Other clinically significant heart disease (e.g. --- T315I --- --- T315I ---

Primary Outcomes

Description: Safety and tolerability of nilotinib therapy in patients with imatinib-sensitive leukemia graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0. Treatment safety failure is defined for a patient with imatinib sensitive Ph+ leukemia as the inability to be able to deliver at least 400 milligrams per day of nilotinib in adults, and 230 milligrams/m2 per day in children, for at least 85% of the time interval between 81 and 365 days after transplant. The overall study will be considered successful if nilotinib is deliverable to more than 75% of the study participants at this minimum specified dose intensity.

Measure: Number of Participants With Treatment Safety Failure

Time: Up to 365 days post-transplant

Secondary Outcomes

Description: To be considered a treatment efficacy success at 1 year posttransplant, the patient's bone marrow must demonstrate complete hematological remission, absence of Philadelphia chromosomes, and not satisfy any of the criteria for treatment failure (>/= 1% aberrantly expressing marrow blasts by multiparameter flow cytometry, >5% BCR/ABL in marrow by fluorescent in situ hybridization, or >1 log rise in peripheral blood BCR/ABL by quantitative polymerase chain reaction (PCR) since day 80).

Measure: The Proportion of Patients at 1 Year With Treatment Efficacy Success

Time: Up to 1 year

Description: The proportion of study participants alive at 1, 2 and 3 years

Measure: Survival

Time: Up to 3 years

Description: The proportion of study participants alive and without hematologic, cytogenetic or molecular evidence of BCR/ABL-positive leukemia at 1 year

Measure: Patients Alive With Out Relapse

Time: Up to 1 year

Description: The proportion of patients with hematologic, cytogenetic or molecular relapse of BCR/ABL-positive leukemia

Measure: Relapse

Time: 1 and 3 years

11 A Randomized Phase Lll Study of Imatinib Dose Optimization Compared With Nilotinib in Patients With Chronic Myelogenous Leukemia and Suboptimal Response to Standard-dose Imatinib

There is no available data on the clinical benefit of dose escalation for patients with suboptimal response to imatinib, and patients may still improve their response with continuation of therapy at the standard dose as shown in the IRIS trial after 5 years of follow-up. However, there is no data yet regarding the potential benefit of using nilotinib in the group of patients with suboptimal response. In this study, the efficacy of nilotinib 400mg BID will be compared to imatinib 600mg QD.

NCT00802841 Chronic Myelogenous Leukemia Drug: nilotinib Drug: imatinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Exclusion criteria: 1. Prior accelerated phase including clonal evolution or blast crisis CML; 2. Prior therapy with imatinib in combination with any other CML drug other than Hydroxyurea and/or Anagrelide; 4.Imatinib therapy started more than 12 months after the date of the original diagnosis; 5.Unable to tolerate imatinib at 400mg; 6.Previous treatment with any other tyrosine kinase inhibitor except Glivec and/or CML therapy other than IFN, hydroxyurea, and /or anagrelide; 7.Myelotoxicity ≥ Grade 2 present at the time of randomization, 8.Previously documented T315I mutations; 9.Impaired cardiac function including one of these: - Long QT syndrome or family history of long QT syndrome - Clinically significant resting brachycardia (<50 bpm) - QTcF >450 msec on screening ECG (using the QTcF formula). --- T315I ---

Primary Outcomes

Description: CCyR was assessed from bone marrow samples. CCyr was defined as having 0% Philadelphia positive (Ph+) chromosome metaphases in bone marrow.

Measure: Percentage of Participants With Complete Cytogenetic Response (CCyR)

Time: 6 months

Secondary Outcomes

Description: MMR was defined as having a fusion gene of the Bcr and Abl genes of (BCR-ACL) less than or equal to 0.1% on the International Scale (IS).

Measure: Percentage of Participants With Major Molecular Response (MMR)

Time: 12 and 24 months

Description: CCyR was assessed from bone marrow samples. CCyr was defined as having 0% Philadelphia positive (Ph+) chromosome metaphases in bone marrow.

Measure: Percentage of Participants With CCyr

Time: 12 and 24 months

Description: Time to CCyR was defined as time from date of randomization to date of first documented CCyR.

Measure: Time to CCyR

Time: 24 months

Description: Duration of CCyR was defined as time from the date of ransomization to the date of first loss of CCyR or death, whichever came first.

Measure: Duration of CCyR

Time: 24 months

Description: PFS was defined as the time from the date of randomization to the date of documented disease progression to accelerated phase or blast crisis (AP/BC), or death due to any cause.

Measure: Progression-Free Survival (PFS)

Time: 24 months

Description: EFS was defined as the time from the date of randomization to the date of the first occurrence of any of the following: loss of Complete Hematological Response (CHR), loss of Partial Cytogenetic Response (PCyR), loss of CCyR, death on treatment or progression to AP/BC.

Measure: Event-Free Survival (EFS)

Time: 24 months

Description: OS was defined as time from date of randomization to the date of the death.

Measure: Overall Survival (OS)

Time: 24 months

12 A Phase II Multi-center, Open-label, Study of Nilotinib at a Dose of 300mg Twice Daily in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

RATIONALE: Nilotinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. PURPOSE: This phase II trial is studying how well nilotinib works in treating patients with newly diagnosed chronic phase chronic myelogenous leukemia.

NCT00809211 Leukemia Drug: nilotinib Genetic: cytogenetic analysis Genetic: mutation analysis Genetic: polymerase chain reaction Other: pharmacological study
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

DISEASE CHARACTERISTICS: - Cytogenetically confirmed chronic myelogenous leukemia (CML) by standard conventional cytogenetic analysis of bone marrow* - Newly diagnosed disease (within the past 6 months) NOTE: *FISH cannot be used - In chronic phase, as defined by the following: - Less than 15% blasts in peripheral blood and bone marrow - Less than 30% blasts plus promyelocytes in peripheral blood and bone marrow - Less than 20% basophils in peripheral blood - Platelet count ≥ 100,000/mm^3 - No evidence of extramedullary leukemic involvement, except for hepatosplenomegaly - Philadelphia chromosome-positive disease as demonstrated by (9;22) translocation (presence of Bcr-Abl) - A review of ≥ 20 metaphases is required - No previously documented T315I mutations PATIENT CHARACTERISTICS: - ECOG performance status 0-2 - Total bilirubin < 1.5 times upper limit of normal (ULN) - AST and ALT < 2.5 times ULN - Estimated glomerular filtration rate ≥ 30 mL/min - Serum amylase and lipase ≤ 1.5 times ULN - Alkaline phosphatase ≤ 2.5 times ULN (unless related to CML) - Potassium ≥ lower limit of normal (LLN) - Magnesium ≥ LLN - Phosphorous ≥ LLN - Total calcium ≥ LLN (corrected for serum albumin) - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception - No impaired cardiac function including, but not limited to, any of the following: - LVEF < 45% or < LLN by ECHO - Inability to determine the QT interval on ECG - Complete left bundle branch block - Congenital long QT syndrome or a known family history of long QT syndrome - History of or presence of clinically significant ventricular or atrial tachyarrhythmias - Clinically significant resting bradycardia (< 50 beats/min) - QTc > 450 msec on an average of 3 serial baseline ECGs (using the QTcF formula) - Clinically documented myocardial infraction within the past 12 months - Unstable angina within the past 12 months - Other clinically significant heart disease (e.g., congestive heart failure or uncontrolled hypertension) - No severe or uncontrolled medical condition (e.g., uncontrolled diabetes or active or uncontrolled infection) - No history of significant congenital or acquired bleeding disorder unrelated to CML - No history of non-compliance to medical regimens - No other primary malignancy unless it is neither currently clinically significant nor requiring active intervention - No impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery) - No acute pancreatitis within the past year - No history of chronic pancreatitis - No acute or chronic liver, pancreatic, or severe renal disease considered unrelated to CML PRIOR CONCURRENT THERAPY: - No prior therapy for CML other than hydroxyurea and/or anagrelide - Prior imatinib mesylate allowed provided it was administered for ≤ 14 days - More than 30 days since prior and no other concurrent investigational agents - More than 4 weeks since prior major surgery and recovered - No other concurrent anticancer agents, including chemotherapy and biologic agents - No concurrent strong CYP3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil) - No concurrent strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John's wort) - No concurrent medications that have the potential to prolong QT interval - No concurrent grapefruit, star fruit, Seville oranges, or their derivatives DISEASE CHARACTERISTICS: - Cytogenetically confirmed chronic myelogenous leukemia (CML) by standard conventional cytogenetic analysis of bone marrow* - Newly diagnosed disease (within the past 6 months) NOTE: *FISH cannot be used - In chronic phase, as defined by the following: - Less than 15% blasts in peripheral blood and bone marrow - Less than 30% blasts plus promyelocytes in peripheral blood and bone marrow - Less than 20% basophils in peripheral blood - Platelet count ≥ 100,000/mm^3 - No evidence of extramedullary leukemic involvement, except for hepatosplenomegaly - Philadelphia chromosome-positive disease as demonstrated by (9;22) translocation (presence of Bcr-Abl) - A review of ≥ 20 metaphases is required - No previously documented T315I mutations PATIENT CHARACTERISTICS: - ECOG performance status 0-2 - Total bilirubin < 1.5 times upper limit of normal (ULN) - AST and ALT < 2.5 times ULN - Estimated glomerular filtration rate ≥ 30 mL/min - Serum amylase and lipase ≤ 1.5 times ULN - Alkaline phosphatase ≤ 2.5 times ULN (unless related to CML) - Potassium ≥ lower limit of normal (LLN) - Magnesium ≥ LLN - Phosphorous ≥ LLN - Total calcium ≥ LLN (corrected for serum albumin) - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception - No impaired cardiac function including, but not limited to, any of the following: - LVEF < 45% or < LLN by ECHO - Inability to determine the QT interval on ECG - Complete left bundle branch block - Congenital long QT syndrome or a known family history of long QT syndrome - History of or presence of clinically significant ventricular or atrial tachyarrhythmias - Clinically significant resting bradycardia (< 50 beats/min) - QTc > 450 msec on an average of 3 serial baseline ECGs (using the QTcF formula) - Clinically documented myocardial infraction within the past 12 months - Unstable angina within the past 12 months - Other clinically significant heart disease (e.g., congestive heart failure or uncontrolled hypertension) - No severe or uncontrolled medical condition (e.g., uncontrolled diabetes or active or uncontrolled infection) - No history of significant congenital or acquired bleeding disorder unrelated to CML - No history of non-compliance to medical regimens - No other primary malignancy unless it is neither currently clinically significant nor requiring active intervention - No impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery) - No acute pancreatitis within the past year - No history of chronic pancreatitis - No acute or chronic liver, pancreatic, or severe renal disease considered unrelated to CML PRIOR CONCURRENT THERAPY: - No prior therapy for CML other than hydroxyurea and/or anagrelide - Prior imatinib mesylate allowed provided it was administered for ≤ 14 days - More than 30 days since prior and no other concurrent investigational agents - More than 4 weeks since prior major surgery and recovered - No other concurrent anticancer agents, including chemotherapy and biologic agents - No concurrent strong CYP3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil) - No concurrent strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John's wort) - No concurrent medications that have the potential to prolong QT interval - No concurrent grapefruit, star fruit, Seville oranges, or their derivatives Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase OBJECTIVES: Primary - To establish the complete cytogenetic response rate at 6 months in patients with newly diagnosed Philadelphia chromosome-positive chronic phase chronic myelogenous leukemia treated with nilotinib. --- T315I ---

DISEASE CHARACTERISTICS: - Cytogenetically confirmed chronic myelogenous leukemia (CML) by standard conventional cytogenetic analysis of bone marrow* - Newly diagnosed disease (within the past 6 months) NOTE: *FISH cannot be used - In chronic phase, as defined by the following: - Less than 15% blasts in peripheral blood and bone marrow - Less than 30% blasts plus promyelocytes in peripheral blood and bone marrow - Less than 20% basophils in peripheral blood - Platelet count ≥ 100,000/mm^3 - No evidence of extramedullary leukemic involvement, except for hepatosplenomegaly - Philadelphia chromosome-positive disease as demonstrated by (9;22) translocation (presence of Bcr-Abl) - A review of ≥ 20 metaphases is required - No previously documented T315I mutations PATIENT CHARACTERISTICS: - ECOG performance status 0-2 - Total bilirubin < 1.5 times upper limit of normal (ULN) - AST and ALT < 2.5 times ULN - Estimated glomerular filtration rate ≥ 30 mL/min - Serum amylase and lipase ≤ 1.5 times ULN - Alkaline phosphatase ≤ 2.5 times ULN (unless related to CML) - Potassium ≥ lower limit of normal (LLN) - Magnesium ≥ LLN - Phosphorous ≥ LLN - Total calcium ≥ LLN (corrected for serum albumin) - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception - No impaired cardiac function including, but not limited to, any of the following: - LVEF < 45% or < LLN by ECHO - Inability to determine the QT interval on ECG - Complete left bundle branch block - Congenital long QT syndrome or a known family history of long QT syndrome - History of or presence of clinically significant ventricular or atrial tachyarrhythmias - Clinically significant resting bradycardia (< 50 beats/min) - QTc > 450 msec on an average of 3 serial baseline ECGs (using the QTcF formula) - Clinically documented myocardial infraction within the past 12 months - Unstable angina within the past 12 months - Other clinically significant heart disease (e.g., congestive heart failure or uncontrolled hypertension) - No severe or uncontrolled medical condition (e.g., uncontrolled diabetes or active or uncontrolled infection) - No history of significant congenital or acquired bleeding disorder unrelated to CML - No history of non-compliance to medical regimens - No other primary malignancy unless it is neither currently clinically significant nor requiring active intervention - No impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery) - No acute pancreatitis within the past year - No history of chronic pancreatitis - No acute or chronic liver, pancreatic, or severe renal disease considered unrelated to CML PRIOR CONCURRENT THERAPY: - No prior therapy for CML other than hydroxyurea and/or anagrelide - Prior imatinib mesylate allowed provided it was administered for ≤ 14 days - More than 30 days since prior and no other concurrent investigational agents - More than 4 weeks since prior major surgery and recovered - No other concurrent anticancer agents, including chemotherapy and biologic agents - No concurrent strong CYP3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil) - No concurrent strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John's wort) - No concurrent medications that have the potential to prolong QT interval - No concurrent grapefruit, star fruit, Seville oranges, or their derivatives DISEASE CHARACTERISTICS: - Cytogenetically confirmed chronic myelogenous leukemia (CML) by standard conventional cytogenetic analysis of bone marrow* - Newly diagnosed disease (within the past 6 months) NOTE: *FISH cannot be used - In chronic phase, as defined by the following: - Less than 15% blasts in peripheral blood and bone marrow - Less than 30% blasts plus promyelocytes in peripheral blood and bone marrow - Less than 20% basophils in peripheral blood - Platelet count ≥ 100,000/mm^3 - No evidence of extramedullary leukemic involvement, except for hepatosplenomegaly - Philadelphia chromosome-positive disease as demonstrated by (9;22) translocation (presence of Bcr-Abl) - A review of ≥ 20 metaphases is required - No previously documented T315I mutations PATIENT CHARACTERISTICS: - ECOG performance status 0-2 - Total bilirubin < 1.5 times upper limit of normal (ULN) - AST and ALT < 2.5 times ULN - Estimated glomerular filtration rate ≥ 30 mL/min - Serum amylase and lipase ≤ 1.5 times ULN - Alkaline phosphatase ≤ 2.5 times ULN (unless related to CML) - Potassium ≥ lower limit of normal (LLN) - Magnesium ≥ LLN - Phosphorous ≥ LLN - Total calcium ≥ LLN (corrected for serum albumin) - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception - No impaired cardiac function including, but not limited to, any of the following: - LVEF < 45% or < LLN by ECHO - Inability to determine the QT interval on ECG - Complete left bundle branch block - Congenital long QT syndrome or a known family history of long QT syndrome - History of or presence of clinically significant ventricular or atrial tachyarrhythmias - Clinically significant resting bradycardia (< 50 beats/min) - QTc > 450 msec on an average of 3 serial baseline ECGs (using the QTcF formula) - Clinically documented myocardial infraction within the past 12 months - Unstable angina within the past 12 months - Other clinically significant heart disease (e.g., congestive heart failure or uncontrolled hypertension) - No severe or uncontrolled medical condition (e.g., uncontrolled diabetes or active or uncontrolled infection) - No history of significant congenital or acquired bleeding disorder unrelated to CML - No history of non-compliance to medical regimens - No other primary malignancy unless it is neither currently clinically significant nor requiring active intervention - No impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery) - No acute pancreatitis within the past year - No history of chronic pancreatitis - No acute or chronic liver, pancreatic, or severe renal disease considered unrelated to CML PRIOR CONCURRENT THERAPY: - No prior therapy for CML other than hydroxyurea and/or anagrelide - Prior imatinib mesylate allowed provided it was administered for ≤ 14 days - More than 30 days since prior and no other concurrent investigational agents - More than 4 weeks since prior major surgery and recovered - No other concurrent anticancer agents, including chemotherapy and biologic agents - No concurrent strong CYP3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil) - No concurrent strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John's wort) - No concurrent medications that have the potential to prolong QT interval - No concurrent grapefruit, star fruit, Seville oranges, or their derivatives Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase OBJECTIVES: Primary - To establish the complete cytogenetic response rate at 6 months in patients with newly diagnosed Philadelphia chromosome-positive chronic phase chronic myelogenous leukemia treated with nilotinib. --- T315I --- --- T315I ---

Primary Outcomes

Measure: Complete cytogenetic response rate at 6 months as assessed by metaphase analysis

Time: 6 months

Secondary Outcomes

Measure: Molecular response rate at 3, 6, 9, 12, 18, and 24 months as assessed by quantitative PCR

Time: 6 months

Measure: Time to disease progression

Time: 6 months

Measure: Duration of event-free survival

Time: 6 months

Measure: Overall toxicity rate

Time: 6 months

Measure: Correlation of pharmacokinetic data with response rate and toxicity

Time: 6 months

Measure: Correlation of Bcr-Abl results using GeneXpert with Bcr-Abl results using international standardized quantitative PCR

Time: 6 months

Measure: Prevalence of Bcr-Abl mutations prior to and during treatment

Time: 6 months

13 Autologous Cytokine Induced Killer Cells as Adjuvant Adoptive Immunotherapy in Patients With Chronic Myeloid Leukemia on Standard Drug Therapy

This is an extension of our ongoing clinical trial using ex vivo expanded autologous Cytokine-induced killer (CIK) cells as an adoptive cellular immunotherapy for haematological malignancies. The pre-existing clinical trial targets patient with acute myeloid leukemia or MDS, and relapsed disease post allogeneic transplant. Chronic myeloid leukemia (CML) is a disease with good response to kinase inhibitors. There are however patients in transformed phase of the disease who do not respond to these treatment. A small proportion of patients with response to Imatinib may develop mutations resulting in drug resistance. In addition, the vast majority of patients with a good response to the kinase inhibitors still have persistent CML cells detectable at a molecular level. It is known that the CML progenitors are not sensitive to the kinase inhibitors. On the other hand, immune mediated mechanism is known to be able to eradicate CML as shown by efficacy of donor lymphocyte infusion in the allogeneic transplant setting. Early clinical trials have shown clearance of bcr-abl using peptide vaccination. There is also convincing mouse data showing eradication of CML at molecular level by autologous CIK cells, but no clinical trial has been done using CIK cells for CML. We therefore plan to expand our current CIK trial to include CML as a disease, for CML patients with various degree of response to the kinase inhibitors which have already offered its maximal effect. We aim to study whether autologous CIK cells may further improve disease response, either in the eradiation of minimal residual disease, or in conjunction with chemotherapy for control of high tumour load disease.

NCT00815321 Chronic Myeloid Leukemia Biological: Autologous CIK cell infusion
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

3. Patients with resistance to the currently available kinase inhibitors due to T315I mutation or other undefined mutations, with progressive relapse either at molecular, cytogenetic or haematological level, and do not have transplant as a curative option. --- T315I ---

Primary Outcomes

Measure: response of CML to Cytokine induced killer cell therapy

Time: 6 -12 months

Secondary Outcomes

Measure: Sustainability of the response

Time: 3 years

14 A Multicenter Phase 1 Clinical and Pharmacokinetic Study of DCC-2036 in Subjects With Leukemias (Ph+CML With T315I Mutation Only)

Rationale: DCC-2036 is a potent broad spectrum inhibitor of BCR-ABL kinase. Inhibition of BCR-ABL has been validated for effective treatment of chronic myeloid leukemia (CML). The emergence of mutant forms of BCR-ABL which resist inhibition by imatinib, dasatinib, and nilotinib is associated with loss of efficacy in treatment of the disease. DCC-2036 is a potent inhibitor of resistant mutants of BCR-ABL including the T315I mutation, and would therefore be expected to effectively treat patients who fail to respond to other BCR-ABL inhibitors. DCC-2036 also inhibits FLT3-ITD, TIE2, KDR, LYN and TRKA kinases. Purpose: to assess the safety and tolerability in patients after continuous administration of DCC-2036 and to determine recommended doses for the conduct of a Phase 2 efficacy trial.

NCT00827138 Chronic Myeloid Leukemi Chronic Myeloid Leukemia Drug: DCC-2036
MeSH:Leukemia Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia

A Multicenter Phase 1 Clinical and Pharmacokinetic Study of DCC-2036 in Subjects With Leukemias (Ph+CML With T315I Mutation Only). --- T315I ---

Study Safety and Preliminary Efficacy of DCC-2036 in Patients With Leukemias (Ph+ CML With T315I Mutation) Rationale: DCC-2036 is a potent broad spectrum inhibitor of BCR-ABL kinase. --- T315I ---

DCC-2036 is a potent inhibitor of resistant mutants of BCR-ABL including the T315I mutation, and would therefore be expected to effectively treat patients who fail to respond to other BCR-ABL inhibitors. --- T315I ---

Inclusion Criteria: Subjects must meet all of the following inclusion criteria to be eligible: - Ph+ CML in Chronic Phase with T315I mutation - 18 years or older - The subject has an ECOG performance status of ≤ 2. - Adequate organ function as indicated by the following laboratory assessments performed within 14 days prior to the first dose of study drug Hepatic: Serum bilirubin ≤1.5 times upper limit (X ULN) of normal unless due to leukemic involvement or Gilbert's syndrome; aspartate aminotransferase or alanine aminotransferase ≤ 2.5 X ULN; alkaline phosphatase ≤ 2.5 X ULN Renal: Serum creatinine ≤ 1.5 X ULN or 24 hour creatinine clearance ≥ 50 mL/min - Female subjects of childbearing potential must have a negative serum or urine beta-human chorionic gonadotropin pregnancy test within 14 days prior to the start of study drug - Sexually active subjects who are fertile must agree to use an effective barrier method of contraception while on therapy and for 30 days following discontinuation of study drug. --- T315I ---

The following exceptions apply: i) Hydroxyurea is permitted at any time prior to study enrollment; ii) Glucocorticoids (natural or synthetic) are allowed up to 48 hours prior to the start of the study drug (with the exception of steroids for pre-medication and topical/nasal steroid use which are allowed at any time) - The subject has AP or BP-CML - Received immunosuppressive therapy ≤ 28 days prior to the first dose of study drug - NY Heart Association class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension or congestive heart failure - Myocardial infarction within 3 months of the start of study drug - Active, uncontrolled systemic infection considered opportunistic, life threatening, or clinically significant - Any other severe concurrent disease and/or uncontrolled medical conditions, which in the judgment of the investigator, could predispose subjects to unacceptable safety risks or compromise compliance with the protocol - Human immunodeficiency virus positive - If female, the subject is pregnant or lactating - Allergic or hypersensitive to any component of the investigational drug product Inclusion Criteria: Subjects must meet all of the following inclusion criteria to be eligible: - Ph+ CML in Chronic Phase with T315I mutation - 18 years or older - The subject has an ECOG performance status of ≤ 2. - Adequate organ function as indicated by the following laboratory assessments performed within 14 days prior to the first dose of study drug Hepatic: Serum bilirubin ≤1.5 times upper limit (X ULN) of normal unless due to leukemic involvement or Gilbert's syndrome; aspartate aminotransferase or alanine aminotransferase ≤ 2.5 X ULN; alkaline phosphatase ≤ 2.5 X ULN Renal: Serum creatinine ≤ 1.5 X ULN or 24 hour creatinine clearance ≥ 50 mL/min - Female subjects of childbearing potential must have a negative serum or urine beta-human chorionic gonadotropin pregnancy test within 14 days prior to the start of study drug - Sexually active subjects who are fertile must agree to use an effective barrier method of contraception while on therapy and for 30 days following discontinuation of study drug. --- T315I ---

Primary Outcomes

Measure: Assess the safety and tolerability of the drug

Time: Completion of the study

Secondary Outcomes

Measure: Determine the Pharmacokinetic profile and preliminary evidence of clinical response

Time: Completion of the study

15 Randomized, Open Label Study of Dasatinib (100mg qd) vs. High-Dose Imatinib (600mg) in Patients With Chronic Phase CML Who Have Had Suboptimal Response After 3-18 Months of Therapy With Imatinib (400mg)

Research Hypothesis: Treatment with dasatinib 100 mg QD is superior to imatinib 600 mg QD in terms of complete cytogenetic response (CCyR) in chronic phase (CP) Philadelphia chromosome-positive (Ph+) Chronic Myeloid Leukemia (CML) subjects who are imatinib failures or who have achieved only a suboptimal response after 3-18 months (12-77 weeks) of therapy with imatinib 400 mg. Primary Objective: The primary objective of this study is to compare the rate of CCyR of dasatinib (100mg QD) to high-dose imatinib (600 mg QD) therapy at 6 months after randomization in CP Ph+ CML subjects who are imatinib failures or who have achieved only a suboptimal response after 3 - 18 months of imatinib monotherapy at 400 mg/day.

NCT00854841 Chronic Myeloid Leukemia Drug: Dasatinib and Imatinib
MeSH:Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia

Exclusion Criteria: 1. Concurrent malignancy 2. Patients who have received SCT 3. Allergy or hypersensitivity reaction to the study drugs 4. Female who are pregnant or breast feeding. 5. T315I mutation 6. History of significant bleeding disorder 7. Women of child bearing potential 8. Uncontrolled or significant CVS disease: IHD. --- T315I ---


16 A Phase II Study of Dasatinib in Patients With Imatinib Resistant or Intolerant Chronic Myeloid Leukemia

The purpose of this study is to evaluate the efficacy and the safety of dasatinib in subject with chronic phase chronic myeloid leukemia(CML) who are either resistant to or intolerant of imatinib mesylate.

NCT00866736 Chronic Myeloid Leukemia Drug: dasatinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

- Prior therapy with dasatinib - Subjects with T315I and/or F317L BCR-ABL point mutations Inclusion Criteria: - Signed Written Informed Consent - Subjects with chronic phase chronic myeloid leukemia (CML) - Subjects resistant/intolerant to imatinib - Subjects presenting: 1. ECOG performance status (PS) score 0-2 2. Adequate hepatic function 3. Adequate renal function 4. Adequate lung function Exclusion Criteria: - Concurrent malignancy other than CML - Women who are pregnant or breastfeeding - Concurrent pleural effusion - Uncontrolled or significant cardiovascular disease - A serious uncontrolled medical disorder that would impair the ability of the subjects to receive protocol therapy. --- T315I ---

- Prior therapy with dasatinib - Subjects with T315I and/or F317L BCR-ABL point mutations Chronic Myeloid Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive null --- T315I ---

Primary Outcomes

Measure: rate of Major Molecular Responses (MMR) in chronic phase chronic myeloid leukemia subjects

Time: at 12 months

Secondary Outcomes

Measure: safety after treatment with dasatinib

Time: 2 year

Measure: rate of Complete Cytogenetic Response(CCyR)

Time: 2 year

Measure: rate of Complete Hematologic Response (CHR)

Time: 2 year

Measure: efficacy on patients with BCR-ABL point mutations

Time: 2 year

Measure: progression free survival

Time: 2 year

17 An Exploratory Trial to Assess the Improvement of Chronic Low-grade Non-hematologic Adverse Events Experienced by Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) Treated With Imatinib When Switched to Nilotinib Treatment

The purpose of this exploratory study will be to examine changes in chronic low grade chronic adverse events, measured by Common Terminology Criteria for Adverse Events (CTCAE) grading, when patients are switched from imatinib to nilotinib therapy.

NCT00980018 Chronic Myelogenous Leukemia Drug: Nilotinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Inclusion Criteria: 1. Male or female patients ≥ 18 years of age 2. ECOG 0, 1, or 2 3. Diagnosis of CML-CP associated with Bcr-Abl quantifiable by RQ-PCR (IS) 4. Patients must be an imatinib responder and achieved the following efficacy milestones as appropriate for the length of time on imatinib therapy as per protocol 5. CML-CP patients initiated on any dose of imatinib 6. Ability to provide written informed consent prior to any study related screening procedures being done Exclusion Criteria: 1. Loss of CHR or cytogenetic response 2. Prior accelerated phase or blast phase CML 3. Previously documented T315I mutation 4. Presence of chromosomal abnormalities (trisomy 8) and/or clonal evolution other than Ph+. 5. Previous treatment with any other tyrosine kinase inhibitor except for imatinib. --- T315I ---

Other protocol-defined inclusion/exclusion criteria may apply Inclusion Criteria: 1. Male or female patients ≥ 18 years of age 2. ECOG 0, 1, or 2 3. Diagnosis of CML-CP associated with Bcr-Abl quantifiable by RQ-PCR (IS) 4. Patients must be an imatinib responder and achieved the following efficacy milestones as appropriate for the length of time on imatinib therapy as per protocol 5. CML-CP patients initiated on any dose of imatinib 6. Ability to provide written informed consent prior to any study related screening procedures being done Exclusion Criteria: 1. Loss of CHR or cytogenetic response 2. Prior accelerated phase or blast phase CML 3. Previously documented T315I mutation 4. Presence of chromosomal abnormalities (trisomy 8) and/or clonal evolution other than Ph+. 5. Previous treatment with any other tyrosine kinase inhibitor except for imatinib. --- T315I ---

Primary Outcomes

Measure: Improvement of (CTCAE grading scale) of imatinib related chronic low grade non hematologic Adverse Event after switch to treatment with nilotinib at End of Cycle 3

Time: 3 months

Secondary Outcomes

Description: Assess CCyR by bone marrow cytogenics

Measure: Rate of Complete Cytogenetic Response (CCyR) present at baseline

Time: 6, 12, and 18 months after starting imatinib. FISH wil be conducted at the end of cycles 1,2,3,6,9,12 after the switch to nilotinib

Description: Measure MMR at the end of Cycles

Measure: Rate of a Major Molecular Response (MMR) after the switch in the therapy

Time: 1,2,3,6,9,12 after the switch to nilotinib

Measure: Magnitude of Bcr-Abl change after the switch in therapy

Time: At the end of cycles 1,2,3,6,9, and 12 after the switch to nilotinib.

Measure: Durability of cytogenetic and molecular response

Time: after the switch to nilotinib until the end of the study

Measure: Time to optimal imatinib-related adverse event improvement

Time: time to first documented and optimal improvement of adverse events associated with imatinib and to the end of the study

18 A Phase 2 Multicenter Study of First-line Dasatinib Plus Conventional Chemotherapy in Adults With Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

The main aim of the present study is to evaluate the clinical efficacy of first-line dasatinib plus conventional chemotherapy for newly diagnosed Ph-positive acute lymphoblastic leukemia. In this study, the investigators will analyze the clinical outcomes for entire patient population as well as those for transplants, respectively. In addition, the results of this study will be compared to those of the investigators current study (imatinib plus conventional chemotherapy). The safety of this treatment will also be studied.

NCT01004497 Acute Lymphoblastic Leukemia Drug: Dasatinib Drug: Cyclophosphamide Drug: Vincristine Drug: Daunorubicin Drug: Dexamethasone Drug: Cytarabine Drug: Mitoxantrone
MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid
HPO:Leukemia Lymphoid leukemia

Dasatinib, a potent dual BCR-ABL/SRC family kinase inhibitor, demonstrated 325-fold greater activity against native BCR-ABL compared with imatinib and has shown efficacy against all imatinib-resistant BCR-ABL mutations with the exception of T315I. --- T315I ---

Primary Outcomes

Measure: To determine the clinical efficacy of dasatinib plus conventional chemotherapy for newly diagnosed Ph-positive ALL in terms of major molecular response rate

Time: by the second 4-week dasatinib therapy

Secondary Outcomes

Measure: To evaluate the long-term clinical outcomes (including transplant outcomes) in terms of treatment toxicity, relapse, disease-free survival, and overall survival

Time: at 2 years after transplantation (for all transplants); at 2 years after starting dasatinib maintenance (for all non-transplants)

19 A Phase IV Study of Nilotinib in Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) Who Have Suboptimal Molecular Response on Imatinib

To evaluate the major molecular response (MMR) rate at 12 months of nilotinib treatment on study in patients with Philadelphia Chromosome Positive (Ph+) chronic myelogenous leukemia in chronic phase (CML-CP) who have a suboptimal molecular response to imatinib at 18 months or later.

NCT01043874 Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase Drug: Nilotinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Philadelphia Chromosome
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Exclusion Criteria: 1. Prior accelerated phase or blast crisis CML. 2. Previously documented T315I mutations. --- T315I ---

Primary Outcomes

Description: MMR is defined as BCR-ABL ratio (%) on IS ≤ 0.1% (corresponds to ≥ 3 log reduction of BCR-ABL transcripts from standardized baseline value

Measure: MMR Rate at 12 Mos. of Nilotinib Treatment on Study in Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) Who Have a Suboptimal Molecular Response to Imatinib at 18 Months or Later.

Time: 12 months after treatment

Secondary Outcomes

Description: MMR is defined as BCR-ABL ratio (%) on IS ≤ 0.1% (corresponds to ≥ 3 log reduction of BCR-ABL transcripts from standardized baseline value

Measure: MMR Rate at 24 Months of Nilotinib Treatment on Study in Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

Time: 24 months after treatment

Description: MMR is defined as BCR-ABL ratio (%) on IS ≤ 0.1% (corresponds to ≥ 3 log reduction of BCR-ABL transcripts from standardized baseline value

Measure: Time to First MMR of Nilotinib in Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) .

Time: month 24

Description: MMR is defined as BCR-ABL ratio (%) on IS ≤ 0.1% (corresponds to ≥ 3 log reduction of BCR-ABL transcripts from standardized baseline value

Measure: Duration of MMR of Nilotinib in Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) .

Time: month 24

20 A Phase II, Multi-center, Open-label, Repeat-dose Study of Lenalidomide (Revlimid ®) Plus Low-dose Dexamethasone in Patients With Refractory B Cell Lineage Acute Lymphoblastic Leukemia or in Relapse After 2 Lines of Treatment

The study objectives are to evaluate the safety and efficacy of the oral administration of lenalidomide in combination with dexamethasone in the treatment of adult patients with refractory or relapsed non-Ph+ B-cell lineage acute lymphoblastic leukemia (ALL).

NCT01116193 Leukemia, Lymphoid Precursor B-Cell Lymphoblastic Leukemia-Lymphoma Drug: Lenalidomide plus dexamethasone
MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
HPO:Leukemia Lymphoid leukemia

The inclusion of a patient with Ph+ ALL can be possible after contacting the principal investigator in presence of a T315I mutation and absence of investigational trial targeting this abnormality. --- T315I ---

Primary Outcomes

Measure: Disease-Free survival (DFS)

Time: 2 years

Secondary Outcomes

Measure: Time to response

Time: 28 days

Measure: Duration of response

Time: 2 years

Measure: To determine quality of life (QOL): European Organization for Research and Treatment of Cancer QOL questionnaire for patients with cancer (EORTC QLQ-C30)

Time: All 28 days

Measure: Progression-free survival

Time: 2 years

Measure: Feasibility of stem cell transplantation (SCT), in case of response, after one or more cycles of lenalidomide plus dexamethasone therapy

Time: all 28 days

Measure: Safety of lenalidomide plus dexamethasone: adverse events (type, frequency, severity of adverse events, and relationship of adverse events to study drug).

Time: All 28 days

Measure: To assess the efficacy of lenalidomide plus low-dose dexamethasone: complete response (CR), complete response without platelets (CRp), partial response (PR), and overall response (CR + CRp + PR).

Time: 1, 8, 15, and 22 of each 28-day cycle (4-weeks cycles) and after treatment, patients will be seen at least twice weekly until they attain a CR

Measure: Overall survival

Time: 2 years

21 A Multi-center, Single Arm Study of Nilotinib in Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) Patients With Low Imatinib Trough Plasma Concentrations

This study is to determine the number of European Leukemia Network (ELN)guideline defined treatment failure events from time of study entry in CML-CP patients with low imatinib trough concentrations treated with nilotinib.

NCT01131325 CML Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia Chronic Phase(CML-CP) Patients With Low Imatinib Trough Levels Drug: nilotinib
MeSH:Leuk Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Philadelphia Chromosome
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Inclusion Criteria: - Ph+ CML-CP within 12 months of diagnosis - Imatinib 400 mg qd for up to 12 months - Imatinib trough plasma concentration <850 ng/mL - Patient that have met response milestones including: 1. CHR and at least minor CyR (Ph+ ≤65%) at 3 months from diagnosis 2. At least pCyR at 6 months from diagnosis (Ph+ ≤35%) 3. CCyR at 12 months from diagnosis Exclusion Criteria: - Prior documented failure events including: - Loss of CHR or CCyR - Less than CHR (stable disease or disease progression) at 3 months after diagnosis - No CyR at 6 months after diagnosis - Less than PCyR at 12 months after diagnosis - Prior accelerated phase or blast phase CML - Previously documented T315I mutation - Previous treatment with any other tyrosine kinase inhibitor except for imatinib. --- T315I ---

- Treatment with other investigational agents within 30 days of Day 1. Inclusion Criteria: - Ph+ CML-CP within 12 months of diagnosis - Imatinib 400 mg qd for up to 12 months - Imatinib trough plasma concentration <850 ng/mL - Patient that have met response milestones including: 1. CHR and at least minor CyR (Ph+ ≤65%) at 3 months from diagnosis 2. At least pCyR at 6 months from diagnosis (Ph+ ≤35%) 3. CCyR at 12 months from diagnosis Exclusion Criteria: - Prior documented failure events including: - Loss of CHR or CCyR - Less than CHR (stable disease or disease progression) at 3 months after diagnosis - No CyR at 6 months after diagnosis - Less than PCyR at 12 months after diagnosis - Prior accelerated phase or blast phase CML - Previously documented T315I mutation - Previous treatment with any other tyrosine kinase inhibitor except for imatinib. --- T315I ---

Primary Outcomes

Measure: To determine the number of ELN-guideline defined treatment failure events from time of study entry in CML-CP patients with low imatinib trough concentrations (<850 ng/mL) treated with nilotinib.

Time: up to 2 years

Secondary Outcomes

Measure: To determine the proportion of ELN-defined optimal responses on nilotinib.

Time: up to 2 years

Measure: To determine the rate and time to loss of CCyR, MMR and CMR on nilotinib.

Time: up to 2 years

Measure: To determine the time to and duration of the CCyR, MMR and CMR achieved on nilotinib.

Time: up to 2 years

Measure: To determine EFS, PFS and OS with up to 2 years of nilotinib treatment and overall safety profile

Time: up to 2 years

22 A Phase I Study of the PARP Inhibitor ABT-888 in Combination With Temozolomide in Acute Leukemias

This phase I clinical trial is studies the side effects and best dose of giving veliparib together with temozolomide in treating patients with acute leukemia. Veliparib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving veliparib together with temozolomide may kill more cancer cells.

NCT01139970 Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11 Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11 Adult Acute Myeloid Leukemia With t(8; Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1 Adult Acute Myeloid Leukemia With t(9;11)(p21.3;q23.3); MLLT3-KMT2A Adult Acute Promyelocytic Leukemia With PML-RARA Adult B Acute Lymphoblastic Leukemia Adult B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1 Adult T Acute Lymphoblastic Leukemia Alkylating Agent-Related Acute Myeloid Leukemia Chronic Myelomonocytic Leukemia Recurrent Adult Acute Lymphoblastic Leukemia Recurrent Adult Acute Myeloid Leukemia Secondary Acute Myeloid Leukemia Other: Laboratory Biomarker Analysis Other: Pharmacological Study Drug: Temozolomide Drug: Veliparib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Leukemia, Myelomonocytic, Chronic Leukemia, Myelomonocytic, Juvenile Leukemia, Promyelocytic, Acute Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Myelodysplastic Syndromes
HPO:Acute megakaryocytic leukemia Acute myeloid leukemia Acute promyelocytic leukemia Chronic myelomonocytic leukemia Juvenile myelomonocytic leukemia Leukemia Lymphoid leukemia Myelodysplasia Myeloid leukemia T-cell acute lymphoblastic leukemias

The plausible relationship between change in DSB repair and clinical response will be examined using the Fisher's exact test.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of one of the following: - Relapsed or refractory acute myeloid leukemia (AML); patients with acute promyelocytic leukemia t(15;17) must have failed tretinoin (ATRA), arsenic, and gemtuzumab ozogamycin to be eligible (patients should be refractory to all three agents-absence of durable hematologic response or relapse with complete remission [CR] duration of less than 6 months) - Relapsed or refractory pre-B- or T-cell acute lymphoblastic leukemia (ALL); patients with Philadelphia chromosome-positive (Ph+) ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different tyrosine kinase inhibitors (TKIs) or have a mutation associated with resistance to TKIs (T315I) - Chronic myelogenous leukemia (CML) in accelerated or blastic phase; patients failed (resistance/intolerance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Chronic myelomonocytic leukemia-2 (CMML-2) defined as having > 10% blasts (including promonocytes) in the bone marrow or > 5-19% blasts (including promonocytes) in the peripheral blood - AML arising in the setting of antecedent myelodysplasia (MDS) or myeloproliferative disorder (MPD) - Therapy-related AML - Untreated AML in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics or molecular markers (fms-related tyrosine kinase 3 [FLT3] internal tandem duplication [ ITD]+), or are unwilling to receive intensive induction chemotherapy; adverse cytogenetics: complex karyotype (>= 3 chromosomal abnormalities), 5q-, 7q-, 9q-, 20q-, abn12p, +21, +8, t(6;9), t(6;11), t(11;19), -7, -5, inv3/t(3;3), abn11q23, abn17p, abn21q - Untreated ALL in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics [t(4;11); t(1;19), hypodyploidy] or are unwilling to receive intensive induction chemotherapy; patients with Ph+ ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Previous therapy - Only patients who have received or are ineligible for established curative regimens, including stem cell transplantation when applicable, can be enrolled on this study - Patients may have received any number of prior chemotherapy regimens, which may include allogeneic or autologous transplantation, provided that performance status and organ function are maintained - Previous cytotoxic chemotherapy should have been completed at least 3 weeks and radiotherapy at least 2 weeks prior to treatment on the study (6 weeks if the last regimen included carmustine [BCNU] or mitomycin C) and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 3 weeks earlier should recover to =< grade 1; patients with hematologic malignancies are expected to have hematologic abnormalities at study entry; these abnormalities which are thought to be primarily related to the underlying leukemia, are not considered to be toxicities (AE) and do not need to resolve to =< grade 1 - Patients should stop taking all biologic agents including hematopoietic growth factors, imatinib or similar TKIs, at least 1 week prior to treatment on the study and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 1 week earlier should recover to =< grade 1; since only patients with advanced Ph+ ALL and CML in accelerated/blast phase are eligible for this study, this short period off TKIs was selected to avoid rapid leukemia progression; if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study - Patients who have undergone autologous stem cell transplantation (ASCT) are eligible provided that they are >= 4 weeks from stem cell infusion and meet other eligibility criteria - Patients who have undergone allogeneic SCT (alloSCT) are eligible if they are >= 60 days post stem cell infusion, have no evidence of graft vs. host disease, and are >= 2 weeks off all immunosuppressive therapy - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Patients have to be able to swallow pills - Total or direct bilirubin < 2 mg/dl - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 5 X institutional upper limit of normal - Creatinine < 2 mg/dl - Female patients of childbearing potential must have a negative pregnancy test - Female patients of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days afterward; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients may not be receiving any other investigational agents, or concurrent chemotherapy, radiation therapy, or immunotherapy - Any previous treatment with temozolomide - Patients with active central nervous system leukemia are excluded from this clinical trial because they may develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; patients with a history of central nervous system (CNS) leukemia but no active disease at the time of enrollment are eligible - Hyperleukocytosis with > 30,000 blasts/ul; (if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study); once patient starts treatment on the study the hydroxyurea use should be avoided, however, for patients with rapidly proliferating disease use of hydroxyurea is allowed on treatment days 1 through 12 if it becomes necessary to control a rising white blood cell (WBC) or leukostasis; the WBC need not reach 30,000/ul to start hydroxyurea during protocol days 1-12; the decision to start hydroxyurea during this time is at the discretion of the treating physician - History of allergic reactions attributed to compounds of similar chemical or biologic composition to ABT-888 or temozolomide used in this study - Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible - Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with ABT-888 - Known human immunodeficiency virus (HIV) infected patients (HIV testing will not be performed as a part of screening) on combination antiretroviral therapy, exclusive of zidovudine or starvudine, or HIV infected patients not on or willing to suspend antiretroviral therapy will be eligible provided that their cluster of differentiation (CD)4 cell count is greater than 250/mm3; HIV infected patients with CD4 count equal or less than 250/mm3 will be excluded Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of one of the following: - Relapsed or refractory acute myeloid leukemia (AML); patients with acute promyelocytic leukemia t(15;17) must have failed tretinoin (ATRA), arsenic, and gemtuzumab ozogamycin to be eligible (patients should be refractory to all three agents-absence of durable hematologic response or relapse with complete remission [CR] duration of less than 6 months) - Relapsed or refractory pre-B- or T-cell acute lymphoblastic leukemia (ALL); patients with Philadelphia chromosome-positive (Ph+) ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different tyrosine kinase inhibitors (TKIs) or have a mutation associated with resistance to TKIs (T315I) - Chronic myelogenous leukemia (CML) in accelerated or blastic phase; patients failed (resistance/intolerance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Chronic myelomonocytic leukemia-2 (CMML-2) defined as having > 10% blasts (including promonocytes) in the bone marrow or > 5-19% blasts (including promonocytes) in the peripheral blood - AML arising in the setting of antecedent myelodysplasia (MDS) or myeloproliferative disorder (MPD) - Therapy-related AML - Untreated AML in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics or molecular markers (fms-related tyrosine kinase 3 [FLT3] internal tandem duplication [ ITD]+), or are unwilling to receive intensive induction chemotherapy; adverse cytogenetics: complex karyotype (>= 3 chromosomal abnormalities), 5q-, 7q-, 9q-, 20q-, abn12p, +21, +8, t(6;9), t(6;11), t(11;19), -7, -5, inv3/t(3;3), abn11q23, abn17p, abn21q - Untreated ALL in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics [t(4;11); t(1;19), hypodyploidy] or are unwilling to receive intensive induction chemotherapy; patients with Ph+ ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Previous therapy - Only patients who have received or are ineligible for established curative regimens, including stem cell transplantation when applicable, can be enrolled on this study - Patients may have received any number of prior chemotherapy regimens, which may include allogeneic or autologous transplantation, provided that performance status and organ function are maintained - Previous cytotoxic chemotherapy should have been completed at least 3 weeks and radiotherapy at least 2 weeks prior to treatment on the study (6 weeks if the last regimen included carmustine [BCNU] or mitomycin C) and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 3 weeks earlier should recover to =< grade 1; patients with hematologic malignancies are expected to have hematologic abnormalities at study entry; these abnormalities which are thought to be primarily related to the underlying leukemia, are not considered to be toxicities (AE) and do not need to resolve to =< grade 1 - Patients should stop taking all biologic agents including hematopoietic growth factors, imatinib or similar TKIs, at least 1 week prior to treatment on the study and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 1 week earlier should recover to =< grade 1; since only patients with advanced Ph+ ALL and CML in accelerated/blast phase are eligible for this study, this short period off TKIs was selected to avoid rapid leukemia progression; if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study - Patients who have undergone autologous stem cell transplantation (ASCT) are eligible provided that they are >= 4 weeks from stem cell infusion and meet other eligibility criteria - Patients who have undergone allogeneic SCT (alloSCT) are eligible if they are >= 60 days post stem cell infusion, have no evidence of graft vs. host disease, and are >= 2 weeks off all immunosuppressive therapy - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Patients have to be able to swallow pills - Total or direct bilirubin < 2 mg/dl - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 5 X institutional upper limit of normal - Creatinine < 2 mg/dl - Female patients of childbearing potential must have a negative pregnancy test - Female patients of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days afterward; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients may not be receiving any other investigational agents, or concurrent chemotherapy, radiation therapy, or immunotherapy - Any previous treatment with temozolomide - Patients with active central nervous system leukemia are excluded from this clinical trial because they may develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; patients with a history of central nervous system (CNS) leukemia but no active disease at the time of enrollment are eligible - Hyperleukocytosis with > 30,000 blasts/ul; (if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study); once patient starts treatment on the study the hydroxyurea use should be avoided, however, for patients with rapidly proliferating disease use of hydroxyurea is allowed on treatment days 1 through 12 if it becomes necessary to control a rising white blood cell (WBC) or leukostasis; the WBC need not reach 30,000/ul to start hydroxyurea during protocol days 1-12; the decision to start hydroxyurea during this time is at the discretion of the treating physician - History of allergic reactions attributed to compounds of similar chemical or biologic composition to ABT-888 or temozolomide used in this study - Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible - Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with ABT-888 - Known human immunodeficiency virus (HIV) infected patients (HIV testing will not be performed as a part of screening) on combination antiretroviral therapy, exclusive of zidovudine or starvudine, or HIV infected patients not on or willing to suspend antiretroviral therapy will be eligible provided that their cluster of differentiation (CD)4 cell count is greater than 250/mm3; HIV infected patients with CD4 count equal or less than 250/mm3 will be excluded Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); --- T315I ---

The plausible relationship between change in DSB repair and clinical response will be examined using the Fisher's exact test.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of one of the following: - Relapsed or refractory acute myeloid leukemia (AML); patients with acute promyelocytic leukemia t(15;17) must have failed tretinoin (ATRA), arsenic, and gemtuzumab ozogamycin to be eligible (patients should be refractory to all three agents-absence of durable hematologic response or relapse with complete remission [CR] duration of less than 6 months) - Relapsed or refractory pre-B- or T-cell acute lymphoblastic leukemia (ALL); patients with Philadelphia chromosome-positive (Ph+) ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different tyrosine kinase inhibitors (TKIs) or have a mutation associated with resistance to TKIs (T315I) - Chronic myelogenous leukemia (CML) in accelerated or blastic phase; patients failed (resistance/intolerance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Chronic myelomonocytic leukemia-2 (CMML-2) defined as having > 10% blasts (including promonocytes) in the bone marrow or > 5-19% blasts (including promonocytes) in the peripheral blood - AML arising in the setting of antecedent myelodysplasia (MDS) or myeloproliferative disorder (MPD) - Therapy-related AML - Untreated AML in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics or molecular markers (fms-related tyrosine kinase 3 [FLT3] internal tandem duplication [ ITD]+), or are unwilling to receive intensive induction chemotherapy; adverse cytogenetics: complex karyotype (>= 3 chromosomal abnormalities), 5q-, 7q-, 9q-, 20q-, abn12p, +21, +8, t(6;9), t(6;11), t(11;19), -7, -5, inv3/t(3;3), abn11q23, abn17p, abn21q - Untreated ALL in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics [t(4;11); t(1;19), hypodyploidy] or are unwilling to receive intensive induction chemotherapy; patients with Ph+ ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Previous therapy - Only patients who have received or are ineligible for established curative regimens, including stem cell transplantation when applicable, can be enrolled on this study - Patients may have received any number of prior chemotherapy regimens, which may include allogeneic or autologous transplantation, provided that performance status and organ function are maintained - Previous cytotoxic chemotherapy should have been completed at least 3 weeks and radiotherapy at least 2 weeks prior to treatment on the study (6 weeks if the last regimen included carmustine [BCNU] or mitomycin C) and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 3 weeks earlier should recover to =< grade 1; patients with hematologic malignancies are expected to have hematologic abnormalities at study entry; these abnormalities which are thought to be primarily related to the underlying leukemia, are not considered to be toxicities (AE) and do not need to resolve to =< grade 1 - Patients should stop taking all biologic agents including hematopoietic growth factors, imatinib or similar TKIs, at least 1 week prior to treatment on the study and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 1 week earlier should recover to =< grade 1; since only patients with advanced Ph+ ALL and CML in accelerated/blast phase are eligible for this study, this short period off TKIs was selected to avoid rapid leukemia progression; if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study - Patients who have undergone autologous stem cell transplantation (ASCT) are eligible provided that they are >= 4 weeks from stem cell infusion and meet other eligibility criteria - Patients who have undergone allogeneic SCT (alloSCT) are eligible if they are >= 60 days post stem cell infusion, have no evidence of graft vs. host disease, and are >= 2 weeks off all immunosuppressive therapy - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Patients have to be able to swallow pills - Total or direct bilirubin < 2 mg/dl - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 5 X institutional upper limit of normal - Creatinine < 2 mg/dl - Female patients of childbearing potential must have a negative pregnancy test - Female patients of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days afterward; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients may not be receiving any other investigational agents, or concurrent chemotherapy, radiation therapy, or immunotherapy - Any previous treatment with temozolomide - Patients with active central nervous system leukemia are excluded from this clinical trial because they may develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; patients with a history of central nervous system (CNS) leukemia but no active disease at the time of enrollment are eligible - Hyperleukocytosis with > 30,000 blasts/ul; (if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study); once patient starts treatment on the study the hydroxyurea use should be avoided, however, for patients with rapidly proliferating disease use of hydroxyurea is allowed on treatment days 1 through 12 if it becomes necessary to control a rising white blood cell (WBC) or leukostasis; the WBC need not reach 30,000/ul to start hydroxyurea during protocol days 1-12; the decision to start hydroxyurea during this time is at the discretion of the treating physician - History of allergic reactions attributed to compounds of similar chemical or biologic composition to ABT-888 or temozolomide used in this study - Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible - Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with ABT-888 - Known human immunodeficiency virus (HIV) infected patients (HIV testing will not be performed as a part of screening) on combination antiretroviral therapy, exclusive of zidovudine or starvudine, or HIV infected patients not on or willing to suspend antiretroviral therapy will be eligible provided that their cluster of differentiation (CD)4 cell count is greater than 250/mm3; HIV infected patients with CD4 count equal or less than 250/mm3 will be excluded Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of one of the following: - Relapsed or refractory acute myeloid leukemia (AML); patients with acute promyelocytic leukemia t(15;17) must have failed tretinoin (ATRA), arsenic, and gemtuzumab ozogamycin to be eligible (patients should be refractory to all three agents-absence of durable hematologic response or relapse with complete remission [CR] duration of less than 6 months) - Relapsed or refractory pre-B- or T-cell acute lymphoblastic leukemia (ALL); patients with Philadelphia chromosome-positive (Ph+) ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different tyrosine kinase inhibitors (TKIs) or have a mutation associated with resistance to TKIs (T315I) - Chronic myelogenous leukemia (CML) in accelerated or blastic phase; patients failed (resistance/intolerance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Chronic myelomonocytic leukemia-2 (CMML-2) defined as having > 10% blasts (including promonocytes) in the bone marrow or > 5-19% blasts (including promonocytes) in the peripheral blood - AML arising in the setting of antecedent myelodysplasia (MDS) or myeloproliferative disorder (MPD) - Therapy-related AML - Untreated AML in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics or molecular markers (fms-related tyrosine kinase 3 [FLT3] internal tandem duplication [ ITD]+), or are unwilling to receive intensive induction chemotherapy; adverse cytogenetics: complex karyotype (>= 3 chromosomal abnormalities), 5q-, 7q-, 9q-, 20q-, abn12p, +21, +8, t(6;9), t(6;11), t(11;19), -7, -5, inv3/t(3;3), abn11q23, abn17p, abn21q - Untreated ALL in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics [t(4;11); t(1;19), hypodyploidy] or are unwilling to receive intensive induction chemotherapy; patients with Ph+ ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Previous therapy - Only patients who have received or are ineligible for established curative regimens, including stem cell transplantation when applicable, can be enrolled on this study - Patients may have received any number of prior chemotherapy regimens, which may include allogeneic or autologous transplantation, provided that performance status and organ function are maintained - Previous cytotoxic chemotherapy should have been completed at least 3 weeks and radiotherapy at least 2 weeks prior to treatment on the study (6 weeks if the last regimen included carmustine [BCNU] or mitomycin C) and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 3 weeks earlier should recover to =< grade 1; patients with hematologic malignancies are expected to have hematologic abnormalities at study entry; these abnormalities which are thought to be primarily related to the underlying leukemia, are not considered to be toxicities (AE) and do not need to resolve to =< grade 1 - Patients should stop taking all biologic agents including hematopoietic growth factors, imatinib or similar TKIs, at least 1 week prior to treatment on the study and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 1 week earlier should recover to =< grade 1; since only patients with advanced Ph+ ALL and CML in accelerated/blast phase are eligible for this study, this short period off TKIs was selected to avoid rapid leukemia progression; if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study - Patients who have undergone autologous stem cell transplantation (ASCT) are eligible provided that they are >= 4 weeks from stem cell infusion and meet other eligibility criteria - Patients who have undergone allogeneic SCT (alloSCT) are eligible if they are >= 60 days post stem cell infusion, have no evidence of graft vs. host disease, and are >= 2 weeks off all immunosuppressive therapy - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Patients have to be able to swallow pills - Total or direct bilirubin < 2 mg/dl - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 5 X institutional upper limit of normal - Creatinine < 2 mg/dl - Female patients of childbearing potential must have a negative pregnancy test - Female patients of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days afterward; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients may not be receiving any other investigational agents, or concurrent chemotherapy, radiation therapy, or immunotherapy - Any previous treatment with temozolomide - Patients with active central nervous system leukemia are excluded from this clinical trial because they may develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; patients with a history of central nervous system (CNS) leukemia but no active disease at the time of enrollment are eligible - Hyperleukocytosis with > 30,000 blasts/ul; (if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study); once patient starts treatment on the study the hydroxyurea use should be avoided, however, for patients with rapidly proliferating disease use of hydroxyurea is allowed on treatment days 1 through 12 if it becomes necessary to control a rising white blood cell (WBC) or leukostasis; the WBC need not reach 30,000/ul to start hydroxyurea during protocol days 1-12; the decision to start hydroxyurea during this time is at the discretion of the treating physician - History of allergic reactions attributed to compounds of similar chemical or biologic composition to ABT-888 or temozolomide used in this study - Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible - Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with ABT-888 - Known human immunodeficiency virus (HIV) infected patients (HIV testing will not be performed as a part of screening) on combination antiretroviral therapy, exclusive of zidovudine or starvudine, or HIV infected patients not on or willing to suspend antiretroviral therapy will be eligible provided that their cluster of differentiation (CD)4 cell count is greater than 250/mm3; HIV infected patients with CD4 count equal or less than 250/mm3 will be excluded Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); --- T315I --- --- T315I ---

The plausible relationship between change in DSB repair and clinical response will be examined using the Fisher's exact test.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of one of the following: - Relapsed or refractory acute myeloid leukemia (AML); patients with acute promyelocytic leukemia t(15;17) must have failed tretinoin (ATRA), arsenic, and gemtuzumab ozogamycin to be eligible (patients should be refractory to all three agents-absence of durable hematologic response or relapse with complete remission [CR] duration of less than 6 months) - Relapsed or refractory pre-B- or T-cell acute lymphoblastic leukemia (ALL); patients with Philadelphia chromosome-positive (Ph+) ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different tyrosine kinase inhibitors (TKIs) or have a mutation associated with resistance to TKIs (T315I) - Chronic myelogenous leukemia (CML) in accelerated or blastic phase; patients failed (resistance/intolerance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Chronic myelomonocytic leukemia-2 (CMML-2) defined as having > 10% blasts (including promonocytes) in the bone marrow or > 5-19% blasts (including promonocytes) in the peripheral blood - AML arising in the setting of antecedent myelodysplasia (MDS) or myeloproliferative disorder (MPD) - Therapy-related AML - Untreated AML in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics or molecular markers (fms-related tyrosine kinase 3 [FLT3] internal tandem duplication [ ITD]+), or are unwilling to receive intensive induction chemotherapy; adverse cytogenetics: complex karyotype (>= 3 chromosomal abnormalities), 5q-, 7q-, 9q-, 20q-, abn12p, +21, +8, t(6;9), t(6;11), t(11;19), -7, -5, inv3/t(3;3), abn11q23, abn17p, abn21q - Untreated ALL in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics [t(4;11); t(1;19), hypodyploidy] or are unwilling to receive intensive induction chemotherapy; patients with Ph+ ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Previous therapy - Only patients who have received or are ineligible for established curative regimens, including stem cell transplantation when applicable, can be enrolled on this study - Patients may have received any number of prior chemotherapy regimens, which may include allogeneic or autologous transplantation, provided that performance status and organ function are maintained - Previous cytotoxic chemotherapy should have been completed at least 3 weeks and radiotherapy at least 2 weeks prior to treatment on the study (6 weeks if the last regimen included carmustine [BCNU] or mitomycin C) and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 3 weeks earlier should recover to =< grade 1; patients with hematologic malignancies are expected to have hematologic abnormalities at study entry; these abnormalities which are thought to be primarily related to the underlying leukemia, are not considered to be toxicities (AE) and do not need to resolve to =< grade 1 - Patients should stop taking all biologic agents including hematopoietic growth factors, imatinib or similar TKIs, at least 1 week prior to treatment on the study and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 1 week earlier should recover to =< grade 1; since only patients with advanced Ph+ ALL and CML in accelerated/blast phase are eligible for this study, this short period off TKIs was selected to avoid rapid leukemia progression; if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study - Patients who have undergone autologous stem cell transplantation (ASCT) are eligible provided that they are >= 4 weeks from stem cell infusion and meet other eligibility criteria - Patients who have undergone allogeneic SCT (alloSCT) are eligible if they are >= 60 days post stem cell infusion, have no evidence of graft vs. host disease, and are >= 2 weeks off all immunosuppressive therapy - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Patients have to be able to swallow pills - Total or direct bilirubin < 2 mg/dl - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 5 X institutional upper limit of normal - Creatinine < 2 mg/dl - Female patients of childbearing potential must have a negative pregnancy test - Female patients of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days afterward; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients may not be receiving any other investigational agents, or concurrent chemotherapy, radiation therapy, or immunotherapy - Any previous treatment with temozolomide - Patients with active central nervous system leukemia are excluded from this clinical trial because they may develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; patients with a history of central nervous system (CNS) leukemia but no active disease at the time of enrollment are eligible - Hyperleukocytosis with > 30,000 blasts/ul; (if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study); once patient starts treatment on the study the hydroxyurea use should be avoided, however, for patients with rapidly proliferating disease use of hydroxyurea is allowed on treatment days 1 through 12 if it becomes necessary to control a rising white blood cell (WBC) or leukostasis; the WBC need not reach 30,000/ul to start hydroxyurea during protocol days 1-12; the decision to start hydroxyurea during this time is at the discretion of the treating physician - History of allergic reactions attributed to compounds of similar chemical or biologic composition to ABT-888 or temozolomide used in this study - Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible - Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with ABT-888 - Known human immunodeficiency virus (HIV) infected patients (HIV testing will not be performed as a part of screening) on combination antiretroviral therapy, exclusive of zidovudine or starvudine, or HIV infected patients not on or willing to suspend antiretroviral therapy will be eligible provided that their cluster of differentiation (CD)4 cell count is greater than 250/mm3; HIV infected patients with CD4 count equal or less than 250/mm3 will be excluded Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of one of the following: - Relapsed or refractory acute myeloid leukemia (AML); patients with acute promyelocytic leukemia t(15;17) must have failed tretinoin (ATRA), arsenic, and gemtuzumab ozogamycin to be eligible (patients should be refractory to all three agents-absence of durable hematologic response or relapse with complete remission [CR] duration of less than 6 months) - Relapsed or refractory pre-B- or T-cell acute lymphoblastic leukemia (ALL); patients with Philadelphia chromosome-positive (Ph+) ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different tyrosine kinase inhibitors (TKIs) or have a mutation associated with resistance to TKIs (T315I) - Chronic myelogenous leukemia (CML) in accelerated or blastic phase; patients failed (resistance/intolerance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Chronic myelomonocytic leukemia-2 (CMML-2) defined as having > 10% blasts (including promonocytes) in the bone marrow or > 5-19% blasts (including promonocytes) in the peripheral blood - AML arising in the setting of antecedent myelodysplasia (MDS) or myeloproliferative disorder (MPD) - Therapy-related AML - Untreated AML in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics or molecular markers (fms-related tyrosine kinase 3 [FLT3] internal tandem duplication [ ITD]+), or are unwilling to receive intensive induction chemotherapy; adverse cytogenetics: complex karyotype (>= 3 chromosomal abnormalities), 5q-, 7q-, 9q-, 20q-, abn12p, +21, +8, t(6;9), t(6;11), t(11;19), -7, -5, inv3/t(3;3), abn11q23, abn17p, abn21q - Untreated ALL in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics [t(4;11); t(1;19), hypodyploidy] or are unwilling to receive intensive induction chemotherapy; patients with Ph+ ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Previous therapy - Only patients who have received or are ineligible for established curative regimens, including stem cell transplantation when applicable, can be enrolled on this study - Patients may have received any number of prior chemotherapy regimens, which may include allogeneic or autologous transplantation, provided that performance status and organ function are maintained - Previous cytotoxic chemotherapy should have been completed at least 3 weeks and radiotherapy at least 2 weeks prior to treatment on the study (6 weeks if the last regimen included carmustine [BCNU] or mitomycin C) and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 3 weeks earlier should recover to =< grade 1; patients with hematologic malignancies are expected to have hematologic abnormalities at study entry; these abnormalities which are thought to be primarily related to the underlying leukemia, are not considered to be toxicities (AE) and do not need to resolve to =< grade 1 - Patients should stop taking all biologic agents including hematopoietic growth factors, imatinib or similar TKIs, at least 1 week prior to treatment on the study and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 1 week earlier should recover to =< grade 1; since only patients with advanced Ph+ ALL and CML in accelerated/blast phase are eligible for this study, this short period off TKIs was selected to avoid rapid leukemia progression; if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study - Patients who have undergone autologous stem cell transplantation (ASCT) are eligible provided that they are >= 4 weeks from stem cell infusion and meet other eligibility criteria - Patients who have undergone allogeneic SCT (alloSCT) are eligible if they are >= 60 days post stem cell infusion, have no evidence of graft vs. host disease, and are >= 2 weeks off all immunosuppressive therapy - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Patients have to be able to swallow pills - Total or direct bilirubin < 2 mg/dl - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 5 X institutional upper limit of normal - Creatinine < 2 mg/dl - Female patients of childbearing potential must have a negative pregnancy test - Female patients of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days afterward; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients may not be receiving any other investigational agents, or concurrent chemotherapy, radiation therapy, or immunotherapy - Any previous treatment with temozolomide - Patients with active central nervous system leukemia are excluded from this clinical trial because they may develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; patients with a history of central nervous system (CNS) leukemia but no active disease at the time of enrollment are eligible - Hyperleukocytosis with > 30,000 blasts/ul; (if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study); once patient starts treatment on the study the hydroxyurea use should be avoided, however, for patients with rapidly proliferating disease use of hydroxyurea is allowed on treatment days 1 through 12 if it becomes necessary to control a rising white blood cell (WBC) or leukostasis; the WBC need not reach 30,000/ul to start hydroxyurea during protocol days 1-12; the decision to start hydroxyurea during this time is at the discretion of the treating physician - History of allergic reactions attributed to compounds of similar chemical or biologic composition to ABT-888 or temozolomide used in this study - Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible - Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with ABT-888 - Known human immunodeficiency virus (HIV) infected patients (HIV testing will not be performed as a part of screening) on combination antiretroviral therapy, exclusive of zidovudine or starvudine, or HIV infected patients not on or willing to suspend antiretroviral therapy will be eligible provided that their cluster of differentiation (CD)4 cell count is greater than 250/mm3; HIV infected patients with CD4 count equal or less than 250/mm3 will be excluded Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); --- T315I --- --- T315I --- --- T315I ---

The plausible relationship between change in DSB repair and clinical response will be examined using the Fisher's exact test.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of one of the following: - Relapsed or refractory acute myeloid leukemia (AML); patients with acute promyelocytic leukemia t(15;17) must have failed tretinoin (ATRA), arsenic, and gemtuzumab ozogamycin to be eligible (patients should be refractory to all three agents-absence of durable hematologic response or relapse with complete remission [CR] duration of less than 6 months) - Relapsed or refractory pre-B- or T-cell acute lymphoblastic leukemia (ALL); patients with Philadelphia chromosome-positive (Ph+) ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different tyrosine kinase inhibitors (TKIs) or have a mutation associated with resistance to TKIs (T315I) - Chronic myelogenous leukemia (CML) in accelerated or blastic phase; patients failed (resistance/intolerance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Chronic myelomonocytic leukemia-2 (CMML-2) defined as having > 10% blasts (including promonocytes) in the bone marrow or > 5-19% blasts (including promonocytes) in the peripheral blood - AML arising in the setting of antecedent myelodysplasia (MDS) or myeloproliferative disorder (MPD) - Therapy-related AML - Untreated AML in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics or molecular markers (fms-related tyrosine kinase 3 [FLT3] internal tandem duplication [ ITD]+), or are unwilling to receive intensive induction chemotherapy; adverse cytogenetics: complex karyotype (>= 3 chromosomal abnormalities), 5q-, 7q-, 9q-, 20q-, abn12p, +21, +8, t(6;9), t(6;11), t(11;19), -7, -5, inv3/t(3;3), abn11q23, abn17p, abn21q - Untreated ALL in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics [t(4;11); t(1;19), hypodyploidy] or are unwilling to receive intensive induction chemotherapy; patients with Ph+ ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Previous therapy - Only patients who have received or are ineligible for established curative regimens, including stem cell transplantation when applicable, can be enrolled on this study - Patients may have received any number of prior chemotherapy regimens, which may include allogeneic or autologous transplantation, provided that performance status and organ function are maintained - Previous cytotoxic chemotherapy should have been completed at least 3 weeks and radiotherapy at least 2 weeks prior to treatment on the study (6 weeks if the last regimen included carmustine [BCNU] or mitomycin C) and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 3 weeks earlier should recover to =< grade 1; patients with hematologic malignancies are expected to have hematologic abnormalities at study entry; these abnormalities which are thought to be primarily related to the underlying leukemia, are not considered to be toxicities (AE) and do not need to resolve to =< grade 1 - Patients should stop taking all biologic agents including hematopoietic growth factors, imatinib or similar TKIs, at least 1 week prior to treatment on the study and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 1 week earlier should recover to =< grade 1; since only patients with advanced Ph+ ALL and CML in accelerated/blast phase are eligible for this study, this short period off TKIs was selected to avoid rapid leukemia progression; if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study - Patients who have undergone autologous stem cell transplantation (ASCT) are eligible provided that they are >= 4 weeks from stem cell infusion and meet other eligibility criteria - Patients who have undergone allogeneic SCT (alloSCT) are eligible if they are >= 60 days post stem cell infusion, have no evidence of graft vs. host disease, and are >= 2 weeks off all immunosuppressive therapy - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Patients have to be able to swallow pills - Total or direct bilirubin < 2 mg/dl - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 5 X institutional upper limit of normal - Creatinine < 2 mg/dl - Female patients of childbearing potential must have a negative pregnancy test - Female patients of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days afterward; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients may not be receiving any other investigational agents, or concurrent chemotherapy, radiation therapy, or immunotherapy - Any previous treatment with temozolomide - Patients with active central nervous system leukemia are excluded from this clinical trial because they may develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; patients with a history of central nervous system (CNS) leukemia but no active disease at the time of enrollment are eligible - Hyperleukocytosis with > 30,000 blasts/ul; (if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study); once patient starts treatment on the study the hydroxyurea use should be avoided, however, for patients with rapidly proliferating disease use of hydroxyurea is allowed on treatment days 1 through 12 if it becomes necessary to control a rising white blood cell (WBC) or leukostasis; the WBC need not reach 30,000/ul to start hydroxyurea during protocol days 1-12; the decision to start hydroxyurea during this time is at the discretion of the treating physician - History of allergic reactions attributed to compounds of similar chemical or biologic composition to ABT-888 or temozolomide used in this study - Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible - Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with ABT-888 - Known human immunodeficiency virus (HIV) infected patients (HIV testing will not be performed as a part of screening) on combination antiretroviral therapy, exclusive of zidovudine or starvudine, or HIV infected patients not on or willing to suspend antiretroviral therapy will be eligible provided that their cluster of differentiation (CD)4 cell count is greater than 250/mm3; HIV infected patients with CD4 count equal or less than 250/mm3 will be excluded Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of one of the following: - Relapsed or refractory acute myeloid leukemia (AML); patients with acute promyelocytic leukemia t(15;17) must have failed tretinoin (ATRA), arsenic, and gemtuzumab ozogamycin to be eligible (patients should be refractory to all three agents-absence of durable hematologic response or relapse with complete remission [CR] duration of less than 6 months) - Relapsed or refractory pre-B- or T-cell acute lymphoblastic leukemia (ALL); patients with Philadelphia chromosome-positive (Ph+) ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different tyrosine kinase inhibitors (TKIs) or have a mutation associated with resistance to TKIs (T315I) - Chronic myelogenous leukemia (CML) in accelerated or blastic phase; patients failed (resistance/intolerance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Chronic myelomonocytic leukemia-2 (CMML-2) defined as having > 10% blasts (including promonocytes) in the bone marrow or > 5-19% blasts (including promonocytes) in the peripheral blood - AML arising in the setting of antecedent myelodysplasia (MDS) or myeloproliferative disorder (MPD) - Therapy-related AML - Untreated AML in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics or molecular markers (fms-related tyrosine kinase 3 [FLT3] internal tandem duplication [ ITD]+), or are unwilling to receive intensive induction chemotherapy; adverse cytogenetics: complex karyotype (>= 3 chromosomal abnormalities), 5q-, 7q-, 9q-, 20q-, abn12p, +21, +8, t(6;9), t(6;11), t(11;19), -7, -5, inv3/t(3;3), abn11q23, abn17p, abn21q - Untreated ALL in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics [t(4;11); t(1;19), hypodyploidy] or are unwilling to receive intensive induction chemotherapy; patients with Ph+ ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Previous therapy - Only patients who have received or are ineligible for established curative regimens, including stem cell transplantation when applicable, can be enrolled on this study - Patients may have received any number of prior chemotherapy regimens, which may include allogeneic or autologous transplantation, provided that performance status and organ function are maintained - Previous cytotoxic chemotherapy should have been completed at least 3 weeks and radiotherapy at least 2 weeks prior to treatment on the study (6 weeks if the last regimen included carmustine [BCNU] or mitomycin C) and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 3 weeks earlier should recover to =< grade 1; patients with hematologic malignancies are expected to have hematologic abnormalities at study entry; these abnormalities which are thought to be primarily related to the underlying leukemia, are not considered to be toxicities (AE) and do not need to resolve to =< grade 1 - Patients should stop taking all biologic agents including hematopoietic growth factors, imatinib or similar TKIs, at least 1 week prior to treatment on the study and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 1 week earlier should recover to =< grade 1; since only patients with advanced Ph+ ALL and CML in accelerated/blast phase are eligible for this study, this short period off TKIs was selected to avoid rapid leukemia progression; if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study - Patients who have undergone autologous stem cell transplantation (ASCT) are eligible provided that they are >= 4 weeks from stem cell infusion and meet other eligibility criteria - Patients who have undergone allogeneic SCT (alloSCT) are eligible if they are >= 60 days post stem cell infusion, have no evidence of graft vs. host disease, and are >= 2 weeks off all immunosuppressive therapy - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Patients have to be able to swallow pills - Total or direct bilirubin < 2 mg/dl - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 5 X institutional upper limit of normal - Creatinine < 2 mg/dl - Female patients of childbearing potential must have a negative pregnancy test - Female patients of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days afterward; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients may not be receiving any other investigational agents, or concurrent chemotherapy, radiation therapy, or immunotherapy - Any previous treatment with temozolomide - Patients with active central nervous system leukemia are excluded from this clinical trial because they may develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; patients with a history of central nervous system (CNS) leukemia but no active disease at the time of enrollment are eligible - Hyperleukocytosis with > 30,000 blasts/ul; (if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study); once patient starts treatment on the study the hydroxyurea use should be avoided, however, for patients with rapidly proliferating disease use of hydroxyurea is allowed on treatment days 1 through 12 if it becomes necessary to control a rising white blood cell (WBC) or leukostasis; the WBC need not reach 30,000/ul to start hydroxyurea during protocol days 1-12; the decision to start hydroxyurea during this time is at the discretion of the treating physician - History of allergic reactions attributed to compounds of similar chemical or biologic composition to ABT-888 or temozolomide used in this study - Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible - Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with ABT-888 - Known human immunodeficiency virus (HIV) infected patients (HIV testing will not be performed as a part of screening) on combination antiretroviral therapy, exclusive of zidovudine or starvudine, or HIV infected patients not on or willing to suspend antiretroviral therapy will be eligible provided that their cluster of differentiation (CD)4 cell count is greater than 250/mm3; HIV infected patients with CD4 count equal or less than 250/mm3 will be excluded Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); --- T315I --- --- T315I --- --- T315I --- --- T315I ---

The plausible relationship between change in DSB repair and clinical response will be examined using the Fisher's exact test.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of one of the following: - Relapsed or refractory acute myeloid leukemia (AML); patients with acute promyelocytic leukemia t(15;17) must have failed tretinoin (ATRA), arsenic, and gemtuzumab ozogamycin to be eligible (patients should be refractory to all three agents-absence of durable hematologic response or relapse with complete remission [CR] duration of less than 6 months) - Relapsed or refractory pre-B- or T-cell acute lymphoblastic leukemia (ALL); patients with Philadelphia chromosome-positive (Ph+) ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different tyrosine kinase inhibitors (TKIs) or have a mutation associated with resistance to TKIs (T315I) - Chronic myelogenous leukemia (CML) in accelerated or blastic phase; patients failed (resistance/intolerance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Chronic myelomonocytic leukemia-2 (CMML-2) defined as having > 10% blasts (including promonocytes) in the bone marrow or > 5-19% blasts (including promonocytes) in the peripheral blood - AML arising in the setting of antecedent myelodysplasia (MDS) or myeloproliferative disorder (MPD) - Therapy-related AML - Untreated AML in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics or molecular markers (fms-related tyrosine kinase 3 [FLT3] internal tandem duplication [ ITD]+), or are unwilling to receive intensive induction chemotherapy; adverse cytogenetics: complex karyotype (>= 3 chromosomal abnormalities), 5q-, 7q-, 9q-, 20q-, abn12p, +21, +8, t(6;9), t(6;11), t(11;19), -7, -5, inv3/t(3;3), abn11q23, abn17p, abn21q - Untreated ALL in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics [t(4;11); t(1;19), hypodyploidy] or are unwilling to receive intensive induction chemotherapy; patients with Ph+ ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Previous therapy - Only patients who have received or are ineligible for established curative regimens, including stem cell transplantation when applicable, can be enrolled on this study - Patients may have received any number of prior chemotherapy regimens, which may include allogeneic or autologous transplantation, provided that performance status and organ function are maintained - Previous cytotoxic chemotherapy should have been completed at least 3 weeks and radiotherapy at least 2 weeks prior to treatment on the study (6 weeks if the last regimen included carmustine [BCNU] or mitomycin C) and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 3 weeks earlier should recover to =< grade 1; patients with hematologic malignancies are expected to have hematologic abnormalities at study entry; these abnormalities which are thought to be primarily related to the underlying leukemia, are not considered to be toxicities (AE) and do not need to resolve to =< grade 1 - Patients should stop taking all biologic agents including hematopoietic growth factors, imatinib or similar TKIs, at least 1 week prior to treatment on the study and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 1 week earlier should recover to =< grade 1; since only patients with advanced Ph+ ALL and CML in accelerated/blast phase are eligible for this study, this short period off TKIs was selected to avoid rapid leukemia progression; if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study - Patients who have undergone autologous stem cell transplantation (ASCT) are eligible provided that they are >= 4 weeks from stem cell infusion and meet other eligibility criteria - Patients who have undergone allogeneic SCT (alloSCT) are eligible if they are >= 60 days post stem cell infusion, have no evidence of graft vs. host disease, and are >= 2 weeks off all immunosuppressive therapy - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Patients have to be able to swallow pills - Total or direct bilirubin < 2 mg/dl - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 5 X institutional upper limit of normal - Creatinine < 2 mg/dl - Female patients of childbearing potential must have a negative pregnancy test - Female patients of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days afterward; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients may not be receiving any other investigational agents, or concurrent chemotherapy, radiation therapy, or immunotherapy - Any previous treatment with temozolomide - Patients with active central nervous system leukemia are excluded from this clinical trial because they may develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; patients with a history of central nervous system (CNS) leukemia but no active disease at the time of enrollment are eligible - Hyperleukocytosis with > 30,000 blasts/ul; (if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study); once patient starts treatment on the study the hydroxyurea use should be avoided, however, for patients with rapidly proliferating disease use of hydroxyurea is allowed on treatment days 1 through 12 if it becomes necessary to control a rising white blood cell (WBC) or leukostasis; the WBC need not reach 30,000/ul to start hydroxyurea during protocol days 1-12; the decision to start hydroxyurea during this time is at the discretion of the treating physician - History of allergic reactions attributed to compounds of similar chemical or biologic composition to ABT-888 or temozolomide used in this study - Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible - Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with ABT-888 - Known human immunodeficiency virus (HIV) infected patients (HIV testing will not be performed as a part of screening) on combination antiretroviral therapy, exclusive of zidovudine or starvudine, or HIV infected patients not on or willing to suspend antiretroviral therapy will be eligible provided that their cluster of differentiation (CD)4 cell count is greater than 250/mm3; HIV infected patients with CD4 count equal or less than 250/mm3 will be excluded Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of one of the following: - Relapsed or refractory acute myeloid leukemia (AML); patients with acute promyelocytic leukemia t(15;17) must have failed tretinoin (ATRA), arsenic, and gemtuzumab ozogamycin to be eligible (patients should be refractory to all three agents-absence of durable hematologic response or relapse with complete remission [CR] duration of less than 6 months) - Relapsed or refractory pre-B- or T-cell acute lymphoblastic leukemia (ALL); patients with Philadelphia chromosome-positive (Ph+) ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different tyrosine kinase inhibitors (TKIs) or have a mutation associated with resistance to TKIs (T315I) - Chronic myelogenous leukemia (CML) in accelerated or blastic phase; patients failed (resistance/intolerance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Chronic myelomonocytic leukemia-2 (CMML-2) defined as having > 10% blasts (including promonocytes) in the bone marrow or > 5-19% blasts (including promonocytes) in the peripheral blood - AML arising in the setting of antecedent myelodysplasia (MDS) or myeloproliferative disorder (MPD) - Therapy-related AML - Untreated AML in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics or molecular markers (fms-related tyrosine kinase 3 [FLT3] internal tandem duplication [ ITD]+), or are unwilling to receive intensive induction chemotherapy; adverse cytogenetics: complex karyotype (>= 3 chromosomal abnormalities), 5q-, 7q-, 9q-, 20q-, abn12p, +21, +8, t(6;9), t(6;11), t(11;19), -7, -5, inv3/t(3;3), abn11q23, abn17p, abn21q - Untreated ALL in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics [t(4;11); t(1;19), hypodyploidy] or are unwilling to receive intensive induction chemotherapy; patients with Ph+ ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Previous therapy - Only patients who have received or are ineligible for established curative regimens, including stem cell transplantation when applicable, can be enrolled on this study - Patients may have received any number of prior chemotherapy regimens, which may include allogeneic or autologous transplantation, provided that performance status and organ function are maintained - Previous cytotoxic chemotherapy should have been completed at least 3 weeks and radiotherapy at least 2 weeks prior to treatment on the study (6 weeks if the last regimen included carmustine [BCNU] or mitomycin C) and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 3 weeks earlier should recover to =< grade 1; patients with hematologic malignancies are expected to have hematologic abnormalities at study entry; these abnormalities which are thought to be primarily related to the underlying leukemia, are not considered to be toxicities (AE) and do not need to resolve to =< grade 1 - Patients should stop taking all biologic agents including hematopoietic growth factors, imatinib or similar TKIs, at least 1 week prior to treatment on the study and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 1 week earlier should recover to =< grade 1; since only patients with advanced Ph+ ALL and CML in accelerated/blast phase are eligible for this study, this short period off TKIs was selected to avoid rapid leukemia progression; if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study - Patients who have undergone autologous stem cell transplantation (ASCT) are eligible provided that they are >= 4 weeks from stem cell infusion and meet other eligibility criteria - Patients who have undergone allogeneic SCT (alloSCT) are eligible if they are >= 60 days post stem cell infusion, have no evidence of graft vs. host disease, and are >= 2 weeks off all immunosuppressive therapy - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Patients have to be able to swallow pills - Total or direct bilirubin < 2 mg/dl - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 5 X institutional upper limit of normal - Creatinine < 2 mg/dl - Female patients of childbearing potential must have a negative pregnancy test - Female patients of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days afterward; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients may not be receiving any other investigational agents, or concurrent chemotherapy, radiation therapy, or immunotherapy - Any previous treatment with temozolomide - Patients with active central nervous system leukemia are excluded from this clinical trial because they may develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; patients with a history of central nervous system (CNS) leukemia but no active disease at the time of enrollment are eligible - Hyperleukocytosis with > 30,000 blasts/ul; (if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study); once patient starts treatment on the study the hydroxyurea use should be avoided, however, for patients with rapidly proliferating disease use of hydroxyurea is allowed on treatment days 1 through 12 if it becomes necessary to control a rising white blood cell (WBC) or leukostasis; the WBC need not reach 30,000/ul to start hydroxyurea during protocol days 1-12; the decision to start hydroxyurea during this time is at the discretion of the treating physician - History of allergic reactions attributed to compounds of similar chemical or biologic composition to ABT-888 or temozolomide used in this study - Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible - Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with ABT-888 - Known human immunodeficiency virus (HIV) infected patients (HIV testing will not be performed as a part of screening) on combination antiretroviral therapy, exclusive of zidovudine or starvudine, or HIV infected patients not on or willing to suspend antiretroviral therapy will be eligible provided that their cluster of differentiation (CD)4 cell count is greater than 250/mm3; HIV infected patients with CD4 count equal or less than 250/mm3 will be excluded Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); --- T315I --- --- T315I --- --- T315I --- --- T315I --- --- T315I ---

The plausible relationship between change in DSB repair and clinical response will be examined using the Fisher's exact test.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of one of the following: - Relapsed or refractory acute myeloid leukemia (AML); patients with acute promyelocytic leukemia t(15;17) must have failed tretinoin (ATRA), arsenic, and gemtuzumab ozogamycin to be eligible (patients should be refractory to all three agents-absence of durable hematologic response or relapse with complete remission [CR] duration of less than 6 months) - Relapsed or refractory pre-B- or T-cell acute lymphoblastic leukemia (ALL); patients with Philadelphia chromosome-positive (Ph+) ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different tyrosine kinase inhibitors (TKIs) or have a mutation associated with resistance to TKIs (T315I) - Chronic myelogenous leukemia (CML) in accelerated or blastic phase; patients failed (resistance/intolerance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Chronic myelomonocytic leukemia-2 (CMML-2) defined as having > 10% blasts (including promonocytes) in the bone marrow or > 5-19% blasts (including promonocytes) in the peripheral blood - AML arising in the setting of antecedent myelodysplasia (MDS) or myeloproliferative disorder (MPD) - Therapy-related AML - Untreated AML in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics or molecular markers (fms-related tyrosine kinase 3 [FLT3] internal tandem duplication [ ITD]+), or are unwilling to receive intensive induction chemotherapy; adverse cytogenetics: complex karyotype (>= 3 chromosomal abnormalities), 5q-, 7q-, 9q-, 20q-, abn12p, +21, +8, t(6;9), t(6;11), t(11;19), -7, -5, inv3/t(3;3), abn11q23, abn17p, abn21q - Untreated ALL in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics [t(4;11); t(1;19), hypodyploidy] or are unwilling to receive intensive induction chemotherapy; patients with Ph+ ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Previous therapy - Only patients who have received or are ineligible for established curative regimens, including stem cell transplantation when applicable, can be enrolled on this study - Patients may have received any number of prior chemotherapy regimens, which may include allogeneic or autologous transplantation, provided that performance status and organ function are maintained - Previous cytotoxic chemotherapy should have been completed at least 3 weeks and radiotherapy at least 2 weeks prior to treatment on the study (6 weeks if the last regimen included carmustine [BCNU] or mitomycin C) and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 3 weeks earlier should recover to =< grade 1; patients with hematologic malignancies are expected to have hematologic abnormalities at study entry; these abnormalities which are thought to be primarily related to the underlying leukemia, are not considered to be toxicities (AE) and do not need to resolve to =< grade 1 - Patients should stop taking all biologic agents including hematopoietic growth factors, imatinib or similar TKIs, at least 1 week prior to treatment on the study and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 1 week earlier should recover to =< grade 1; since only patients with advanced Ph+ ALL and CML in accelerated/blast phase are eligible for this study, this short period off TKIs was selected to avoid rapid leukemia progression; if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study - Patients who have undergone autologous stem cell transplantation (ASCT) are eligible provided that they are >= 4 weeks from stem cell infusion and meet other eligibility criteria - Patients who have undergone allogeneic SCT (alloSCT) are eligible if they are >= 60 days post stem cell infusion, have no evidence of graft vs. host disease, and are >= 2 weeks off all immunosuppressive therapy - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Patients have to be able to swallow pills - Total or direct bilirubin < 2 mg/dl - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 5 X institutional upper limit of normal - Creatinine < 2 mg/dl - Female patients of childbearing potential must have a negative pregnancy test - Female patients of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days afterward; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients may not be receiving any other investigational agents, or concurrent chemotherapy, radiation therapy, or immunotherapy - Any previous treatment with temozolomide - Patients with active central nervous system leukemia are excluded from this clinical trial because they may develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; patients with a history of central nervous system (CNS) leukemia but no active disease at the time of enrollment are eligible - Hyperleukocytosis with > 30,000 blasts/ul; (if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study); once patient starts treatment on the study the hydroxyurea use should be avoided, however, for patients with rapidly proliferating disease use of hydroxyurea is allowed on treatment days 1 through 12 if it becomes necessary to control a rising white blood cell (WBC) or leukostasis; the WBC need not reach 30,000/ul to start hydroxyurea during protocol days 1-12; the decision to start hydroxyurea during this time is at the discretion of the treating physician - History of allergic reactions attributed to compounds of similar chemical or biologic composition to ABT-888 or temozolomide used in this study - Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible - Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with ABT-888 - Known human immunodeficiency virus (HIV) infected patients (HIV testing will not be performed as a part of screening) on combination antiretroviral therapy, exclusive of zidovudine or starvudine, or HIV infected patients not on or willing to suspend antiretroviral therapy will be eligible provided that their cluster of differentiation (CD)4 cell count is greater than 250/mm3; HIV infected patients with CD4 count equal or less than 250/mm3 will be excluded Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of one of the following: - Relapsed or refractory acute myeloid leukemia (AML); patients with acute promyelocytic leukemia t(15;17) must have failed tretinoin (ATRA), arsenic, and gemtuzumab ozogamycin to be eligible (patients should be refractory to all three agents-absence of durable hematologic response or relapse with complete remission [CR] duration of less than 6 months) - Relapsed or refractory pre-B- or T-cell acute lymphoblastic leukemia (ALL); patients with Philadelphia chromosome-positive (Ph+) ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different tyrosine kinase inhibitors (TKIs) or have a mutation associated with resistance to TKIs (T315I) - Chronic myelogenous leukemia (CML) in accelerated or blastic phase; patients failed (resistance/intolerance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Chronic myelomonocytic leukemia-2 (CMML-2) defined as having > 10% blasts (including promonocytes) in the bone marrow or > 5-19% blasts (including promonocytes) in the peripheral blood - AML arising in the setting of antecedent myelodysplasia (MDS) or myeloproliferative disorder (MPD) - Therapy-related AML - Untreated AML in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics or molecular markers (fms-related tyrosine kinase 3 [FLT3] internal tandem duplication [ ITD]+), or are unwilling to receive intensive induction chemotherapy; adverse cytogenetics: complex karyotype (>= 3 chromosomal abnormalities), 5q-, 7q-, 9q-, 20q-, abn12p, +21, +8, t(6;9), t(6;11), t(11;19), -7, -5, inv3/t(3;3), abn11q23, abn17p, abn21q - Untreated ALL in adults 60 years of age and older who are not candidates for induction chemotherapy due to poor-risk features including adverse cytogenetics [t(4;11); t(1;19), hypodyploidy] or are unwilling to receive intensive induction chemotherapy; patients with Ph+ ALL [t(9;22)] will be eligible provided that they have failed (intolerance/resistance) at least 2 different TKIs or have a mutation associated with resistance to TKIs (T315I) - Previous therapy - Only patients who have received or are ineligible for established curative regimens, including stem cell transplantation when applicable, can be enrolled on this study - Patients may have received any number of prior chemotherapy regimens, which may include allogeneic or autologous transplantation, provided that performance status and organ function are maintained - Previous cytotoxic chemotherapy should have been completed at least 3 weeks and radiotherapy at least 2 weeks prior to treatment on the study (6 weeks if the last regimen included carmustine [BCNU] or mitomycin C) and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 3 weeks earlier should recover to =< grade 1; patients with hematologic malignancies are expected to have hematologic abnormalities at study entry; these abnormalities which are thought to be primarily related to the underlying leukemia, are not considered to be toxicities (AE) and do not need to resolve to =< grade 1 - Patients should stop taking all biologic agents including hematopoietic growth factors, imatinib or similar TKIs, at least 1 week prior to treatment on the study and all adverse events (excluding alopecia, acne, rash) due to agents administered more than 1 week earlier should recover to =< grade 1; since only patients with advanced Ph+ ALL and CML in accelerated/blast phase are eligible for this study, this short period off TKIs was selected to avoid rapid leukemia progression; if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study - Patients who have undergone autologous stem cell transplantation (ASCT) are eligible provided that they are >= 4 weeks from stem cell infusion and meet other eligibility criteria - Patients who have undergone allogeneic SCT (alloSCT) are eligible if they are >= 60 days post stem cell infusion, have no evidence of graft vs. host disease, and are >= 2 weeks off all immunosuppressive therapy - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Patients have to be able to swallow pills - Total or direct bilirubin < 2 mg/dl - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 5 X institutional upper limit of normal - Creatinine < 2 mg/dl - Female patients of childbearing potential must have a negative pregnancy test - Female patients of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days afterward; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients may not be receiving any other investigational agents, or concurrent chemotherapy, radiation therapy, or immunotherapy - Any previous treatment with temozolomide - Patients with active central nervous system leukemia are excluded from this clinical trial because they may develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; patients with a history of central nervous system (CNS) leukemia but no active disease at the time of enrollment are eligible - Hyperleukocytosis with > 30,000 blasts/ul; (if using hydroxyurea, corticosteroids, or leukopheresis for blast count control, patients must be off >= 24 hrs before starting treatment on the study); once patient starts treatment on the study the hydroxyurea use should be avoided, however, for patients with rapidly proliferating disease use of hydroxyurea is allowed on treatment days 1 through 12 if it becomes necessary to control a rising white blood cell (WBC) or leukostasis; the WBC need not reach 30,000/ul to start hydroxyurea during protocol days 1-12; the decision to start hydroxyurea during this time is at the discretion of the treating physician - History of allergic reactions attributed to compounds of similar chemical or biologic composition to ABT-888 or temozolomide used in this study - Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible - Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with ABT-888 - Known human immunodeficiency virus (HIV) infected patients (HIV testing will not be performed as a part of screening) on combination antiretroviral therapy, exclusive of zidovudine or starvudine, or HIV infected patients not on or willing to suspend antiretroviral therapy will be eligible provided that their cluster of differentiation (CD)4 cell count is greater than 250/mm3; HIV infected patients with CD4 count equal or less than 250/mm3 will be excluded Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); --- T315I --- --- T315I --- --- T315I --- --- T315I --- --- T315I --- --- T315I ---

Primary Outcomes

Measure: MTD of veliparib, determined according to incidence of dose limiting toxicity, graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

Time: 28 days

Secondary Outcomes

Description: The proportion of responders will be estimated and reported with the corresponding 90% confidence interval.

Measure: Response rate at the MTD, assessed using revised International Working Group response criteria

Time: Up to 30 days

Description: The proportion of subjects with significant inhibition will be estimated for each dose level. Summary statistics and results of the statistical tests for contingency tables will be reported.

Measure: Changes in levels of poly(ADP-ribose) (PAR)

Time: From baseline to 6 hours after drug administration on day 1 of course 1

Description: Average expression of MGMT will be measured and classified as positive versus negative (less than 20% of mean value) for all patients regardless of the administered drug dose. We will use the Fisher's exact test for 2 x 2 tables to assess whether the lack of MGMT expression correlates with the response.

Measure: Average expression of MGMT

Time: Up to 30 days

Description: The average change from baseline level in γ-H2AX and RAD51 foci will be estimated for all patients to assess whether increase in foci and response to treatment are associated. Assessed using a single group repeated measures analysis of variance (ANOVA) with 0.05 significance level.

Measure: Average change from baseline level in y-H2AX foci

Time: From baseline to 30 days

Description: The average change from baseline level in γ-H2AX and RAD51 foci will be estimated for all patients to assess whether increase in foci and response to treatment are associated. Assessed using a single group repeated measures ANOVA with 0.05 significance level.

Measure: Average change from baseline level in RAD51 foci

Time: From baseline to 30 days

Description: Repeated measures data structure will provide adequate power to estimate intra- and inter-patient variability.

Measure: Non-homologous end joining repair

Time: Up to 30 days

Description: The plausible relationship between change in DSB repair and clinical response will be examined using the Fisher's exact test.

Measure: Double strand break (DSB) repair

Time: Up to 30 days

23 A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients With Refractory Chronic Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia

The purpose of this study is to determine the efficacy of ponatinib in patients with chronic myeloid leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast phase (BP) or with philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who either are resistant or intolerant to either dasatinib or nilotinib, or have the (T)hreonine-315-(I)soleucine (T315I) mutation.

NCT01207440 Chronic Myeloid Leukemia Ph+ Acute Lymphoblastic Leukemia Drug: Ponatinib
MeSH:Leukemia Leukemia, Myeloid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Lymphoid leukemia Myeloid leukemia

Ponatinib for Chronic Myeloid Leukemia (CML) Evaluation and Ph+ Acute Lymphoblastic Leukemia (ALL) The purpose of this study is to determine the efficacy of ponatinib in patients with chronic myeloid leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast phase (BP) or with philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who either are resistant or intolerant to either dasatinib or nilotinib, or have the (T)hreonine-315-(I)soleucine (T315I) mutation. --- T315I ---

- Have active Central Nervous System (CNS) disease - Have significant or active cardiovascular disease - Have a significant bleeding disorder unrelated to CML or Ph+ALL - Have a history of pancreatitis or alcohol abuse - Have uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL) - Have malabsorption syndrome or other gastrointestinal illness that could affect absorption of ponatinib - Diagnosed with another primary malignancy in the past 3 years - Pregnant or lactating - Underwent major surgery within 14 days prior to first dose of ponatinib - Have ongoing or active infection - Suffer from any other condition or illness that would compromise safety or interfere with evaluation of the drug Chronic Myeloid Leukemia Ph+ Acute Lymphoblastic Leukemia Leukemia Leukemia, Myeloid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Leukemia, Myelogenous, Chronic, BCR-ABL Positive The preliminary analysis of the phase 1 clinical trial revealed evidence of clinical antitumor activity in patients with resistance to approved second-generation tyrosine kinase inhibitors (TKI), dasatinib and nilotinib, including patients with the T315I mutation of the BCR-ABL gene (BCR-ABL). --- T315I ---

This Phase 1 study, taken together with the strong preclinical data that characterize ponatinib, provides the rationale for moving to a pivotal phase 2 trial of this agent in a population of patients with chronic myeloid leukemia (CML) and Ph+ Acute Lymphoblastic Leukemia (ALL) who are resistant or intolerant to prior TKI therapy and in those patients with the T315I mutation. --- T315I ---

Primary Outcomes

Description: MCyR is defined as percentage of participants with complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). Cytogenetic response is the percentage of Philadelphia chromosome positive (Ph+) metaphases in bone marrow (BM). Response is further defined as MCyR: CCyR or PCyR, where CCyR: no Ph+ cells; PCyR: 1 to 35% Ph+ cells.

Measure: Percentage of CP-CML Participants With Major Cytogenetic Response (MCyR)

Time: Up to 12 months after initiation of study treatment

Description: MaHR is defined as percentage of participants with complete hematologic response (CHR) or no evidence of leukemia (NEL). Response criteria for CHR is reported as white blood cells (WBC)≤institutional upper limit of normal, absolute neutrophil count (ANC)≥1000/mm^3, platelets≥100,000/mm^3, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement; Response criteria for NEL is reported as WBC≤institutional upper limit of normal, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement, at least 1 of the following: (i) 20,000/mm^3≤platelets<100,000/mm^3; (ii) 500/mm^3≤ANC<1000/mm^3.

Measure: Percentage of AP-CML Participants With Major Hematologic Response (MaHR)

Time: Up to 6 months after initiation of study treatment

Description: MaHR is defined as percentage of participants with CHR or NEL. Response criteria for CHR is reported as WBC≤institutional upper limit of normal, ANC≥1000/mm^3, platelets ≥100,000/mm^3, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement; Response criteria for NEL is reported as WBC≤ institutional upper limit of normal, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement, at least 1 of the following: (i) 20,000/mm^3 ≤platelets<100,000/mm^3; (ii) 500/mm^3≤ANC<1000/mm^3.

Measure: Percentage of BP-CML/Ph+ ALL Participants With MaHR

Time: Up to 6 months after initiation of study treatment

Secondary Outcomes

Description: Response criteria for CHR is reported as WBC≤institutional upper limit of normal, platelets<450,000/mm^3, no blasts or promyelocytes in peripheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement (including no hepatomegaly or splenomegaly).

Measure: Percentage of CP-CML Participants With CHR

Time: Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose)

Description: Confirmed MCyR is defined as 2 assessments of CCyR or PCyR at least 28 days apart. For CP participants entering the trial in PCyR, confirmed MCyR is defined as 2 assessments of CCyR at least 28 days apart.

Measure: Percentage of CP-CML Participants With Confirmed MCyR

Time: Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose)

Description: MMR is defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL ≤0.1% on the international scale (equivalent to a 3-log reduction in transcript).

Measure: Percentage of CP-CML Participants With Major Molecular Response (MMR)

Time: Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose)

Description: MCyR is defined as percentage of participants with CCyR or PCyR. Cytogenetic response is the percentage of Ph+ metaphases in BM. Response is further defined as MCyR: CCyR or PCyR, where CCyR: no Ph+ cells; PCyR: 1 to 35% Ph+ cells.

Measure: Percentage of AP-CML or BP-CML/Ph+ ALL Participants With MCyR

Time: Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose)

Description: Confirmed MCyR is defined as 2 assessments of CCyR or PCyR at least 28 days apart.

Measure: Percentage of AP-CML or BP-CML/Ph+ ALL Participants With Confirmed MCyR

Time: Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose)

Description: MMR is defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL ≤0.1% on the international scale (equivalent to a 3-log reduction in transcript).

Measure: Percentage of AP-CML or BP-CML/Ph+ ALL Participants With MMR

Time: Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose)

Description: Time to response is defined as the interval from the first dose of study treatment until the criteria for response are first met, censored at the last assessment of response. Median time to response was estimated using the Kaplan-Meier method.

Measure: Time to Response

Time: Up to approximately 48 months after first dose

Description: Duration of Response is defined as the interval between the first assessment at which the criteria for response are met until the criteria for progression are met, censored at the last date at which the criteria for response are met. Duration of response was estimated by the Kaplan-Meier method as the probability of remaining in response.

Measure: Duration of Response

Time: Up to approximately 48 months after first dose

Description: PFS is defined as the interval from the first dose of study treatment until the criteria for progression or death are met, censored at the last response assessment. Progression from CP is reported as death, development of AP or BP, loss of CHR (in the absence of cytogenetic response), confirmed by development in complete blood counts (CBCs) at least 4 weeks apart, loss of MCyR, increasing WBC in participant without CHR defined by doubling of WBC to >20K on 2 occasions at least 4 weeks apart; Progression from AP is reported as death, development of confirmed BP, loss of previous major or minor hematologic response over a 2-week period, no decrease from baseline levels in percentage blasts in peripheral blood or BM on all assessments over a 4-week period; Progression from BP or Ph+ ALL is reported as death, increasing blasts in peripheral blood or BM over a 4 week period.

Measure: Progression-free Survival (PFS)

Time: Every 12 weeks ± 2 weeks from last dose of study drug or the investigator/participant decision to discontinue treatment, whichever occurred later (Up to approximately 96 months after last dose)

Description: OS is defined as the interval from the first dose of study treatment until death, censored at the last date at which participant was known to be alive.

Measure: Overall Survival (OS)

Time: From the first dose of study treatment until death (Up to 96 months post last dose)

Description: An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy.

Measure: Number of Participants With Treatment-Emergent Adverse Event (TEAE) and Serious AE (SAE)

Time: From first dose up to 30 days after last dose of the study drug (Up to approximately 49 months)

24 Dasatinib (BMS-354825) Combined With SMO Inhibitor (BMS-833923; XL139) in CML With Resistance or Suboptimal Response to a Prior TKI

The purpose of the study is to determine the safety and tolerability of the combination of BMS-833923 plus dasatinib in patients with chronic myeloid leukemia.

NCT01218477 Leukemia Drug: Dasatinib Drug: BMS-833923
MeSH:Leukemia
HPO:Leukemia

Grade 4, >5.0.. Key Inclusion Criteria - Age ≥18 years - Diagnosis of chronic myeloid leukemia (CML) and cytogenetic positive for the Philadelphia chromosome (Ph+), documented Ph+ cells on bone marrow assessment (BMA) ≤6 weeks prior to treatment - Either chronic-phase CML, with <15% blasts in peripheral blood and bone marrow, or advanced-phase CML, including Ph+ acute lymphoblastic leukemia (ALL) (> 5% blasts) or hematologic progression with ≥15% blasts not in complete cytogenetic remission - Resistance or suboptimal response to imatinib, dasatinib, or nilotinib and no known T315I/A Abl-kinase mutation. --- T315I ---

Key Exclusion Criteria - Known Abl-kinase T315I or T315A mutation - CCyR at baseline - Any serious or uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy - Uncontrolled or significant cardiovascular disease - Grade 3 or higher peripheral blood counts - Serum calcium or phosphate below the lower limit of normal - Baseline hypomagnesemia and amylase or lipase at least Grade 1 or higher - Reduced renal function, defined as serum creatinine level >3*upper limit of normal - Prior therapies for CML or Ph+ ALL permitted, with the following restriction: - Therapy permitted with corticosteroids, hydroxyurea, or anagrelide prior to starting treatment and during the first 4 weeks on study - 6 months or longer after stem cell transplantation - 28 days or longer after any investigational agent - 7 days or longer after any standard chemotherapy agent - Concomitant use of medications with a known risk of causing Torsades de Pointes - Concomitant use of strong inhibitors of the CYP3A4 isoenzyme Key Inclusion Criteria - Age ≥18 years - Diagnosis of chronic myeloid leukemia (CML) and cytogenetic positive for the Philadelphia chromosome (Ph+), documented Ph+ cells on bone marrow assessment (BMA) ≤6 weeks prior to treatment - Either chronic-phase CML, with <15% blasts in peripheral blood and bone marrow, or advanced-phase CML, including Ph+ acute lymphoblastic leukemia (ALL) (> 5% blasts) or hematologic progression with ≥15% blasts not in complete cytogenetic remission - Resistance or suboptimal response to imatinib, dasatinib, or nilotinib and no known T315I/A Abl-kinase mutation. --- T315I ---

Key Exclusion Criteria - Known Abl-kinase T315I or T315A mutation - CCyR at baseline - Any serious or uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy - Uncontrolled or significant cardiovascular disease - Grade 3 or higher peripheral blood counts - Serum calcium or phosphate below the lower limit of normal - Baseline hypomagnesemia and amylase or lipase at least Grade 1 or higher - Reduced renal function, defined as serum creatinine level >3*upper limit of normal - Prior therapies for CML or Ph+ ALL permitted, with the following restriction: - Therapy permitted with corticosteroids, hydroxyurea, or anagrelide prior to starting treatment and during the first 4 weeks on study - 6 months or longer after stem cell transplantation - 28 days or longer after any investigational agent - 7 days or longer after any standard chemotherapy agent - Concomitant use of medications with a known risk of causing Torsades de Pointes - Concomitant use of strong inhibitors of the CYP3A4 isoenzyme Key Inclusion Criteria - Age ≥18 years - Diagnosis of chronic myeloid leukemia (CML) and cytogenetic positive for the Philadelphia chromosome (Ph+), documented Ph+ cells on bone marrow assessment (BMA) ≤6 weeks prior to treatment - Either chronic-phase CML, with <15% blasts in peripheral blood and bone marrow, or advanced-phase CML, including Ph+ acute lymphoblastic leukemia (ALL) (> 5% blasts) or hematologic progression with ≥15% blasts not in complete cytogenetic remission - Resistance or suboptimal response to imatinib, dasatinib, or nilotinib and no known T315I/A Abl-kinase mutation. --- T315I --- --- T315A --- --- T315I ---

Key Exclusion Criteria - Known Abl-kinase T315I or T315A mutation - CCyR at baseline - Any serious or uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy - Uncontrolled or significant cardiovascular disease - Grade 3 or higher peripheral blood counts - Serum calcium or phosphate below the lower limit of normal - Baseline hypomagnesemia and amylase or lipase at least Grade 1 or higher - Reduced renal function, defined as serum creatinine level >3*upper limit of normal - Prior therapies for CML or Ph+ ALL permitted, with the following restriction: - Therapy permitted with corticosteroids, hydroxyurea, or anagrelide prior to starting treatment and during the first 4 weeks on study - 6 months or longer after stem cell transplantation - 28 days or longer after any investigational agent - 7 days or longer after any standard chemotherapy agent - Concomitant use of medications with a known risk of causing Torsades de Pointes - Concomitant use of strong inhibitors of the CYP3A4 isoenzyme Leukemia Leukemia null --- T315I ---

Primary Outcomes

Description: The following drug-related adverse events (AEs) occurring in the first 28 days of treatment were considered dose-limiting toxicities (DLT): Grade 4 hematologic AE lasting >7 days; ≥Grade 3 nonhematologic AE, despite medical intervention; ≥Grade 2 AE uncontrolled by medical intervention and requiring treatment interruption for >7 days. RP2D was that dose at which ≤1 of 6 patients had a DLT in the first 4 weeks of treatment. If <3 patients were DLT-evaluable, up to 6 additional patients entered the same dose level. Accrual to a dose level closed if 6 patients were enrolled and <3 were DLT-evaluable. If ≥3 patients at a dose level had no DLTs when a new patient enrolled, the dose was escalated to next level. If 1 DLT was observed in <6 patients, ≥6 patients were required; if no additional DLT was observed, the dose was escalated to the next highest level. If ≥2 DLTs were observed in <6 patients, that level exceeded the RP2D, and the dose was deescalated to the next lowest level.

Measure: Recommended Phase 2 Dose (RP2D) of BMS-833923 Plus Dasatinib in Chronic Myeloid Leukemia-Chronic Phase

Time: Day 1 to Week 80, with observation for DLT in Weeks 5-8

Secondary Outcomes

Description: Cytogenetic response (CyR) was based on the proportion of Philadelphia chromosome-positive (Ph+) cells in metaphase analysis of bone marrow. Complete cytogenetic response (CCyR)=0 Ph+ cells; Partial CyR (PCyR)=1 to 35 Ph+ cells; Minor CyCR= 36-65 Ph+ cells; Minimal CyCR= 66-95 Ph+ cells; No response= >96 Ph+ cells. MCyR=CCyR + PCyR. Nilo=nilotinib; SOR=suboptimal response.

Measure: Percentage of Participants With a Major Cytogenetic Response (MCyR) in Chronic Myeloid Leukemia-Advanced Phase (CML-Adv) and Chronic Myeloid Leukemia-Chronic Phase (CML-CP)

Time: Day 1 to Week 80

Description: MHR was defined as complete hematologic response (CHR) or no evidence of leukemia (NEL). CHR for CML-Adv criteria: white blood cell count (WBC) ≤upper limit normal; absolute neutrophil count (ANC) ≥1,000/mm^3; platelets ≥100,000/mm^3; no blasts or promyelocytes in peripheral blood (PB); basophils <5% in PB; myelocytes + metamyelocytes < 5% in PB; no extramedullary involvement; blasts must be <5%, if bone marrow assessment (BMA) performed. NEL had same criteria, but with lower thresholds for reconstitution of PB counts, as follows: Platelets ≥ 20,000/mm^3 or ANC >500/mm^3. Confirmed MHR obtained if these criteria met and maintained for ≥28 days. CHR for CML-CP criteria WBC ≤10,000/mm^3; platelets <450,000/mm^3; basophils <5% in PB; no blasts or promyelocytes in PB; myelocytes + metamyelocytes <5% in PB; no extramedullary involvement; blasts must be <5% if BMA performed. Confirmed CHR obtained if these criteria met and maintained for ≥28 days. Nilo=nilotinib; SOR=suboptimal response.

Measure: Percentage of Participants With a Major Hematologic Response (MHR) in Chronic Myeloid Leukemia-Advanced Phase (CML-Adv) and Chronic Myeloid Leukemia-Chronic Phase (CML-CP)

Time: Day 1 to Week 80

Description: AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment and may or may not be related to treatment. SAE=an untoward medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Drug-related=having certain, probable, possible, or missing relationship to study drug. The following drug-related AEs occurring during the first 28 days of treatment with both agents were considered to be dose-limiting toxicities (DLTs): Grade 4 hematologic AE lasting >7 days; ≥Grade 3 nonhematologic AE, despite adequate medical intervention; ≥Grade 2 AE not controlled by medical intervention and requiring treatment interruption for >7 days.

Measure: Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Adverse Events (AEs) Leading to Discontinuation, Drug-related AEs Leading to Discontinuation, at Least 1 Drug-related AE, and Dose-limiting Toxicities

Time: Day 1 to Week 80, continuously, with observation for dose-limiting toxicities (DLTs) in Weeks 5-8

Description: ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal. Abnormalities were graded according to the Common Toxicity Criteria of the National Cancer Institute from 1 (least severe) to 4 (life threatening). ANC (*10^9): Grade 3, <1.0- 0.5; Grade 4, <0.5. Hemoglobin (mmol/L): Grade 3, <4.9-4.0; Grade 4, <4.0. Platelet count (*10^9/L): Grade 3, <50.0-25.0; Grade 4, <25. WBCs (*10^9): Grade 3, <2.0-1.0; Grade 4, <1.0. Hypocalcemia (mmol/L): Grade 3, <1.75-1.5; Grade 4, <1.5. Hyperkalemia (mmol/L): Grade 3, >6.0-7.0; Grade 4, >7.0. Hypokalemia (mmol/L): Grade 3, <3.0-2.5; Grade 4, <2.5. Hyponatremia (mmol/L), Grade 3, <130-120; Grade 4, <120. Hypermagnesemia (mg/dL): Grade 3, >1.23-3.30; Grade 4, >3.30. Phosphorus (mmol/L): Grade 3, <0.6-0.3; Grade 4, <0.3. Lipase (*ULN): Grade 3, >2.0-5.0; Grade 4, >5.0.

Measure: Number of Participants With Grade 3-4 Abnormalities on Laboratory Test Results

Time: Day 1 to Week 80

25 An Open Label, Nonrandomized, Single-center, Phase I Trial of Pretreated Philadelphia Chromosome Positive (Ph+) Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) With Nilotinib in Combination With Low Dose Interferon-alpha (IFN) - NICOLI Study -

This study will assess the maximum tolerated dose of low dose interferon in conjunction with nilotinib in pretreated Philadelphia chromosome positive (Ph+) chronic myeloid leukemia patients in chronic phase (CML-CP).

NCT01220648 Chronic Myeloid Leukemia Drug: Nilotinib, interferon-alfa
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Philadelphia Chromosome
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Inclusion Criteria: - Patients with chronic myeloid leukemia in chronic phase (CML-CP) at screening - Initial diagnosis of CML cytogenetically confirmed by the presence of the Ph+ metaphases from the bone marrow - Patients who have been treated with nilotinib for a minimum of 6 months (1 month represents 28 days) after switch from previous CML treatments - Patients who have been treated with stable dosing of 2x400mg nilotinib within the last month before start of study treatment - No grade 3-4 CTC toxicities on nilotinib alone in the last month preceding the start of the study regimen Exclusion Criteria: - Patients who are considered Ph- because they do not have a confirmed cytogenetic diagnosis of the t(9;22) translocation in their bone marrow metaphases - Evidence of a point mutation within the BCR-ABL gene leading to a clinically relevant amino acid exchange in the kinase domain at position T315 (gatekeeper mutation T315I) - Impaired cardiac function - Severe or uncontrolled medical conditions (i.e. --- T315I ---

Other protocol-defined inclusion/exclusion criteria may apply Inclusion Criteria: - Patients with chronic myeloid leukemia in chronic phase (CML-CP) at screening - Initial diagnosis of CML cytogenetically confirmed by the presence of the Ph+ metaphases from the bone marrow - Patients who have been treated with nilotinib for a minimum of 6 months (1 month represents 28 days) after switch from previous CML treatments - Patients who have been treated with stable dosing of 2x400mg nilotinib within the last month before start of study treatment - No grade 3-4 CTC toxicities on nilotinib alone in the last month preceding the start of the study regimen Exclusion Criteria: - Patients who are considered Ph- because they do not have a confirmed cytogenetic diagnosis of the t(9;22) translocation in their bone marrow metaphases - Evidence of a point mutation within the BCR-ABL gene leading to a clinically relevant amino acid exchange in the kinase domain at position T315 (gatekeeper mutation T315I) - Impaired cardiac function - Severe or uncontrolled medical conditions (i.e. --- T315I ---

Primary Outcomes

Measure: Number of Clinically significant adverse events or abnormal laboratory values (dose-limiting toxicities) unrelated to disease progression, intercurrent illness, or concomitant medications on the combination treatment

Time: 12 months

Secondary Outcomes

Measure: Rate of major cytogenetic response (MCyR) at 6 and 12 months

Time: 12 months

Measure: Rate of complete cytogenetic response (CCyR) at 6 and 12 months

Time: 12 months

Measure: Rate of major molecular response (MMR) at 12 months

Time: 12 months

Measure: Safety profile of nilotinib in combination with interferon alfa, i.e. the number of dose limiting toxicities (DLT) for each interferon alfa dose level

Time: 12 months

Measure: Progression-free survival (PFS)

Time: 12 months

Measure: Event-free survival

Time: 12 months

Measure: Overall survival (OS)

Time: 12 months

26 A Single-arm, Open-label, Multi-center Study of Complete Molecular Response (CMR) in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

"This is a single-arm, open-label, multi-center study of complete molecular response (CMR) in adult patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia in chronic phase (CML-CP). The study is designed to evaluate early and deep molecular responses up to 4 years on nilotinib treatment. The primary end point is Rate of confirmed CMR in newly diagnosed Philadelphia chromosome positive CML-CP patients."

NCT01227577 Chronic Myelogenous Leukemia in Chronic Phase Drug: Nilotinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Exclusion Criteria: Previously documented T315I mutation. --- T315I ---

Primary Outcomes

Description: CMR was defined as at least 4.5 log reduction of breakpoint cluster region gene/Abelson proto-oncogene (Bcr-Abl) transcipts from the standardized baseline on the international scale (equivalent to Bcr-Abl <=0.0032% IS) with a minimum of 25,614 ABL control copies. CMR was to be confirmed by a second polymerase chain reaction (PCR) sample drawn 3 months later where the results should be less than or equal to 0.0032% with a minimum of 25,614 Abelson proto-oncogene (ABL) control copies.

Measure: Number of Participants With Confirmed Complete Molecular Response (CMR)

Time: 4 years

Secondary Outcomes

Description: CCyR was defined as 0% Philadelphia chromosome-positive (Ph+) metaphases in the bone marrow. MMR was defined as a 3 log reduction of Bcr-Abl transcripts from the standardized baseline on the international scale (equivalent to Bcr-Abl ≤ 0.1% IS). Bcr-Abl transcripts assessed by peripheral blood quatitative real time polymerase chain reaction (RQ-PCR) were used for the determination of all molecular responses.

Measure: Number of Participants With Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMR)

Time: 4 years

Description: Time to CMR, CCyR, and MMR was defined as the time from the date of enrollment to the date of first documented CMR, CCyR and MMR, respectively.

Measure: Time to CMR, CCyR and MMR

Time: 4 years

Description: Duration of CMR, CCyR and MMR were defined as the time from the first date of achievement of the response to the date of first documented loss of the response.

Measure: Duration of CMR, CCyR and MMR

Time: 4 years

Description: Progression to AP/BC is defined as loss of CCyR, MMR, and CMR and was summarized by frequencies and percentages.

Measure: Number of Participants With Progression to Accelerated Phase/Blastic Crisis (AP/BC)

Time: 4 years

Description: Time to progression of AP/BC was defined as the time from the date of the first dose of study drug to the date of first documented progression of AP/BC.

Measure: Time to Progression of AP/BC

Time: 4 years

Description: Rate of loss of CMR was defined as an increase in the Bcr-Abl transcripts to greater than 0.0032% IS. Rate of loss of CCyR was defined as an increase in the Ph+ bone marrow cells to greater than 0%. Rate of loss of MMR was defined as an increase in the Bcr-Abl transcripts to greater than 0.1% IS.

Measure: Number of Participants With Loss of CCyR, MMR and CMR

Time: 4 years

Description: CMR was defined as at least 4.5 log reduction of breakpoint cluster region gene/Abelson proto-oncogene (Bcr-Abl) transcipts from the standardized baseline on the international scale (equivalent to Bcr-Abl <=0.0032% IS) with a minimum of 25,614 ABL control copies. CMR was to be confirmed by a second polymerase chain reaction (PCR) sample drawn 3 months later where the results should be less than or equal to 0.0032% with a minimum of 25,614 Abelson proto-oncogene (ABL) control copies.

Measure: Number of Participants With CMR Who Were Dosed to 400 mg b.i.d.

Time: 4 years

Description: Event-free survival was defined as the time from the date of enrollment to the date of first occurrence of any of the following: loss of Complete Hematological Response (CHR), loss of CCyR, loss of Partial Cytogenetic Response (PCyR), progression to the accelerated phase or blast crisis, and death from any cause. Progression-free survival was defined as the time from the date of enrollment to the date of first occurrence of any of the following: progression to the accelerated phase or blast crisis, death, and loss of CMR. Overall survival was defined as the time from the date of enrollment until death due to any cause.

Measure: Event-free Survival, Progression-free Survival and Overall Survival

Time: 4 years

27 Extending Molecular Responses With Nilotinib in Newly Diagnosed Chronic Myeloid Leukemia (CML) Patients in Chronic Phase

This study will further investigate the safety and efficacy of nilotinib in newly diagnosed chronic myeloid leukemia patients in the chronic phase

NCT01254188 Chronic Myeloid Leukemia Drug: Nilotinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Time is censored at the date of last assessment in the trial for patients without event.. Inclusion Criteria: -Patients with chronic myeloid leukemia in the chronic phase diagnosed within 6 months of study entry Exclusion Criteria: - Treatment with tyrosine kinase inhibitor or other antileukemic agents or treatments (including HSCT) for longer than 2 weeks, with exception of hydroxyurea and/or anagrelide - Uncontrolled congestive heart failure or hypertension - Myocardial infarction or unstable angina pectoris within past 12 months - Known T315I mutations - QTcF >450 msec - Significant arrhythmias Other protocol-defined inclusion/exclusion criteria may apply Inclusion Criteria: -Patients with chronic myeloid leukemia in the chronic phase diagnosed within 6 months of study entry Exclusion Criteria: - Treatment with tyrosine kinase inhibitor or other antileukemic agents or treatments (including HSCT) for longer than 2 weeks, with exception of hydroxyurea and/or anagrelide - Uncontrolled congestive heart failure or hypertension - Myocardial infarction or unstable angina pectoris within past 12 months - Known T315I mutations - QTcF >450 msec - Significant arrhythmias Other protocol-defined inclusion/exclusion criteria may apply Chronic Myeloid Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive null --- T315I ---

Time is censored at the date of last assessment in the trial for patients without event.. Inclusion Criteria: -Patients with chronic myeloid leukemia in the chronic phase diagnosed within 6 months of study entry Exclusion Criteria: - Treatment with tyrosine kinase inhibitor or other antileukemic agents or treatments (including HSCT) for longer than 2 weeks, with exception of hydroxyurea and/or anagrelide - Uncontrolled congestive heart failure or hypertension - Myocardial infarction or unstable angina pectoris within past 12 months - Known T315I mutations - QTcF >450 msec - Significant arrhythmias Other protocol-defined inclusion/exclusion criteria may apply Inclusion Criteria: -Patients with chronic myeloid leukemia in the chronic phase diagnosed within 6 months of study entry Exclusion Criteria: - Treatment with tyrosine kinase inhibitor or other antileukemic agents or treatments (including HSCT) for longer than 2 weeks, with exception of hydroxyurea and/or anagrelide - Uncontrolled congestive heart failure or hypertension - Myocardial infarction or unstable angina pectoris within past 12 months - Known T315I mutations - QTcF >450 msec - Significant arrhythmias Other protocol-defined inclusion/exclusion criteria may apply Chronic Myeloid Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive null --- T315I --- --- T315I ---

Primary Outcomes

Description: MMR is defined as BCR-ABL ratio (%) on IS <= 0.1% (corresponds to >=3 log reduction of BCR-ABL transcripts from standardized baseline value). Clopper-Pearson method

Measure: The Percentage of Patients Achieving MMR by 12 Months

Time: 12 months

Secondary Outcomes

Description: Estimated median time to first MMR by Kaplan-Meier method

Measure: Time to Molecular Response at 24 Months

Time: 24 months

Description: Kaplan-Meier estimates of duration of first MMR among patients who achieved MMR (FAS) Duration of first MMR (months) = (Minimum date of (loss of first MMR , CML-related death, progression to AP/BC during study treatment, censoring) - date of first MMR + 1) / 30.4375

Measure: Duration of Major Molecular Response

Time: 3, 6, 9, 12, 15, 18, 21, 24 Months after MMR was detected

Description: Complete cytogenetic response (CCyR) is defined as a value of 0% Ph+ metaphases in bone marrow.

Measure: Complete Cytogenetic Response

Time: 6 months

Description: * CCyR = 0% Ph+ metaphases based on at least 20 metaphases from bone marrow cytogenetics. Duration of first CCyR (months) = (date of CCyR loss or censoring - date of first CCyR +1) / 30.4375

Measure: Percentage of Participants Estimated to Maintain Their First CCyR for 6, 12, 18, and 24 Months After the First CCyR Was Achieved as Determined by Kaplan Meier Estimatation.

Time: 6,12,18 and 24 months

Description: OS was defined as the time between date of study entry and date of death due to any cause at any time during the study, including the follow-up period after discontinuation of treatment.

Measure: Overall Survival

Time: 3, 6, 9, 12, 15, 18, 21, 24 Months

Description: PFS was defined as the time from the date of study entry to the date of event defined as the first documented disease progression to AP/BC or the date of death from any cause occurring on treatment.

Measure: Kaplan-Meier Estimates of Progression-free Survival

Time: 3,6,9,12,15,18,21,and 24 months

Description: Time to event (months) = (date of event or censoring - date of study entry + 1) / 30.4375. Date of event is the earliest date of the following events during treatment : discontinuation of nilotinib for nilotinib-related adverse events, death due to any cause, progression to AP or BC, loss of PCyR, loss of CCyR, loss of CHR. Time is censored at the date of last assessment in the trial for patients without event.

Measure: Kaplan-Meier Estimates of Failure-free Survival

Time: 3,6,9,12,15,18,21,and 24 months

28 ENESTChina: A Phase III Multi-center, Open-label, Randomized Study of Nilotinib Versus Imatinib in Chinese Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

The study will compare the efficacy and safety of Nilotinib versus Imatinib in newly diagnosed Chinese patients with CML-CP.

NCT01275196 Chronic Myeloid Leukemia Drug: Nilotinib Drug: Imatinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, M Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Exclusion Criteria: - Patients with previously documented T315I mutations; - Treatment with tyrosine kinase inhibitor(s) prior to study entry is not allowed, except in the following situation: in emergent cases where the patient requires disease management while awaiting study start, commercial supplies of Gleevec/Glivec at any dose may be prescribed to the patient but for no longer than 2 weeks in duration. --- T315I ---

Primary Outcomes

Description: Major molecular response (MMR) was defined as a value of ≤ 0.1% of BCR-ABL ratio on the IS. The minimum number of control genes for a sample to be valid was 3000. For statistical comparison purpose, MMR was considered as a binary variable with patients achieving MMR grouped as 'responders' and patients not achieving MMR, patients with missing PCR evaluations or patients with atypical transcripts at baseline grouped as 'non-responders'. This endpoint was calculated based on the 12 month analysis.

Measure: Major Molecular Response (MMR) at 12 Months - With Imputation.

Time: 12 months

Secondary Outcomes

Description: Major molecular response (MMR) was defined as a value of ≤ 0.1% of BCR-ABL ratio on the IS. The minimum number of control genes for a sample to be valid was 3000. For statistical comparison purpose, MMR was considered as a binary variable with patients achieving MMR grouped as 'responders' and patients not achieving MMR, patients with missing PCR evaluations or patients with atypical transcripts at baseline grouped as 'non-responders'. These time points including the 12 month data were calculated based on the final analysis after the end of the study.

Measure: MMR Rate at Each Time Point

Time: Months 3,6,9,12,15, 18, 21, 24, 36

Description: Best MMR rates by scheduled time point are cumulative response rates up to that time point. In this analysis, patients who had achieved MMR at or before the time point were counted as responders, no matter if they lost the response/discontinued or not. Therefore, this response rate represented the best observed response rate up to that specific time point.

Measure: Best MMR by Each Timepoint

Time: Months 3,6,9,12,15, 18, 21, 24, 36

Description: Time to first MMR (months) = (date of first MMR or censoring - date of randomization + 1) / 30.4375.

Measure: Kaplan-Meier Estimates of Time to First MMR

Time: End of study (up to 40 months)

Description: The rate of durable MMR at 24 months, defined as the proportion of patients who have achieved MMR at 12 months, and also maintain continuous MMR until the 24 month time point (1 month = 28 days) without intervening loss of MMR in between 12 and 24 months

Measure: Durable MMR Rate at 24 Months

Time: 24 months

Description: Duration of first MMR (months) = (date of loss of MMR or censoring-date of first MMR + 1)/30.4375.

Measure: Kaplan-Meier Estimates of Duration of First MMR Among Patients Who Achieved MMR

Time: End of Study (Up to 40 months)

Description: CCyR is defined as 0% Ph+ metaphases based on at least 20 metaphases from bone marrow cytogenetics.

Measure: Best Complete Cytogenic Response (CCyR) Rate by Each Time Point

Time: Months 6, 12, 18, 30, 24, 36

Description: Time to first CCyR (months) = (date of first CCyR - date of randomization + 1) / 30.4375.

Measure: Kaplan-Meier Estimates of Time to First CCYR

Time: End of study (up to 40 months)

Description: Duration of CCyR (months) = (date of CCyR loss or censoring-date of first CCyR + 1)/30.4375

Measure: Kaplan-Meier Estimates of Duration of First CCyR Among Patients Who Achieved CCyR

Time: End of Study (up to 40 months)

Description: Time to progression to AP/BC was defined as the time from the date of randomization to the date of event defined as the first disease progression to AP/BC or the date of CML-related death, whichever is earlier. This variable was analyzed in 2 ways: On-treatment: included progressions to AP/BC or CML-related deaths occurring on treatment in the study as events. The time was censored at the date of last on-treatment assessment (hematology, extramedullary disease, or cytogenetic evaluation) in the study for patients without event. On-study: included progressions to AP/BC or CML-related deaths occurring in the study or during the follow-up period after discontinuation of treatment as events. The time was censored at the last assessment date in the study for patients who were still being treated and at the date of last contact for patients who discontinued treatment

Measure: Kaplan-Meier Estimates of Time to Progression to Accelerated Phase/Blast Crisis (AP/BC) on Treatment

Time: End of study (up to 40 months)

Description: Event-free survival was defined as the time from the date of randomization to the date of first occurrence of any of the following:-Death due to any cause, - Progression to AP or BC, Loss of partial cytogenetic response (PCyR), - Loss of CCyR, - Loss of CHR

Measure: Kaplan-Meier Estimates of Event-free Survival (EFS) on Treatment

Time: End of Study (up to 40 months)

Description: Progression-free survival was defined as the time from the date of randomization to the date of event defined as the first disease progression to AP/BC or the date of death from any cause, whichever is earlier. This variable was analyzed in 2 ways: On-treatment: included progressions to AP/BC or deaths occurring only on-treatment in the study as events. The time was censored at the date of last on-treatment assessment (hematology, extramedullary disease or cytogenetic evaluation) in the study before the cut-off date of the analysis for patients without event. On-study: included progressions to AP/BC or deaths occurring in the study or during the follow-up period after discontinuation of study treatment as events. The time was censored at the last assessment date in the study for patients who were still being treated and at the date of last contact for patients who discontinued treatment.

Measure: Kaplan-Meier Estimates of Progression-free Survival (PFS) on Treatment

Time: End of study (up to 40 months)

Description: Patients who discontinued study treatment early or completed the study protocol and did not enter into the extension protocol were to be followed for survival every 3 months for up to 2 calendar years from the date the last patient randomized received the first dose of study drug and every 6 months until Last Patient Last Visit. Overall survival (all deaths) was defined as the time between date of randomization and date of death due to any cause at any time during the study, including the follow-up period after discontinuation of treatment, i.e. overall survival on-study. The time was censored at the date of last assessment in the study for patients who are still being treated and at the date of last contact for patients who discontinued treatment.

Measure: Kaplan-Meier Estimates of Overall Survival (OS) on Treatment

Time: End of Study (up to 40 months)

Description: CHR was defined as having all of the following criteria present at any assessment, which was confirmed by another assessment at least after 4 weeks: • WBC count < 10 x 10E9 /L • Platelet count < 450 x 10E9 /L • Basophils < 5% • No blasts and promyelocytes in peripheral blood • Myelocytes + metamyelocytes < 5 % in peripheral blood • No evidence of extramedullary involvement. The assessment was not considered CHR, if there were any values indicative of CML in AP or BC (i.e. by blasts in bone marrow). For confirmation of CHR, both the initial CHR as well as the confirming assessment (at least 4 weeks after the initial assessment) had to satisfy all criteria mentioned above, without any assessment in between which indicated 'No response'.

Measure: Best Complete Hematologic Response (CHR)

Time: Months 1, 3, 4, 5, 6, 9,12, 15,18, 21, 24, 30, 36

Description: Patients satisfying criteria for several "modified ELN 2009" categories are presented once under the worst category (Optimal> Suboptimal > Treatment failure). Patients in the "Discontinued" category are those who discontinued before the time point considered without satisfying any of the ELN 2009 criteria. Patients in the "Missing" category are those ongoing in the trial at the time point considered but with only missing or non evaluable data for ELN 2009 criteria.

Measure: Modified ELN2009 Criteria

Time: End of Study (up to 40 months)

Description: Total dose/time on treatment (periods of zero dose were included).

Measure: Actual Dose Intensity

Time: End of Study (up to 40 months)

Description: Pharmacokinetic Analysis Set

Measure: Summary Statistics of Trough Imatinib and Major Metabolite CGP74588 of Imatinib and Nilotinib PK Concentration by Time Point

Time: 12 Months

29 A Study of Complete Molecular Response for Chronic Myeloid Leukemia in Chronic Phase Patients, Treated With Dasatinib

The purpose of this study is to evaluate complete molecular response of Dasatinib in patients for Philadelphia chromosome-positive chronic myeloid leukemia

NCT01342679 Chronic Myeloid Leukemia Drug: dasatinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Inclusion Criteria: - Chronic Myeloid Leukemia in the Chronic Phase - 20 years old over - ECOG performance status (PS) score 0-2 - Patients for major molecular response (MMR) with no CMR - Adequate organ function (hepatic, renal and lung) - Signed written informed consent Exclusion Criteria: - A case with the double cancer of the activity - Women who are pregnant or breastfeeding - The case of Pleural effusion clearly - Patients with complications or a history of severe or uncontrolled cardiovascular failure following - have a Myocardial infarction within 6 months - have an Angina within 3 months - have a Congestive heart failure within 3 months - have a suspected congenital QT syndrome - have a QTc interval of more than 450msec at baseline - A serious uncontrolled medical disorder that would impair the ability of the subjects to receive protocol therapy - Prior treatment with dasatinib - Subjects with T315I, F317L and V299L BCR-ABL point mutations Inclusion Criteria: - Chronic Myeloid Leukemia in the Chronic Phase - 20 years old over - ECOG performance status (PS) score 0-2 - Patients for major molecular response (MMR) with no CMR - Adequate organ function (hepatic, renal and lung) - Signed written informed consent Exclusion Criteria: - A case with the double cancer of the activity - Women who are pregnant or breastfeeding - The case of Pleural effusion clearly - Patients with complications or a history of severe or uncontrolled cardiovascular failure following - have a Myocardial infarction within 6 months - have an Angina within 3 months - have a Congestive heart failure within 3 months - have a suspected congenital QT syndrome - have a QTc interval of more than 450msec at baseline - A serious uncontrolled medical disorder that would impair the ability of the subjects to receive protocol therapy - Prior treatment with dasatinib - Subjects with T315I, F317L and V299L BCR-ABL point mutations Chronic Myeloid Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive null --- T315I ---

Inclusion Criteria: - Chronic Myeloid Leukemia in the Chronic Phase - 20 years old over - ECOG performance status (PS) score 0-2 - Patients for major molecular response (MMR) with no CMR - Adequate organ function (hepatic, renal and lung) - Signed written informed consent Exclusion Criteria: - A case with the double cancer of the activity - Women who are pregnant or breastfeeding - The case of Pleural effusion clearly - Patients with complications or a history of severe or uncontrolled cardiovascular failure following - have a Myocardial infarction within 6 months - have an Angina within 3 months - have a Congestive heart failure within 3 months - have a suspected congenital QT syndrome - have a QTc interval of more than 450msec at baseline - A serious uncontrolled medical disorder that would impair the ability of the subjects to receive protocol therapy - Prior treatment with dasatinib - Subjects with T315I, F317L and V299L BCR-ABL point mutations Inclusion Criteria: - Chronic Myeloid Leukemia in the Chronic Phase - 20 years old over - ECOG performance status (PS) score 0-2 - Patients for major molecular response (MMR) with no CMR - Adequate organ function (hepatic, renal and lung) - Signed written informed consent Exclusion Criteria: - A case with the double cancer of the activity - Women who are pregnant or breastfeeding - The case of Pleural effusion clearly - Patients with complications or a history of severe or uncontrolled cardiovascular failure following - have a Myocardial infarction within 6 months - have an Angina within 3 months - have a Congestive heart failure within 3 months - have a suspected congenital QT syndrome - have a QTc interval of more than 450msec at baseline - A serious uncontrolled medical disorder that would impair the ability of the subjects to receive protocol therapy - Prior treatment with dasatinib - Subjects with T315I, F317L and V299L BCR-ABL point mutations Chronic Myeloid Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive null --- T315I --- --- F317L --- --- V299L --- --- T315I ---

Primary Outcomes

Measure: Rate of complete molecular response (CMR) after treatment with dasatinib

Time: at 12 months

Secondary Outcomes

Measure: Dasatinib of dose intensity

Time: at 12 months

Measure: Expansions rate of large granular lymphocyte

Time: at 12 months

Measure: Progression free survival

Time: at 12 months

Measure: Number of Participants with Adverse Events

Time: at 12 months

30 An Open-Label, Randomized, Multicenter Phase 2 Trial of Dasatinib (SPRYCEL®) vs. Dasatinib Plus Smoothened Antagonist (BMS-833923) in the Treatment of Subjects With Newly Diagnosed Chronic Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia (CML).

The purpose of the study is to compare response rates in newly diagnosed Chronic Phase (CP) CML subjects treated with dasatinib plus BMS-833923 versus dasatinib alone.

NCT01357655 Leukemia Drug: Dasatinib Drug: BMS-833923
MeSH:Leukemia
HPO:Leukemia

- Eastern Co-Operative Group (ECOG) Performance Status (PS) Score 0 - 2 Exclusion Criteria: - Known Abl-kinase T315I or T315A mutation - Serious or uncontrolled medical disorder (including infection or cardiovascular disease) or dementia or other serious psychiatric condition - Prior chemotherapy. --- T315I ---

Primary Outcomes

Description: Major molecular response (MMR) was assessed using BCR-ABL transcript levels measured by real-time quantitative polymerase chain reaction (qPCR). MMR was defined as a ratio BCR-ABL/ABL ≤0.1% on the international scale (ie, at least 3 log reduction from a standardized baseline value). Number of participants with MMR by timepoint are cumulative.

Measure: Number of Participants With Major Molecular Response

Time: Baseline up to 12 months

Secondary Outcomes

Measure: Complete Molecular Response at Any Time

Time: Baseline to End of study (approximately 48 months)

Measure: Progression-free Survival, Measured by the Time From Start of Treatment to Progression or Death

Time: Baseline to End of study (approximately 48 months)

Measure: Event-free Survival, Measured by the Time From Start of Treatment to Progression, Death or Treatment Discontinuation

Time: Baseline to End of study (approximately 48 months)

Measure: Transformation-free Survival Measured by the Time From Start of Treatment to Criteria for Accelerated or Blast Phase CML Are Met and Death

Time: Baseline to End of study (approximately 48 months)

Description: AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Drug-related=having certain, probable, possible, or missing relationship to study drug.

Measure: Number of Participants Experiencing Serious Adverse Events (SAE), Drug-Related Adverse Event (AE), AE Leading to Discontinuation, and Death

Time: From date of first dose of study treatment up to the date of the last dose plus 30 days (approximately 49 months)

31 An Open-label, Multicenter Study of Oral AMN107 (Nilotinib) in Adult Patients With Imatinib - Resistant or - Intolerant Chronic Myeloid Leukemia in Blast Crisis, Accelerated Phase or Chronic Phase Previously Enrolled to ENACT (CAMN107A2109) Trial

The purpose of this study is to provide patients with imatinib resistant/intolerant chronic myeloid leukemia - in blast crisis, accelerated phase and chronic phase, who have been previously enrolled to CAMN107A2109 and benefit from the treatment, with access to nilotinib (AMN107) in Poland until such time as the treatment with this drug is financed by the National Health Found in Poland (via 'therapeutic program') or for a period of 18 months, whichever comes first.

NCT01368523 Chronic Myelogenous Leukemia Drug: nilotinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Blast Crisis
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Exclusion Criteria: 1. Known T315I mutations 2. Impaired cardiac function including any one of the following: - LVEF < 45% or below the institutional lower limit of the normal range (whichever is higher) as determined by echocardiogram - Inability to determine the QT interval on ECG - Complete left bundle branch block - Use of a ventricular-paced pacemaker - Congenital long QT syndrome or a known family history of long QT syndrome - History of or presence of clinically significant ventricular or atrial tachyarrhythmias - Clinically significant resting brachycardia (< 50 beats per minute) - QTc > 450 msec on the average of three serial baseline ECG (using the QTcF formula). --- T315I ---

Primary Outcomes

Measure: hematologic response

Time: 18 months

Secondary Outcomes

Measure: cytogenetic response

Time: 18 months

32 A Phase III Multi-center, Open-label, Randomized Study of the Efficacy of Nilotinib Versus Imatinib in Adult Patients With Ph+ CML in Early CP Who Have a Suboptimal Molecular Response to Imatinib

In this study, the efficacy of nilotinib at 400 mg BID will be compared with imatinib at 400 mg BID in suboptimal molecular response patients. To determine study eligibility, suboptimal molecular response will be defined as patients who have achieved a complete cytogenetic response (CCyR) but have not achieved a MMR, after at least 18 months of treatment on first line imatinib therapy at a minimum dose of 400mg daily (Baccarani 2006).

NCT01400074 Chronic Myeloid Leukemia Drug: Nilotinib, Imatinib
MeSH:Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia

- Previously documented T315I mutations. --- T315I ---

Primary Outcomes

Description: To evaluate the cumulative rate of MMR at 12 months of nilotinib compared to imatinib in adult patients with Ph+ CML in early CP who have suboptimal molecular response to imatinib

Measure: the cumulative rate of MMR

Time: 12 months

33 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 --- --- T315I ---

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)

34 Phase II Study of Flumatinib Versus Imatinib in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

It is an open-label, randomized, multi-center study. The efficacy and safety of two flumatinib doses, 400 mg once daily and 600 mg once daily, will be compared with imatinib 400 mg once daily in newly diagnosed (within 6 months) patients with Philadelphia chromosome-positive (Ph+) Chronic Myelogenous Leukemia in the chronic phase (CML-CP).

NCT01503502 Myelogenous Leukemia, Chronic Drug: flumatinib Drug: imatinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Philadelphia Chromosome
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Exclusion Criteria: 1. Previously documented T315I mutations. --- T315I ---

Primary Outcomes

Description: Obtain major molecular response (MMR) rate at 6 months in newly diagnosed Ph+ CML patients through comparison of the efficacy results of flumatinib with that of imtinib.

Measure: To compare the rate of MMR at 6 months

Time: 6 months

Secondary Outcomes

Measure: To compare the rate of MMR at 12 months

Time: 12 months

35 An Open Label Phase II Study to Evaluate the Efficacy and Safety of Induction and Consolidation Therapy With Nilotinib in Combination With Chemotherapy in Patients Aged 55 Years and Over With Philadelphia Chromosome Positive (Ph+ or BCR-ABL+) Acute Lymphoblastic Leukemia (ALL)

The goal of this trial is to evaluate the efficacy and the tolerance of the combination of nilotinib with chemotherapy in the front-line setting as induction and consolidation therapy in Ph+ ALL patient aged 55 years and over. A European consensus has been reached to adopt a common chemotherapeutic schedule for patients aged 55 years and over. This schedule will be used in this trial with the addition of nilotinib as concomitant therapy during induction, consolidation and maintenance. The patients will be prospectively monitored for minimal residual disease and bcr-abl tyrosine kinase domain mutations.

NCT01528085 Philadelphia Chromsome Positive Acute Lymphoblastic Leukemia Drug: Nilotinib
MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Philadelphia Chromosome
HPO:Leukemia Lymphoid leukemia

T315I or p-loop Mutations. --- T315I ---

Detection of a T315I or p-loop BCR-ABL TK domain mutation. --- T315I ---

Primary Outcomes

Description: rate of patients without event

Measure: Evaluation of efficacy of a nilotinib-based induction and consolidation therapy

Time: after 12 months

Secondary Outcomes

Description: The rate of complete haematological remission after induction treatment

Measure: complete haematological remission

Time: after induction treatment (week 5)

Description: major molecular response defined by a BCR-ABL/ABL < 0.1% in bone marrow

Measure: major molecular response in bone marrow

Description: complete molecular response defined by a BCR-ABL/ABL < 0.001% in bone marrow

Measure: complete molecular response

Description: The proportion of patients with confirmed undetectable BCR-ABL level with a test sensitivity of at least 4.5 log.

Measure: undetectable BCR-ABL level

Measure: Event free survival

Measure: Relapse free survival

Measure: Progression free survival

Description: Detection of a T315I or p-loop BCR-ABL TK domain mutation

Measure: T315I or p-loop Mutations

Description: The proportion of patients with molecular relapse or progression

Measure: molecular relapse or progression

Measure: Overall survival

Description: Tolerability as determined by descriptive assessment of adverse events and discontinuation due to treatment-related SAEs

Measure: Tolerability

Description: (all patients who started treatment)

Measure: Death during induction

Time: End of induction (week 5)

Measure: Death in complete remission

36 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

Inclusion Criteria: - Patients with Philadelphia chromosome-positive or BCR-ABL positive CML - Chronic, Accelerated phase CML patients who show an inappropriate response to the imatinib treatment or failed the treatment according to ELN 2009 RECOMMENDATION - Patients with ECOG performance status of 0-3 - Patients who consent to the use of study information and study specimen Exclusion Criteria: - Patients with diseases other than CML - Patients treated with myelosuppressive anticancer therapy other than Hydroxyurea and Angrelide - Patients who have been treated with second-generation cancer-targeting drug - Patients who do not consent to the use of study information and study specimen - Previously documented T315I mutation - Impaired cardiac function including any of the following: LVEF by echocardiography < 45% or below the institutional lower range (whichever is greater); complete left bundle branch block; long QT syndrome or family history of; history or presence of significant ventricular or atrial tachyarrhythmias; clinically significant brachycardia (< 50 bpm); QTcF > 450 msec at baseline; right bundle branch block plus left anterior hemiblock; bifascicular block; myocardial infarction ≤ 12 months; uncontrolled angina; other clinically significant heart disease (e.g., congestive heart failure) - Treatment with strong inhibitors of CYP3A4 or medication that are well documented to prolong the QT interval are contraindicated - Impaired gastrointestinal(GI)function or GI disease that may significantly alter the absorption of the study drug (e.g., ulcerative diseases, uncontrolled nausea, vomitting, diarrhea, malabsorption syndrome, small bowel resection or gastric bypass surgery) - History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis - Know cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required) - Patients who previously had a bone marrow or stem cell transplantation - Pregnant or breast-feeding patients - Hypersensitivity to nilotinib or any of the excipients - The capsules contain lactose, and nilotinib is therefore not recommended for patients with rare hereditary problem of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption Inclusion Criteria: - Patients with Philadelphia chromosome-positive or BCR-ABL positive CML - Chronic, Accelerated phase CML patients who show an inappropriate response to the imatinib treatment or failed the treatment according to ELN 2009 RECOMMENDATION - Patients with ECOG performance status of 0-3 - Patients who consent to the use of study information and study specimen Exclusion Criteria: - Patients with diseases other than CML - Patients treated with myelosuppressive anticancer therapy other than Hydroxyurea and Angrelide - Patients who have been treated with second-generation cancer-targeting drug - Patients who do not consent to the use of study information and study specimen - Previously documented T315I mutation - Impaired cardiac function including any of the following: LVEF by echocardiography < 45% or below the institutional lower range (whichever is greater); complete left bundle branch block; long QT syndrome or family history of; history or presence of significant ventricular or atrial tachyarrhythmias; clinically significant brachycardia (< 50 bpm); QTcF > 450 msec at baseline; right bundle branch block plus left anterior hemiblock; bifascicular block; myocardial infarction ≤ 12 months; uncontrolled angina; other clinically significant heart disease (e.g., congestive heart failure) - Treatment with strong inhibitors of CYP3A4 or medication that are well documented to prolong the QT interval are contraindicated - Impaired gastrointestinal(GI)function or GI disease that may significantly alter the absorption of the study drug (e.g., ulcerative diseases, uncontrolled nausea, vomitting, diarrhea, malabsorption syndrome, small bowel resection or gastric bypass surgery) - History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis - Know cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required) - Patients who previously had a bone marrow or stem cell transplantation - Pregnant or breast-feeding patients - Hypersensitivity to nilotinib or any of the excipients - The capsules contain lactose, and nilotinib is therefore not recommended for patients with rare hereditary problem of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption Chronic Myeloid Leukemia Leukemia, Myelogenous, Chronic, BCR-ABL Positive Recently the treatment strategy of Philadelphia chromosome-positive leukemia has undergone groundbreaking changes due to the development of new second-generation cancer-targeting drugs. --- T315I ---

Inclusion Criteria: - Patients with Philadelphia chromosome-positive or BCR-ABL positive CML - Chronic, Accelerated phase CML patients who show an inappropriate response to the imatinib treatment or failed the treatment according to ELN 2009 RECOMMENDATION - Patients with ECOG performance status of 0-3 - Patients who consent to the use of study information and study specimen Exclusion Criteria: - Patients with diseases other than CML - Patients treated with myelosuppressive anticancer therapy other than Hydroxyurea and Angrelide - Patients who have been treated with second-generation cancer-targeting drug - Patients who do not consent to the use of study information and study specimen - Previously documented T315I mutation - Impaired cardiac function including any of the following: LVEF by echocardiography < 45% or below the institutional lower range (whichever is greater); complete left bundle branch block; long QT syndrome or family history of; history or presence of significant ventricular or atrial tachyarrhythmias; clinically significant brachycardia (< 50 bpm); QTcF > 450 msec at baseline; right bundle branch block plus left anterior hemiblock; bifascicular block; myocardial infarction ≤ 12 months; uncontrolled angina; other clinically significant heart disease (e.g., congestive heart failure) - Treatment with strong inhibitors of CYP3A4 or medication that are well documented to prolong the QT interval are contraindicated - Impaired gastrointestinal(GI)function or GI disease that may significantly alter the absorption of the study drug (e.g., ulcerative diseases, uncontrolled nausea, vomitting, diarrhea, malabsorption syndrome, small bowel resection or gastric bypass surgery) - History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis - Know cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required) - Patients who previously had a bone marrow or stem cell transplantation - Pregnant or breast-feeding patients - Hypersensitivity to nilotinib or any of the excipients - The capsules contain lactose, and nilotinib is therefore not recommended for patients with rare hereditary problem of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption Inclusion Criteria: - Patients with Philadelphia chromosome-positive or BCR-ABL positive CML - Chronic, Accelerated phase CML patients who show an inappropriate response to the imatinib treatment or failed the treatment according to ELN 2009 RECOMMENDATION - Patients with ECOG performance status of 0-3 - Patients who consent to the use of study information and study specimen Exclusion Criteria: - Patients with diseases other than CML - Patients treated with myelosuppressive anticancer therapy other than Hydroxyurea and Angrelide - Patients who have been treated with second-generation cancer-targeting drug - Patients who do not consent to the use of study information and study specimen - Previously documented T315I mutation - Impaired cardiac function including any of the following: LVEF by echocardiography < 45% or below the institutional lower range (whichever is greater); complete left bundle branch block; long QT syndrome or family history of; history or presence of significant ventricular or atrial tachyarrhythmias; clinically significant brachycardia (< 50 bpm); QTcF > 450 msec at baseline; right bundle branch block plus left anterior hemiblock; bifascicular block; myocardial infarction ≤ 12 months; uncontrolled angina; other clinically significant heart disease (e.g., congestive heart failure) - Treatment with strong inhibitors of CYP3A4 or medication that are well documented to prolong the QT interval are contraindicated - Impaired gastrointestinal(GI)function or GI disease that may significantly alter the absorption of the study drug (e.g., ulcerative diseases, uncontrolled nausea, vomitting, diarrhea, malabsorption syndrome, small bowel resection or gastric bypass surgery) - History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis - Know cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required) - Patients who previously had a bone marrow or stem cell transplantation - Pregnant or breast-feeding patients - Hypersensitivity to nilotinib or any of the excipients - The capsules contain lactose, and nilotinib is therefore not recommended for patients with rare hereditary problem of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption Chronic Myeloid Leukemia Leukemia, Myelogenous, Chronic, BCR-ABL Positive Recently the treatment strategy of Philadelphia chromosome-positive leukemia has undergone groundbreaking changes due to the development of new second-generation cancer-targeting drugs. --- T315I --- --- T315I ---

T315I mutation exhibits strong resistance to both of these cancer-targeting therapies. --- T315I ---

According to the results of the recent studies including the one conducted by our center, it is assumed that imatinib resistance caused by point mutations in patients induces more point mutations and causes selective increase in T315I point mutations during treatment of the second-generation cancer-targeting therapy. --- T315I ---

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

37 Expanded Access Program of Ponatinib (AP24534) for Patients With Refractory Chronic Myeloid Leukemia or Ph+ Acute Lymphoblastic Leukemia

This protocol will allow expanded access of ponatinib to patients ≥18 years with chronic myeloid leukemia (CML) any phase or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) who have failed all available treatment options.

NCT01592136 Chronic Myeloid Leukemia (CML) Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Drug: ponatinib
MeSH:Leukemia Leukemia, Myeloid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Philadelphia Chromosome
HPO:Chronic myelogenous leukemia Leukemia Lymphoid leukemia Myeloid leukemia

Main Inclusion Criteria: 1. CP-CML and AP-CML patients previously treated with and resistant or intolerant to imatinib, dasatinib and nilotinib or those who developed the T315I mutation after any TKI therapy. --- T315I ---

BP-CML and Ph+ ALL patients previously treated with and resistant or intolerant to imatinib and dasatinib or those who developed the T315I mutation after any TKI therapy. --- T315I ---

Patients with chronic (CP) or accelerated phase (AP) CML must be previously treated with and resistant or intolerant to imatinib, dasatinib and nilotinib or develop the T315I mutation after any tyrosine kinase inhibitor (TKI) therapy. --- T315I ---

Patients with blast phase (BP) CML and Ph+ ALL must be previously treated with and resistant or intolerant to imatinib and dasatinib or develop the T315I mutation after any TKI therapy. --- T315I ---


38 An Open Label, Randomized (2:1) Phase IIb Study of Dasatinib Versus Imatinib in Patients With Chronic Phase Chronic Myeloid Leukemia Who Have Not Achieved an Optimal Response to 3 Months of Therapy With 400 mg Imatinib

The purpose of this study is to test the hypothesis that patients with CML who have not achieved optimal response after 3 months of treatment with imatinib will have a better response by switching to dasatinib compared to staying on their original imatinib regimen.

NCT01593254 Chronic Phase Chronic Myeloid Leukemia Drug: Imatinib Drug: Dasatinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Patients with no evidence of clonal evolution, including those patients whose cytogenetic testing fails or bone marrow aspiration is a dry tap at 3 months, are eligible for the study - Subjects with less than CHR after 3 months of imatinib treatment or lost CHR after initial achievement - Documented T315I/A, F317L, or V299L mutations (if already available - not required for screening) - A serious uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com. --- T315I ---

Patients with no evidence of clonal evolution, including those patients whose cytogenetic testing fails or bone marrow aspiration is a dry tap at 3 months, are eligible for the study - Subjects with less than CHR after 3 months of imatinib treatment or lost CHR after initial achievement - Documented T315I/A, F317L, or V299L mutations (if already available - not required for screening) - A serious uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy Chronic Phase Chronic Myeloid Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase null --- T315I ---

Primary Outcomes

Description: Major Molecular Response, is defined as a 3-log reduction in BCR-ABL transcripts from the standardized baseline, which represents 100% on the international scale, so a 3-log reduction is fixed at 0.1% for MMR; N/A = not applicable. 95% CI is Clopper-Pearson(Exact) two-sided 95% confidence intervals. P-value is based on Cochran-Mantel-Haenszel (CMH) test stratified by Sokal score(high, intermediate, low, and unknown) and time between 3 month molecular analysis and randomization (<=4 weeks vs >4 weeks). Month 12 is calculated fro

Measure: Percentage of Patients Achieving Major Molecular Response (MMR) After 12 Months of CML Treatment

Time: At 12 months after Day 1 initiation of 1st line treatment with imatinib or imatinib at any dose, after less than optimal response to first-line imatinib.

Secondary Outcomes

Description: Time to MMR is how fast patients achieve optimal response. It is the time between randomization date and first date that MMR criteria are satisfied.

Measure: Median Time to Major Molecular Response (MMR)

Time: Up to 10 years

Description: Time to MR^4.5 is how fast patients achieve a deeper response. It is the time between randomization date and first date that MR^4.5 criteria are satisfied.

Measure: Time to Molecular Response (MR)^4.5

Time: Up to 10 years

Description: PFS is how long patients are likely to live without progression of their disease. It is the time from randomization date to progression date or death date, whichever occurs first.

Measure: Progression Free Survival (PFS)

Time: Up to 10 years

Description: OS is how long patients are likely to remain alive. It is the time from randomization date to death date.

Measure: Overall Survival (OS)

Time: Up to 10 years

39 A Phase II, Non Randomized, Open Label, Trial Evaluating Nilotinib as Treatment for Newly Diagnosed CML Patients in Accelerated Phase.

This is an open label, non randomized, prospective, multicenter, phase II clinical trial evaluating nilotinib 400 mg BID for the treatment of newly diagnosed CML-AP patients. Patients enrolled into the study will receive 400mg of nilotinib, orally, twice daily (800mg/day)

NCT01605981 Chronic Myeloid Leukemia (CML) Drug: AMN107
MeSH:Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia

- Treatment with tyrosine kinase inhibitors or other antileukemic agents or treatments (including HSCT) for longer than 2 weeks, with the exception of HU and/or anagrelide - Previously documented T315I mutations; - Uncontrolled congestive heart failure or hypertension; - Myocardial infarction or unstable angina pectoris within past 12 months; - Significant arrhythmias, including history or presence of clinically significant ventricular or atrial tachyarrhythmias, clinically significant bradycardias, long QT syndrome and/or QTc > 450 msec on screening ECG (using the QTcF formula). --- T315I ---

Primary Outcomes

Description: The toxicity criteria will be evaluated according to National Cancer Institute - Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 3.0.

Measure: To evaluate the safety and tolerability profile of nilotinib in newly diagnosed CML-AP

Time: 12 month

Description: To test the efficacy of nilotinib 400 mg BID in inducing complete cytogenetic response (CCyR) at 12 months in newly diagnosed CML-AP patients

Measure: To test the efficacy of nilotinib 400 mg BID

Time: 12 months

Secondary Outcomes

Description: Evaluate the rate of complete hematologic response (CHR) with nilotinib 400 mg BID at 3 months.

Measure: Evaluate the rate of complete hematologic response (CHR)

Time: 3 months

Description: Evaluate the Quality of Life by FACT-Leu Version 4 questionnaire at 3, 6, 9, 12, 15, 18 and 24 months.

Measure: Evaluate the Quality of Life

Time: 3, 6, 9, 12, 15, 18 and 24 months

Description: Evaluate the median time to achieve molecular response and the cumulative probability of obtaining molecular response during the first 2 years of treatment. This will be undertaken through the analysis of the best molecular response at 3, 6, 12, 18 and 24 months. MMR will be preferred and it will be defined as a BCR-ABL/ABL ratio ≤ 0.1% IS using RQ-PCR, but any log reduction between 1 and 4,5 logs will be considered a molecular response.

Measure: Evaluate the median time to achieve molecular response

Time: uring the first 2 years of treatment

Description: Evaluate the proportion of patients achieving CCyR at 3, 6, 12, 18 and 24 months or undetectable BCR-ABL levels at 12, 18 and 24 months as well as the duration of sustained response.

Measure: Evaluate the proportion of patients achieving CCyR

Time: 3, 6, 12, 18 and 24 months or undetectable BCR-ABL levels at 12, 18 and 24 months

Description: To correlate the probability of reaching MMR, CMR and CCyR with the risk of progression to blastic phase, relapse and overall survival.

Measure: To correlate the probability of reaching MMR, CMR and CCyR

Time: 2 years

40 Discontinuation of Dasatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase Who Have Maintained Complete Molecular Remission for Two Years; Dasatinib Stop Trial

The purpose of this study is to assess whether dasatinib can be discontinued without occurrence of molecular relapse in patients with chronic myeloid leukemia in chronic phase in complete molecular remission (CMR) while on dasatinib.

NCT01627132 Chronic Myeloid Leukemia Drug: Dasatinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

- Patients with mutation of T315I, F317L, V299L. --- T315I ---

Primary Outcomes

Measure: The overall probability of maintenance of complete molecular remission at 12 months after stopping dasatinib.

Time: at 12 months

Secondary Outcomes

Measure: Rate of complete molecular remission that will be sustained after dasatinib rechallenge.

Time: at 12 months

41 Front-line Treatment of Philadelphia Positive/BCR-ABL Positive Acute Lymphoblastic Leukemia With Ponatinib, a New Potent Tyrosine Kinase Inhibitor.

Drug resistance resulting from emergence of Imatinib-resistant BCR-ABL clones is a significant problem in Ph positive ALL patients because after a very good initial response to one TKI inhibitor, many patients relapse within one year, relapse being almost always associated with a BCR-ABL kinase domain point mutation. The patients who relapse after treatment with one TKI can be rescued to remission with another TKI, but the second remission is usually shorter than the previous one. A more potent TKI inhibitor, and pan-active not only on all the BCR-ABL variants (including the second generation TKI resistant T315I mutant), but also on others molecular targets can do better. In this context, Ponatinib is a novel synthetic orally active tyrosine kinase inhibitor (TKI), specifically developed to inhibit BCR-ABL, the fusion protein that is the product of the Philadelphia chromosome (Ph) in chronic myeloid leukemia (CML) and in a subset of acute lymphoblastic leukemia (Ph+ ALL). It potently inhibits the BCR-ABL protein as well as mutated forms of the protein that arise in patients resistant to prior therapies with TKIs. Ponatinib has been demonstrated to inhibit all the mutations that have been detected so far, in vitro and in vivo and to uniformly suppress the emerge of single-mutant clones in a mutagenesis assay. In the Phase II study, 41% of Philadelphia chromosome positive acute lymphoblastic leukemia patients treated with Ponatinib achieved major hematologic response, 47% had a major cytogenetic response, 38% obtained a complete cytogenetic response, showing that Ponatinib provides significant benefit despite previous intolerance or refractoriness to other TKIs. The Phase I trial showed that patients with a more recent diagnosis had increased rates of major molecular response: 79% for 14 patients with 0 to 5 years since diagnosis vs. 29% for 14 patients with more than 5 to 9 years since diagnosis (P=0.02) and 27% for 15 patients with more than 9 to 24 years since diagnosis (P=0.009). These characteristics support the hypothesis for a role of Ponatinib not only in patients resistant to prior TKI therapy but also in untreated ALL Ph+ patients, in order to prevent the emergence of resistant caused by the selection of mutated Ph+ clones and in order to avoid rapid progression of the disease.

NCT01641107 Philadelphia Positive BCR-ABL Positive Acute Lymphoblastic Leukemia Drug: Ponatinib
MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid
HPO:Leukemia Lymphoid leukemia

A more potent TKI inhibitor, and pan-active not only on all the BCR-ABL variants (including the second generation TKI resistant T315I mutant), but also on others molecular targets can do better. --- T315I ---

Primary Outcomes

Description: The primary endpoint is the proportion of patients who are in CHR at 6 months, calculated on the total number of patients who have been enroled and have received at least one dose of the first drug (prednisone).

Measure: Proportion of patients who are in Complete Hematological Response (CHR).

Time: At 6 months from study entry.

Secondary Outcomes

Description: CHR requires that all of the following are present: Bone marrow with less than 5% blast cells Peripheral blood differential without blasts PMN ≥ 1.5 x 109/L PLT ≥ 100 x 109/L No evidence of extramedullary involvement from leukemia

Measure: The rate of Complete Hematological Response (CHR).

Time: At 6, 12, 24, 36 and 48 weeks from study entry.

Description: CgR is defined based on the percentage of Ph pos metaphases, as evaluated by chromosome banding analysis (CBA) of at least 20 marrow cell metaphases: Complete (CCgR) if Ph pos 0 Partial (PCgR) if Ph pos 1-34% Minor (mCgR) if Ph pos 35-65% Minimal or none (min/none CgR) if Ph pos > 65% If only interphase FISH data are available, the response can be defined only as non-complete or complete - to be complete by FISH, it is required that less than 1% of nuclei (minimum number 200) have a positive signal.

Measure: The rate of complete Cytogenetic Response (CgR).

Time: At 6, 12, 24, 36 and 48 weeks from study entry.

Description: Duration of CCgR is measured by the date of the achievement of CCgR to the date of CCgR loss.

Measure: Duration of Complete Cytogenetic Response (CCgR).

Time: After four years from study entry.

Description: Molecular response is classified as: • Complete if by RT-Q-PCR the BCR-ABL: ABL ratio is below 0.01, with a sensitivity of at least 30,000 molecules of ABL.

Measure: The rate of Complete Molecular Response (CMoIR).

Time: At 12, 24, 36 and 48 weeks from study entry.

Description: Molecular response (MR) is classified as: • Major (MMolR) if by RT-Q-PCR the BCR-ABL: ABL ratio is lower than 0.10, with a sensitivity of at least 30,000 molecules of ABL.

Measure: The rate of major molecular response.

Time: At 12, 24, 36 and 48 weeks from study entry.

Description: Duration of CMR is measured by the date of the achievement of CMR to the date of CMR loss.

Measure: Duration of Complete molecular response (CMR).

Time: After four years from study entry.

Measure: Type and number of BCR-ABL kinase domain mutations.

Time: At the end of the study. At four years after enrollment of first patient.

Measure: Percentage of relationships between the response and the biomarkers.

Time: At six months from study entry.

Description: Events are induction failure, relapse and death whichever comes first.

Measure: Event Free Survival.

Time: After four years from study entry.

Description: Overall survival is measured in all patients from the data of enrolment to the date of death, by any causes.

Measure: Overall survival

Time: At the end of study. After four years from enrolment.

Measure: Failure Free Survival

Time: After four years from study entry.

Measure: Rate of Rate of side effects, adverse events and serious adverse events.

Time: After four years from study entry.

42 A Phase IV, Open-label, Multicenter Study of Dasatinib in Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Patients With Chronic, Low-grade Non-Hematologic Toxicity to Imatinib

This study proposes to evaluate the number of chronic, Grade 1 or 2, non-hematologic Adverse Events (AEs) that reduce in grade or resolve at 3 months after switching therapy from imatinib to dasatinib.

NCT01660906 Chronic Phase Chronic Myeloid Leukemia Drug: Dasatinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

- Previous treatment with any other tyrosine-kinase inhibitor (TKI), except for imatinib - Current grade 3 or 4 imatinib related adverse event - Prior documented T315I mutation - Prior diagnosis of accelerated phase or blast crisis CML - Previous loss of complete hematologic response (CHR) or major cytogenetic response (MCyR) on imatinib - Concurrent medical condition of uncontrolled infection, cardiovascular diseases of cardiac failure, congenital long QT syndrome, ventricular arrhythmias, prolonged QT interval, second or third degree heart block, uncontrolled angina, myocardial infarction (MI) in the last 6 months, uncontrolled hypertension, pulmonary arterial hypertension, pleural or pericardial effusions, or history of bleeding disorder Inclusion Criteria: - Patients with CML-CP patients achieving an optimal response to imatinib treatment with Grade 1 or 2 non-hematologic adverse events persisting for at least 2 months or recurring at least 3 times in the preceding 12 months, despite best supportive care - Men and women with Chronic Myeloid Leukemia- Chronic Phase (CML-CP) Ph+ ≥ age 18 - Daily Eastern Co-Operative Group (ECOG) performance status = 0 - 2 - Patient willing and able to give informed consent - Life expectancy > 6 months - Adequate renal function - Adequate hepatic function Exclusion Criteria: - Patients who are pregnant or breast feeding - Men whose partner is unwilling to avoid pregnancy. --- T315I ---

- Previous treatment with any other tyrosine-kinase inhibitor (TKI), except for imatinib - Current grade 3 or 4 imatinib related adverse event - Prior documented T315I mutation - Prior diagnosis of accelerated phase or blast crisis CML - Previous loss of complete hematologic response (CHR) or major cytogenetic response (MCyR) on imatinib - Concurrent medical condition of uncontrolled infection, cardiovascular diseases of cardiac failure, congenital long QT syndrome, ventricular arrhythmias, prolonged QT interval, second or third degree heart block, uncontrolled angina, myocardial infarction (MI) in the last 6 months, uncontrolled hypertension, pulmonary arterial hypertension, pleural or pericardial effusions, or history of bleeding disorder Chronic Phase Chronic Myeloid Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase null --- T315I ---

Primary Outcomes

Description: Dasatinib treatment was administered and its impact on the imatinib-related Grade 1/2 adverse events was assessed. The severity of an adverse event is ranked based on grades that range from 1 to 4. Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4= Potentially Life-threatening or disabling. Resolved, AE no longer present or resolution of imatinib-related chronic Grade 1 or Grade 2 non-hematologic AEs. Improved, AE grade reduced from Grade 2 to Grade 1. Unchanged, AE did not improve or worsen or no change in grade. Worsened, grade Increased.

Measure: The Number of Imatinib-related Adverse Events (AEs) That Were Resolved, Improved, Remained Unchanged, or Worsened After 3 Months of Dasatinib Treatment

Time: 3 months after switch to dasatinib

Secondary Outcomes

Description: The MD Anderson Symptom Inventory Chronic Myeloid Leukemia (MDASI-CML) is a validated questionnaire completed by study participants to assess symptom severity and symptom interference on daily function. These categories are divided into 5 domain summary scores: Core Symptom Severity Score, Interference Score, Symptom Severity Score, CML-Specific Symptom Severity Score, and 5 Most Severe Symptom Score. Scores were evaluated at baseline and after switching to Dasatinib on a range from 1 to 10; 1=not present/did not interfere, 10=as bad as you can imagine/interfered completely.

Measure: Mean Change From Baseline in Patient Reported CML Symptom Severity and Interference by MD Anderson Symptom Inventory - Chronic Myeloid Leukemia (MDASI-CML) Score After Switching to Dasatinib

Time: Baseline to 3, 6, 12 months

Description: The EORTC QLQ-C30 questionnaire is completed by study participants to assess quality of life through nine multi-item scales: five functional scales (physical, role, cognitive, emotional and social functioning); three symptom scales (fatigue, pain and nausea/vomiting); and a global health status/QoL scale. Six single-item scales are also included (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). All of the scales and single-item measures were evaluated at baseline and after switching to Dasatinib as an average raw score that was standardized by transformation, so that final scores were on a range in score from 0 to 100. A high score for a functional scale represents a healthy level of functioning, a high score for the global health status/QoL represents a high QoL, but a high score for a symptom scale and single-item measures represents a high level of problematic symptomatology.

Measure: Mean Change From Baseline in Patient Reported Quality of Life Measurements by The European Organization for Research and Treatment of Cancer - Quality of Life (QoL) Questionnaire (EORTC QLQ) Score After Switching to Dasatinib

Time: Baseline to 6, 12 months

Description: SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Treatment-related=having certain, probable, possible, or missing relationship to study drug, dasatinib.

Measure: Number of Participants With at Least 1 AE, Discontinuations Due to AE, Treatment-related AE, Serious Adverse Event (SAE), Treatment-related SAE, or Death as Outcome

Time: Date of first dose to 30 post last dose of study drug, an average of 3 years

Description: Dasatinib treatment was administered and its impact on the Imatinib-related Grade 1/2 adverse events was assessed. The percentage of participants is based on the number that had pre-existing Imatinib-related AEs. Measure assesses the participants with reduction or improvement of at least 1 Imatinib-related Grade 1 or Grade 2 chronic AE, without a worsening of any Imatinib-related, chronic adverse events after Dasatinib treatment. The severity of an adverse event is ranked based on grades that range from 1 to 4. Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4= Potentially Life-threatening or disabling. Improved, AE grade reduced from Grade 2 to Grade 1. Worsened, Grade Increased. Confidence interval from Clopper-Pearson method.

Measure: The Percentage of Participants With at Least 1 Imatinib-related Grade 1 or Grade 2 Chronic Adverse Events (AEs) That Improved Without Worsening Within 3 Months of Switching to Dasatinib

Time: 3 months

Other Outcomes

Description: Molecular responses were assessed at 6 and 12 months after switching to dasatinib to determine if these baseline responses could be maintained. MR4.5, the number of treated participants with BCR-ABL transcripts ≤ 0.0032% (IS) at 6 and 12 months from the date of dasatinib initiation; MMR, Major Molecular Response = 3-log reduction in BCR-ABL gene transcripts from a standardized baseline.

Measure: Number of Participants With a Major Molecular Response (MMR) and MR 4.5 After Switching to Dasatinib

Time: 6 and 12 months

43 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 ---

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

44 A Phase II Randomized, Multicenter Study of Treatment-free Remission in Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Patients Who Achieve and Sustain MR4.5 After Switching to Nilotinib

To evaluate molecular relapse free rates 6 months after stopping nilotinib therapy in patients who achieve MR4.5

NCT01744665 CML Drug: nilotinib

Inclusion Criteria: - diagnosis of CML - Treated with at least 1 year of imatinib - Bcr-Abl level by PCR must be less than or equal to 0.1% and greater than 0.0032% by PCR reported on the International scale confirmed during screening - Written informed consent obtained prior to any screening procedures performed Exclusion Criteria: - T315I mutation - Prior imatinib failure or had accelerated phase or blast crisis CML - Impaired cardiac function - Pregnant or lactating women Inclusion Criteria: - diagnosis of CML - Treated with at least 1 year of imatinib - Bcr-Abl level by PCR must be less than or equal to 0.1% and greater than 0.0032% by PCR reported on the International scale confirmed during screening - Written informed consent obtained prior to any screening procedures performed Exclusion Criteria: - T315I mutation - Prior imatinib failure or had accelerated phase or blast crisis CML - Impaired cardiac function - Pregnant or lactating women CML Study protocol included criteria for study termination that was met when > 2 patients lost CCyR during TFR phase (> 1% BCR-ABL); This study was terminated early as > 2 cases of confirmed loss of complete cytogenetic response were reported despite BCR-ABL monitoring during the TFR Phase. --- T315I ---

Inclusion Criteria: - diagnosis of CML - Treated with at least 1 year of imatinib - Bcr-Abl level by PCR must be less than or equal to 0.1% and greater than 0.0032% by PCR reported on the International scale confirmed during screening - Written informed consent obtained prior to any screening procedures performed Exclusion Criteria: - T315I mutation - Prior imatinib failure or had accelerated phase or blast crisis CML - Impaired cardiac function - Pregnant or lactating women Inclusion Criteria: - diagnosis of CML - Treated with at least 1 year of imatinib - Bcr-Abl level by PCR must be less than or equal to 0.1% and greater than 0.0032% by PCR reported on the International scale confirmed during screening - Written informed consent obtained prior to any screening procedures performed Exclusion Criteria: - T315I mutation - Prior imatinib failure or had accelerated phase or blast crisis CML - Impaired cardiac function - Pregnant or lactating women CML Study protocol included criteria for study termination that was met when > 2 patients lost CCyR during TFR phase (> 1% BCR-ABL); This study was terminated early as > 2 cases of confirmed loss of complete cytogenetic response were reported despite BCR-ABL monitoring during the TFR Phase. --- T315I --- --- T315I ---

Primary Outcomes

Description: Percentage of particpants without confirmed loss of MMR within 6 months following nilotinib TFR is calculated by dividing the number of patients with no documented confirmed loss of MR4, in the first 6 months after starting nilotinib TFR phase by the number of patients who entered nilotinib TFR phase. Molecular relapse is defined as having a confirmed BCR-ABL ratio above MMR (2 consecutive BCR-ABL levels >0.1% IS taken approximately 4 weeks apart).

Measure: Percentage of Participants Without Molecular Relapse Within 6 Months After Starting the TFR Phase

Time: 6 months after stopping nilotinib therapy

Secondary Outcomes

Description: Relapse-free survival after the start of the TFR phase was summarized using the product-limit (Kaplan-Meier) estimates. The median for the relapse free survival and its 95% confidence intervals were provided. This analysis was performed on the FAS. Patients who dropped out without relapse were treated as censored observations.

Measure: Relapse Free Survival is Defined as Time From the Date of Nilotinib Treatment Discontinuation to the First Documented Molecular Relapse (Confirmed Loss of MR4.5).

Time: 7 years

Description: The percentage of participants without confirmed loss of MRR at 12 and 24 months is calculated by dividing the number of patients with no documented confirmed loss of MR4 at 12 and 24 months after starting the nilotinib TFR phase by the number of patients who entered nilotinib TFR phase.

Measure: Percentage of Participants Without Molecular Relapse Within 12 and 24 Months After Starting the Treatment -Free Remission (TFR) Phase

Time: 12 and 24 months after starting the TFR

Description: The percentage of participants who regained MR4.5 after restarting nilotinib will be calculated as the number of patients who achieved MR4.5 after having lost MR4 divided by the number of patients who lost MR4.

Measure: Percentage of Participants Who Regained MR4.5 After Restarting Nilotinib Due to Molecular Relapse

Time: Restart of nilotinib up to month 6, 12 and 24

Description: Progression to AP/BC and death where the "failure" event is the earliest occurrence of the following event: progression to AP/BC date.

Measure: Number of Participants Who Progressed to Accelerated Phase/Blastic Crisis (AP/BC) or Died From From Any Cause.

Time: Baseline up to approximately 5 years

Description: OS was defined as the time from the date of cessation of nilotinib therapy to the date of death from any cause.

Measure: Overall Survival (OS)

Time: Baseline up to approximately 5 years

Description: The M.D. Anderson Symptom Inventory for CML patients (MDASI-CML) was used to assess the nature and impact of symptom burden on life. It consisted of 20 validated symptom items and 6 validated interference items. Each item was assessed on an 11 point scale with responses from 0-10, 0=not present and 10=as bad as you can imagine. Symptom score (SS) was calculated when a patient scored at least 8 items of the symptom items using the formula: (sum of scores for the items answered) / number of items answered. If a subject responded to < 8 symptom items, the score was considered missing. Interference score (IS) was calculated when a patient scored at least 4 items using the formula: (sum of scores for the items answered)/number of items answered. If a subject responded to < 4 interference items, the score was considered missing. The total symptom score was 0-200 and total interference score was 0-60. Mean change from baseline was summarized at all post-baseline time points

Measure: Change in Symptom-burden Scores by the M.D. Anderson Symptom Inventory - Chronic Myeloid Leukemia (MDASI-CML) Assessment

Time: From baseline to time to when MR4.5 is confirmed, up to 24 months, and from end of Consolidation Phase to 6 and 12 months into the TFR Phase

Description: The EQ-5D-3L questionnaire comprises 5 items: mobility, self-care, usual activities, pain/discomfort and anxiety/depression and visual analog has a scale 0 to 100 (0=worst imaginable health state, 100=best imaginable health state).

Measure: Change in Health Utility Assessed by EuroQol Group-5D-3L (EQ-5D-3L) Visual Analogue - Safety Set

Time: From baseline to time to when MR4.5, up to 24 months, is confirmed and from end of Consolidation Phase to 6 and 12 months into the TFR Phase

Description: The SF-8 questionnaire consisted of 8 items (general health, physical functioning, role physical, bodily pain, vitality, social functioning, role-emotional and mental health) and was used to assess the impact of nilotinib treatment discontinuation on the quality of life. Each item had a 1 to 5 or 1 to 6 point response range and the higher number in the raw scores indicated poorer quality of life. The physical and mental component summary measures were calculated using a norm-based scoring method given in the instrument guidelines. These norm-based scores were summarized at baseline and mean change from baseline for post-baseline time points. The norm-based scores (based on the US population) had a mean of 50 and standard deviation of 10. Higher norm-based summary scores indicated better health

Measure: Change in Observed Scores for Patient Quality of Life Assessed by SF-8 - Safety Set

Time: From baseline to time to when MR4.5 is confirmed and from end of Consolidation Phase to 6 and 12 months into the TFR Phase

Description: The EuroQol Five Dimensional Three-level (EQ-5D-3L) questionnaire comprises 5 items: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each item has 3 levels (no problems, some problems and extreme problems). The percentages of patients at each level of the five items of the EQ-5D-3L will be summarized at each time point

Measure: Percentage of Participants' Scores at Each Level Assessed by EQ-5D-3L for Month 3 in Consolidation Phase - Safety Set

Time: At month 3 in Consolidation Phase

Description: The EuroQol Five Dimensional Three-level (EQ-5D-3L) questionnaire comprises 5 items: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each item has 3 levels (no problems, some problems and extreme problems). The percentages of patients at each level of the five items of the EQ-5D-3L will be summarized at each time point

Measure: Percentage of Participants' Scores at Each Level Assessed by EQ-5D-3L for Month 12 in Consolidation Phase - Safety Set

Time: Month 12 in Consolidation Phase

Description: The EuroQol Five Dimensional Three-level (EQ-5D-3L) questionnaire comprises 5 items: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each item has 3 levels (no problems, some problems and extreme problems). The percentages of patients at each level of the five items of the EQ-5D-3L will be summarized at each time point

Measure: Percentage of Participants' Scores at Each Level Assessed by EQ-5D-3L for Month 24 in Consolidation Phase - Safety Set

Time: Month 24 in Consolidation Phase

Description: The EuroQol Five Dimensional Three-level questionnaire (EQ-5D-3L) comprises 5 items: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each item has 3 levels (no problems, some problems and extreme problems). The percentages of patients at each level of the five items of the EQ-5D-3L will be summarized at each time point

Measure: Percentage of Participants' Scores at Each Level Assessed by EQ-5D-3L for Month 6 in Treatment Free Remission Phase - Safety Set

Time: Month 6 in in Treatment Free Remission Phase

Description: The EuroQol Five Dimensional Three-level questionnaire (EQ-5D-3L) comprises 5 items: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each item has 3 levels (no problems, some problems and extreme problems). The percentages of patients at each level of the five items of the EQ-5D-3L will be summarized at each time point

Measure: Percentage of Participants' Scores at Each Level Assessed by EQ-5D-3L for Month 12 in Treatment Free Remission Phase - Safety Set

Time: Month 12 in in Treatment Free Remission Phase

45 A Phase I, Dose-finding Study of the Oral, Dual Phosphatidylinositol 3(PI3)-Kinase / Mammilian Target of Rapamycin (mTOR) Inhibitor BEZ235 in Adult Patients With Relapsed or Refractory Acute Leukemia

Primary objectives: - To establish the maximum tolerated dose (MTD), and the recommended Phase 2 dose (RP2D) of BEZ235 when administered twice daily (BID) as a single agent in patients with relapsed or refractory acute leukemia - To determine the dose-limiting toxicity (DLT) Secondary objectives: - Assess the safety and tolerability of daily oral administration of BEZ235 with a BID schedule - To describe preliminary anti-leukemic activity of BEZ235 in patients with acute leukemia - To correlate changes in pharmacodynamic biomarkers with basic pharmacokinetic data Exploratory objectives: - To assess pre-treatment phosphatidylinositol 3-kinase (PI3K) pathway-related genes in blast cells and all other malignant cells derived from blood or bone marrow. - To assess the pharmacodynamic changes in components of the PI3K-protein kinase B (AKT)-mTOR pathway in bone marrow following treatment as potential predictive biomarkers of pharmacodynamic (PD) activity of BEZ235 in association with clinical responses. - To identify potential resistance mechanisms and biomarkers that may correlate with efficacy and response from blood and bone marrow samples pre-and post-treatment in case of resistance

NCT01756118 Acute Lymphoblastic Leukemia Leukemia, Myelocytic, Acute Chronic Myelogenous Leukemia With Crisis of Blast Cells Drug: BEZ235
MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Acute
HPO:Acute megakaryocytic leukemia Acute myeloid leukemia Chronic myelogenous leukemia Leukemia Myeloid leukemia

If a point mutation threonine 315 to isoleucine (T315I) bcr-abl mutation has been identified, prior treatment with a second TKI is not required. --- T315I ---

or: 3. Patients with Philadelphia chromosome and/or bcr-abl positive B-precursor ALL or prior CML-BP with presence of minimal residual disease (MRD) and the presence of T315I mutation or a high-resistance mutation shown to be unresponsive to approved thyrosine kinase inhibitors (TKI). --- T315I ---

Primary Outcomes

Measure: Recommended Phase 2 dose (RP2D) of BEZ235 in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and chronic myeloid leukemia in blastic phase (CML-BP)

Time: 6 months after inclusion of first patient

Measure: Incidence of dose-limiting toxicity (DLT)

Time: 6 months after inclusion of first patient

Secondary Outcomes

Measure: Adverse events as graded by NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.

Time: 1.5 years

Measure: Investigator-reported best overall response (BOR) as determined from the response categories during treatment period.

Time: 1.5 years

Measure: Time to progression

Time: 1.5 years

Measure: Remission duration

Time: 1.5 years

Measure: Biomarker evaluation

Time: 1.5 years

Measure: BEZ235 and metabolite levels in plasma

Time: 1.5 years

Measure: Clinical laboratory tests as graded by NCI CTCAE v4.

Time: 1.5 years

46 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

More interesting and more important (Table 2), Nilotinib is more active that Imatinib against a number of BCR-ABL mutants, with the exception of the T315I. --- T315I ---

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

47 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 ---

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

48 A Phase 1B Dose Escalation Study to Investigate the Safety, Tolerability and Preliminary Efficacy for the Combination Dasatinib (BMS-354825) Plus Nivolumab (BMS-936558) in Patients Chronic Myeloid Leukemia (CML)

The purpose of this study is to find a dose of Nivolumab that can be safely added to Dasatinib in patients with Chronic Myeloid Leukemia.

NCT02011945 Chronic Myeloid Leukemia Drug: Dasatinib Drug: Nivolumab
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

T315I or T315A) For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com. --- T315I ---

T315I or T315A) Chronic Myeloid Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive null --- T315I ---

Primary Outcomes

Description: DLT will be determined based on the incidence and intensity of drug related adverse events (AEs). The following drug-related AEs (whether related to one or both agents) occurring during the first 6 weeks of combined treatment with both dasatinib plus nivolumab (ie, Weeks 3 to 8, inclusive) would be considered DLTs: Grade 4 hematologic AE lasting > 7 days despite appropriate medical intervention, except as noted below; Grade 3 or Grade 4 nonhematologic AE irrespective of duration; Grade 2 nonhematologic AE lasting > 7 days despite appropriate medical intervention (exception: asymptomatic laboratory values of Grade 2 which do not require medical intervention); Any toxicity managed by discontinuation of nivolumab; Grade ≥ 2 AE not controlled by medical intervention and requiring dasatinib treatment interruption for > 28 consecutive days; Grade ≥ 2 AE not controlled by medical intervention and requiring missing 2 consecutive doses of nivolumab.

Measure: Incidence of Dose Limiting Toxicities (DLT)

Time: Week 3 to week 6

Description: Any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation subject administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of investigational product, whether or not considered related to the investigational product.

Measure: Incidence of Adverse Events (AEs)

Time: Initiation of study drug to discontinuation of nivolumab stop date + 100 days or discontinuation of dasatinib + 30 days

Description: Any untoward medical occurrence that at any dose: results in death, is life threatening, requires in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is a important medical event.Requires inpatient hospitalization or causes prolongation of existing hospitalization, results.

Measure: Incidence of Serious Adverse Events (SAEs)

Time: Initiation of study drug to within 100 days of discontinuation of nivolumab dosing and 30 days of dasatinib dosing

Description: The number of participants with a shift in laboratory test results from baseline to Grade 3-4 in hematology

Measure: Incidence of Change From Baseline in Clinical Laboratory Tests: Hematology

Time: Up to 40 Months

Description: The number of participants with an abnormal Liver function test. Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Upper Limit of Normal (ULN)

Measure: Incidence of Abnormalities in Clinical Laboratory Tests: Liver Tests

Time: Up to 40 Months

Description: Free T3 (FT3) Free T4 (FT4) Lower Limit of Normal (LLN)

Measure: Incidence of Laboratory Abnormalities in Specific Thyroid Tests

Time: Up to 40 Months

Secondary Outcomes

Description: Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (RQ-PCR). MMR is defined as ≥ 3-log reduction in BCR-ABL transcripts or a ratio of ≤ 0.1% on the International Scale (IS).

Measure: Rate of Major Molecular Response (MMR) : Chronic Myelogenous Leukemia - Chronic Phase (CML-CP), No Prior Dasatinib Participants

Time: upto 36 Months

Description: Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (RQ-PCR). MMR is defined as ≥ 3-log reduction in BCR-ABL transcripts or a ratio of ≤ 0.1% on the International Scale (IS).

Measure: Rate of Major Molecular Response (MMR) : Chronic Myelogenous Leukemia - Chronic Phase (CML-CP), Prior Dasatinib Participants

Time: upto 36 Months

Description: Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (RQ-PCR). MMR is defined as ≥ 3-log reduction in BCR-ABL transcripts or a ratio of ≤ 0.1% on the International Scale (IS).

Measure: Rate of Major Molecular Response (MMR) : Chronic Myelogenous Leukemia - Advanced Phase (CML-AP) Participants

Time: upto 36 Months

Description: Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (RQ-PCR). A molecular response 4.5 (MR4.5) was defined as ≥ 4.5-log reduction in BCR-ABL transcripts or a ratio of ≤ 0.00316% on the International Scale (IS).

Measure: Rate of Molecular Response 4.5 (MR4.5) : Chronic Myelogenous Leukemia - Chronic Phase (CML-CP), No Prior Dasatinib Participants

Time: upto 36 Months

Description: Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (RQ-PCR). A molecular response 4.5 (MR4.5) was defined as ≥ 4.5-log reduction in BCR-ABL transcripts or a ratio of ≤ 0.00316% on the International Scale (IS).

Measure: Rate of Molecular Response 4.5 (MR4.5) : Chronic Myelogenous Leukemia - Chronic Phase (CML-CP), Prior Dasatinib Participants

Time: upto 36 Months

Description: Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (RQ-PCR). A molecular response 4.5 (MR4.5) was defined as ≥ 4.5-log reduction in BCR-ABL transcripts or a ratio of ≤ 0.00316% on the International Scale (IS).

Measure: Rate of Molecular Response 4.5 (MR4.5) : Chronic Myelogenous Leukemia - Advanced Phase (CML-AP) Participants

Time: upto 36 Months

Description: measured from the date of first dosing until measurement criteria are first met for MMR. The participants who do not respond will be censored on the date of their last molecular assessment. It is defined for all treated participants.

Measure: Time to Major Molecular Response (MMR) - CML-CP No Prior Dasatinib Participants

Time: Up to 36 Months

Description: measured from the date of first dosing until measurement criteria are first met for MMR. The participants who do not respond will be censored on the date of their last molecular assessment. It is defined for all treated participants.

Measure: Time to Major Molecular Response (MMR) - CML-CP Prior Dasatinib Participants

Time: Up to 36 Months

Description: measured from the date of first dosing until measurement criteria are first met for MMR. The participants who do not respond will be censored on the date of their last molecular assessment. It is defined for all treated participants.

Measure: Time to Major Molecular Response (MMR) - CML-AP Participants

Time: Up to 36 Months

Description: will be computed for participants who have achieved MMR. It will be defined as the time from the first assessment in which MMR, is documented until the first assessment at which disease progression (or confirmed loss of MMR) is documented. Participants who neither progress nor die will be censored on the date of their last molecular assessment

Measure: Duration of Major Molecular Response (MMR) - CML-CP No Prior Dasatinib Participants

Time: Up to 36 Months

Description: will be computed for participants who have achieved MMR. It will be defined as the time from the first assessment in which MMR, is documented until the first assessment at which disease progression (or confirmed loss of MMR) is documented. Participants who neither progress nor die will be censored on the date of their last molecular assessment

Measure: Duration of Major Molecular Response (MMR) - CML-CP Prior Dasatinib Participants

Time: Up to 36 Months

Description: will be computed for participants who have achieved MMR. It will be defined as the time from the first assessment in which MMR, is documented until the first assessment at which disease progression (or confirmed loss of MMR) is documented. Participants who neither progress nor die will be censored on the date of their last molecular assessment

Measure: Duration of Major Molecular Response (MMR) - CML-AP Participants

Time: Up to 36 Months

Description: measured from the date of first dosing until measurement criteria are first met for MR4.5. The participants who do not respond will be censored on the date of their last molecular assessment. It is defined for all treated participants.

Measure: Time to Molecular Response 4.5(MR4.5) - CML-CP No Prior Dasatinib Participants

Time: Up to 36 Months

Description: measured from the date of first dosing until measurement criteria are first met for MR4.5. The participants who do not respond will be censored on the date of their last molecular assessment. It is defined for all treated participants.

Measure: Time to Molecular Response 4.5(MR4.5) - CML-CP Prior Dasatinib Participants

Time: Up to 36 Months

Description: measured from the date of first dosing until measurement criteria are first met for MR4.5. The participants who do not respond will be censored on the date of their last molecular assessment. It is defined for all treated participants.

Measure: Time to Molecular Response 4.5(MR4.5) - CML-AP Participants

Time: Up to 36 Months

Description: will be computed for participants who have achieved MR4.5. It will be defined as the time from the first assessment in which MR4.5, is documented until the first assessment at which disease progression (or confirmed loss of MR4.5 documented. Participants who neither progress nor die will be censored on the date of their last molecular assessment

Measure: Duration of Molecular Response 4.5 (MR4.5) - CML-CP No Prior Dasatinib Participants

Time: Up to 36 Months

Description: will be computed for participants who have achieved MR4.5. It will be defined as the time from the first assessment in which MR4.5, is documented until the first assessment at which disease progression (or confirmed loss of MR4.5 documented. Participants who neither progress nor die will be censored on the date of their last molecular assessment

Measure: Duration of Molecular Response 4.5 (MR4.5) - CML-CP Prior Dasatinib Participants

Time: Up to 36 Months

Description: will be computed for participants who have achieved MR4.5. It will be defined as the time from the first assessment in which MR4.5, is documented until the first assessment at which disease progression (or confirmed loss of MR4.5 documented. Participants who neither progress nor die will be censored on the date of their last molecular assessment

Measure: Duration of Molecular Response 4.5 (MR4.5) - CML-AP Participants

Time: Up to 36 Months

49 A Phase I, Multicenter, Open-label Study of Oral ABL001 in Patients With Chronic Myelogenous Leukemia (CML) or Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL)

The design of a phase I, open label, dose finding study was chosen in order to establish a safe and tolerated dose of single agent ABL001 in CML and Ph+ ALL patients who are relapsed or refractory to or are intolerant of TKIs, and of ABL001+Nilotinib, ABL001+Imatinib and ABL001+Dasatinib in Ph positive CML patients who are relapsed or refractory to TKIs.

NCT02081378 Chronic Myelogenous Leukemia Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia Drug: ABL001 Drug: ABL001 + Nilotinib Drug: ABL001 Drug: ABL001+imatinib Drug: ABL001+dasatinib
MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Philadelphia Chromosome
HPO:Chronic myelogenous leukemia Leukemia Lymphoid leukemia Myeloid leukemia

Inclusion Criteria: For CML patients either: - a. Patients with Ph+ CML in chronic or accelerated phase who were previously treated with at least two different tyrosine kinase inhibitors prior to study entry and are relapsed, refractory to or intolerant of TKIs as determined by investigators or - b. Patients with CML in chronic or accelerated phase who exhibit relapsed disease associated with the presence of the T315I "gatekeeper mutation" after at least one TKI are also eligible provided that no other effective therapy exists For ALL and CML-BP patients: - Patients with CML BP or Ph+ ALL who have a cytopathologically confirmed diagnosis and are relapsed or refractory to at least one prior TKI or intolerant of TKIs. --- T315I ---

At least four weeks must have elapsed since prophylactic CNS irradiation given as part of a front-line therapy regimen for ALL - Major surgery within 2 weeks before the first dose of study treatment Other protocol-defined inclusion/exclusion criteria may apply Inclusion Criteria: For CML patients either: - a. Patients with Ph+ CML in chronic or accelerated phase who were previously treated with at least two different tyrosine kinase inhibitors prior to study entry and are relapsed, refractory to or intolerant of TKIs as determined by investigators or - b. Patients with CML in chronic or accelerated phase who exhibit relapsed disease associated with the presence of the T315I "gatekeeper mutation" after at least one TKI are also eligible provided that no other effective therapy exists For ALL and CML-BP patients: - Patients with CML BP or Ph+ ALL who have a cytopathologically confirmed diagnosis and are relapsed or refractory to at least one prior TKI or intolerant of TKIs. --- T315I ---

Primary Outcomes

Description: Determine the MTD and/or RDE of ABL001 as single agent in CML and Ph+ ALL, and in combination with either nilotinib or imatinib or dasatinib in CML patients

Measure: Incidence of dose limiting toxicities (DLTs) during the first cycle of study treatment

Time: First Cycle is 28 days

Secondary Outcomes

Measure: Hematologic Response

Time: At screening and first day of cycle 2 and 3 and every 12 weeks afterwards

Measure: Cytogenetic response

Time: at screening or when a patient's BCR-ABL ratio has risen to >1%

Measure: BCR-ABL transcript level

Time: At screening and first day of cycle 2 and 3 and every 12 weeks afterwards

Measure: Cmax of ABL001 as measured in plasma

Time: Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6.

Measure: Cmin of ABL001 as measured in plasma

Time: Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6.

Measure: AUCinf of ABL001 as measured in plasma

Time: Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6.

Measure: AUClast of ABL001 as measured in plasma

Time: Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6.

Measure: AUCtau of ABL001 as measured in plasma

Time: Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6.

Measure: T1/2 of ABL001 as measured in plasma

Time: Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6.

Measure: Adverse events

Time: Collected from screening visit through post-treatment follow-up period

50 Efficacy and Safety Assessment of NIlotinib in CML Patients With Suboptimal Response on Imatinib Therapy (NISRI)

whether Nilotinib at the two sequential dosage forms will induce quicker and deeper response in those patients, and if FISH on PB (Peripheral blood) would be an effective way to monitor response compared to conventional cytogenetics on bone marrow (BM) sample

NCT02086487 Myeloid Leukemia, Chronic Drug: Nilotinib 300 mg.
MeSH:Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia

5. Pregnant or lactating females 6. Patients with prolonged QT intervals 7. Patient with history of pancreatitis 8. Previously documented T315I mutations; 9. Uncontrolled congestive heart failure or hypertension; 10. --- T315I ---

Primary Outcomes

Measure: The primary efficacy variable of this study is the overall Major molecular response at 12 month after starting Nilotinib 300mg twice daily for patient who suboptimally responded to Imatinib as per the ELN guidelines

Time: 12 Months

Secondary Outcomes

Measure: Rate of cytogenetic response (complete cytogenetic response CCyR and Major cytogenetic response MCyR) and Major molecular response MMR at 3, 6 and 12 months of starting Nilotinib in patients who had a suboptimal response on Imatinib.

Time: 12Months

Measure: Rate of CCyR at 6 months and MMR at 6 and 12 months from Nilotinib dose escalating to 400 mg BID.

Time: 12 months

Measure: Rate and duration of Complete Hematologic Response CHR.

Time: 12 months

Measure: Rate of CMR at 12 months of Nilotinib.

Time: 12 months

Measure: Comparison of FISH results with conventional cytogenetics at 3, 6 & 12 months.

Time: 12

Measure: Overall survival.

Time: 12

Other Outcomes

Measure: Mutational analysis for the patients with suboptimal response at the pre defined end points as per the ELN guidelines.

Time: 12 months

51 Open-label Multicenter Trial to Evaluate the Improvement of Chronic Low-grade Adverse Events Experienced by Patients With Ph+ Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) With Optimal Response to Imatinib When Switched From Imatinib to Nilotinib Treatment

Primary Objective for this study is to evaluate changes in chronic low grade non-hematological adverse events experienced by patients who have been treated with at least 6 months of imatinib and who have not responded to supportive measures, when they are switched to nilotinib (CTCAE grading system).

NCT02115386 Philadelphia Positive (Ph+) Chronic Myeloid Leukemia Drug: Nilotinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Ability to provide written informed consent prior to any study related screening procedures being done Exclusion criteria: 1. Patients who have experienced any Grade 3 or higher non-hematologic toxicity 30 days prior to screening 2. Loss of response (hematologic, cytogenetic, molecular) any time prior to inclusion 3. Prior accelerated phase or blast phase CML 4. Previously documented T315I mutation 5. Chromosomal abnormalities (trisomy 8) and/or clonal evolution other than Ph+. 6. --- T315I ---

Primary Outcomes

Description: Improvement was defined as decreasing of grade of non-hematological toxicity from 2 to <2 or from 1 to <1. In case of multiple low-grade non-hematological toxicities improvement was defined as an improvement of at least one non-hematological AE and no worsening of any other persistent non-hematological AEs.

Measure: Number of Participants With Improvement of Grades of Persistent Non-hematological Adverse Event (AE) for Grade 1 and 2 at 6 Months

Time: at 6 month after switching from imatinib to nilotinib

Secondary Outcomes

Description: Improvement was defined as decreasing of grade of non-hematological toxicity from 2 to <2 or from 1 to <1. In case of multiple low-grade non-hematological toxicities improvement was defined as an improvement of at least one non-hematological AE and no worsening of any other persistent non-hematological AEs.

Measure: Number of Participants With Improvement of Grades of Persistent Non-hematological Adverse Event (AE) for Grade 1 and 2 at 3 Months

Time: at 3 month after switching from imatinib to nilotinib

Description: Cytogenetic response will be assessed as the percentage of Ph+ metaphases in the bone marrow and is defined as the following: Complete (CCyR) - 0% Ph+ metaphases.

Measure: Number of Participants With Complete Cytogenetic Response (CCyR)

Time: at months 6,12 and 24 after switching from imatinib to nilotinib

Description: MMR was defined as a ≥ 3.0 log reduction in BCR-ABL transcripts compared to the standardized baseline or ≤ 0.1 % BCR-ABL/ABL % by international scale as measured by RQ-PCR, confirmed by duplicate analysis of the same sample. Molecular response was described for all time points except screening where response was estimated.

Measure: Number of Participants With a Major Molecular Response

Time: Months 1, 3, 6, early termination

Description: to evaluate time to achievement and duration of CCyR and MMR after switching from imatinib to nilotinib

Measure: Time to and Duration of CCyR and MMR After Switch From Imatinib to Nilotinib at 24 Months

Time: at 24 Months

Description: Evaluate time to first improvement of low-grade non-hematologic adverse events, experienced by patients treated with imatinib and persistent despite of best supportive measures after switching to nilotinib therapy. Optimal improvement is defined as AE grade decreasing to 0.

Measure: Time to First Improvement of Persistant Chronic Low-grade Non-hematologic AEs at 24 Months After Switch From Imatinib to Nilotinib

Time: first improvement of AEs after switch to 24 Months

Description: EORTC-QLQ-C30 was administered to evaluate quality of life changes after switching to nilotinib. Scores ranged from 1 (very poor) to 6 (excellent)

Measure: Lisiting by Participant of EORTC-QLQ-C30 for Quality of Life

Time: Screening, months 1, 3, 6, after switch to nilotinib

52 A PHASE 4 SAFETY AND EFFICACY STUDY OF BOSUTINIB (BOSULIF (REGISTERED)) IN PATIENTS WITH PHILADELPHIA CHROMOSOME POSITIVE CHRONIC MYELOID LEUKEMIA PREVIOUSLY TREATED WITH ONE OR MORE TYROSINE KINASE INHIBITORS

The purpose of this study is to fulfill the post-authorization commitment made by Pfizer to the European Medicines Agency in providing additional safety and efficacy data in approximately 150 Philadelphia Chromosome Positive Chronic Myeloid Leukemia patients with high unmet medical need, including 75 Chronic Phase, Accelerated Phase or Blast Phase patients in the fourth or later line treatment setting (i.e., after treatment with at least 3 other Tyrosine Kinase Inhibitors).

NCT02228382 Previously Treated PH + CML Drug: Bosutinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Philadelphia Chromosome
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

- Known T315I or V299L mutation. --- T315I ---

Primary Outcomes

Description: Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive cells in metaphase from Bone Marrow sample.

Measure: Percentage of Participants with Major Cytogenetic Response (MCyR) by Week 52 in Chronic Phase Second-line Population and Chronic Phase Third-line Population of Philadelphia Chromosome Positive Chronic Myeloid Leukemia patients.

Time: Week 52

Description: Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive cells in metaphase from Bone Marrow sample.

Measure: Percentage of Participants with Major Cytogenetic Response (MCyR) by Week 52 in Chronic Phase Fourth-line and later-line Population of Philadelphia Chromosome Positive Chronic Myeloid Leukemia patients.

Time: Week 52

Description: OHR includes Complete Hematological Response (CHR) or return to chronic phase (RCP).

Measure: Percentage of Participants with Overall Hematologic Response (OHR) by Week 52 in Advanced Leukemia Population patients.

Time: Week 52

Secondary Outcomes

Description: Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive cells in metaphase from Bone Marrow sample.

Measure: Estimate cumulative probability of Percentage of Participants with Major Cytogenetic Response in Chronic Phase and Advanced Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient populations.

Time: Week 52

Description: OHR includes Complete Hematological Response (CHR) or return to chronic phase (RCP).

Measure: Estimate cumulative probability of Percentage of Participants with Overall Hematologic Response in the Accelerated Phase and Blast Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient population by number of lines of prior therapy.

Time: Week 52

Measure: Characterize distribution of best response (molecular, cytogenetic, or hematologic) in the Chronic Phase, Accelerated Phase and Blast Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient populations.

Time: Week 52

Measure: Estimating probability of Percentage of Participants with Major Cytogenetic Response at 3, 6, 12, 18, and 24 months in the Chronic Phase, Accelerated Phase and Blast Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient populations.

Time: Month 3, 6, 12, 18, and 24

Measure: Estimating the probability of confirmed Overall Hematologic Response at 3, 6, 9, 12, 18, and 24 months in the Accelerated Phase and Blast Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient populations.

Time: Month 3, 6, 9, 12, 18, and 24

Measure: Estimating the probability of cumulative confirmed Complete Hematologic Response in the Chronic Phase, Accelerated Phase and Blast Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient populations.

Time: Week 52

Measure: Estimating the probability of cumulative major molecular response in the Chronic Phase, Accelerated Phase and Blast Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient populations.

Time: Week 52

53 A Phase I/II Study of Bosutinib in Combination With Inotuzumab Ozogamicin in CD22-Positive Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia and Chronic Myeloid Leukemia Lymphoid Blast Phase

This phase I/II trial studies the side effects and best dose of bosutinib when given together with inotuzumab ozogamicin and to see how well it works in treating patients with acute lymphoblastic leukemia or chronic myeloid leukemia that has come back or does not respond to treatment. Bosutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotoxins, such as inotuzumab ozogamicin, are antibodies linked to a toxic substance and may help find cancer cells that express CD22 and kill them without harming normal cells. Giving bosutinib together with inotuzumab ozogamicin may be a better treatment for acute lymphoblastic leukemia or chronic myeloid leukemia.

NCT02311998 B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1 Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Blasts More Than 5 Percent of Bone Marrow Nucleated Cells CD22 Positive Philadelphia Chromosome Positive, BCR-ABL1 Positive Chronic Myelogenous Leukemia Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive Drug: Bosutinib Biological: Inotuzumab Ozogamicin Other: Laboratory Biomarker Analysis
MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Blast Crisis Philadelphia Chromosome
HPO:Chronic myelogenous leukemia Leukemia Lymphoid leukemia Myeloid leukemia

Cox regression models will be used to determine the relationship with the time-to-events (e.g., OS) and the potential prognostic factors.. Inclusion Criteria: - Relapsed or refractory B-cell ALL or CML in lymphoid blast phase; Philadelphia chromosome must be present at screening (as determined by cytogenetic analysis, fluorescence in situ hybridization [FISH], or polymerase chain reaction [PCR] [i.e., BCR-ABL positive]); Note: patients with CML who have received treatment with tyrosine kinase inhibitors for their CML, and have progressed to lymphoid blast phase are eligible for frontline treatment; Frontline Ph+ ALL or CML-lymphoid blast phase (LBC) Cohort: Patients with newly-diagnosed Ph+ ALL or CML-LBC, who have received no or minimal treatment (minimal treatment is defined as treatment with steroids/hydroxyurea of =< 2 week duration; vincristine =< 2 doses; tyrosine kinase inhibitor of =< 4 week duration; =< 2 doses of cytarabine) and are >= 60 years or older are eligible; patients must have bone marrow blasts > 5% at the time of screening - Expression of CD-22 in >= 20% blasts - Eastern Cooperative Oncology Group (ECOG) performance status score of < or = 2 - Serum bilirubin < or = 2.0 mg/dl - Serum creatinine < or = 2.0 mg/dl - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < or = 3 x upper limit of normal (ULN) - Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (beta-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use one of the following effective contraception methods during the study and for 30 days following the last dose of study drug; effective methods of birth control include: birth control pills, shots, implants (placed under the skin by a health care provider) or patches (placed on the skin); intrauterine devices (IUDs); condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide; females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy - Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug - Patients or their legally authorized representative must provide written informed consent Exclusion Criteria: - History of another primary invasive malignancy that has not been definitively treated or in remission for at least 2 years; patients with non-melanoma skin cancers or with carcinomas in situ are eligible regardless of the time from diagnosis (including concomitant diagnoses) - Patients with active unstable angina, concomitant clinically significant active arrhythmias, myocardial infarction within 6 months, or congestive heart failure New York Heart Association class III-IV; patients with a cardiac ejection fraction (as measured by either multi gated acquisition scan [MUGA] or echocardiogram) < 40% are excluded - Known evidence of active cerebral/meningeal disease; patients may have history of central nervous system (CNS) leukemic involvement if definitively treated with prior therapy and no evidence of active disease (defined as >= 2 consecutive spinal fluid assessments with no evidence of disease) at that time of registration - Previous treatment with any anti-CD22 directed therapy - Patients with previous allogeneic stem cell transplant (SCT) if they meet either of the following criteria: - < 100 days from allogeneic SCT - Active acute or chronic graft-versus-host disease (GvHD), or - Receiving immunosuppressive therapy as treatment for GvHD within the last 7 days - Patients with uncontrolled active infections (viral, bacterial, or fungal) are not eligible - Active hepatitis B or C infection, or known seropositivity for human immunodeficiency virus (HIV) - Patients with liver cirrhosis or other serious active liver disease or with suspected alcohol abuse - History of autoimmune diseases (such as systemic lupus erythematosus [SLE], Wegener's, Wegener's granulomatosis, polyarteritis nodosa); Note: Prior autoimmune diseases are allowed as long as clinically stable - Prior chemotherapy/radiotherapy/investigational therapy within 2 weeks before the start of study drugs with the following exceptions: - To reduce the circulating lymphoblast count or palliation: steroids, hydroxyurea; no washout necessary for these agents - For ALL maintenance/CML treatment: mercaptopurine, methotrexate, vincristine, single-agent, single-dose of cytarabine and/or tyrosine kinase inhibitors; these agents should be discontinued at least 48 hours prior to start of study drugs; (Note: the interval of time from last dose of any approved tyrosine kinase inhibitor [TKI] to start of protocol treatment is 48 hours regardless of the indication for treatment with the TKI) - Patients who have not recovered from acute non hematologic toxicity (to =< grade 1) of all previous therapy prior to enrollment - Females who are pregnant or lactating - Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study - Patients previously exposed to bosutinib are eligible unless they carry T315I - Patients with T315I mutations will be excluded (this criteria is not applicable for the frontline Ph+ ALL or CML-LBC cohort) Inclusion Criteria: - Relapsed or refractory B-cell ALL or CML in lymphoid blast phase; Philadelphia chromosome must be present at screening (as determined by cytogenetic analysis, fluorescence in situ hybridization [FISH], or polymerase chain reaction [PCR] [i.e., BCR-ABL positive]); Note: patients with CML who have received treatment with tyrosine kinase inhibitors for their CML, and have progressed to lymphoid blast phase are eligible for frontline treatment; Frontline Ph+ ALL or CML-lymphoid blast phase (LBC) Cohort: Patients with newly-diagnosed Ph+ ALL or CML-LBC, who have received no or minimal treatment (minimal treatment is defined as treatment with steroids/hydroxyurea of =< 2 week duration; vincristine =< 2 doses; tyrosine kinase inhibitor of =< 4 week duration; =< 2 doses of cytarabine) and are >= 60 years or older are eligible; patients must have bone marrow blasts > 5% at the time of screening - Expression of CD-22 in >= 20% blasts - Eastern Cooperative Oncology Group (ECOG) performance status score of < or = 2 - Serum bilirubin < or = 2.0 mg/dl - Serum creatinine < or = 2.0 mg/dl - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < or = 3 x upper limit of normal (ULN) - Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (beta-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use one of the following effective contraception methods during the study and for 30 days following the last dose of study drug; effective methods of birth control include: birth control pills, shots, implants (placed under the skin by a health care provider) or patches (placed on the skin); intrauterine devices (IUDs); condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide; females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy - Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug - Patients or their legally authorized representative must provide written informed consent Exclusion Criteria: - History of another primary invasive malignancy that has not been definitively treated or in remission for at least 2 years; patients with non-melanoma skin cancers or with carcinomas in situ are eligible regardless of the time from diagnosis (including concomitant diagnoses) - Patients with active unstable angina, concomitant clinically significant active arrhythmias, myocardial infarction within 6 months, or congestive heart failure New York Heart Association class III-IV; patients with a cardiac ejection fraction (as measured by either multi gated acquisition scan [MUGA] or echocardiogram) < 40% are excluded - Known evidence of active cerebral/meningeal disease; patients may have history of central nervous system (CNS) leukemic involvement if definitively treated with prior therapy and no evidence of active disease (defined as >= 2 consecutive spinal fluid assessments with no evidence of disease) at that time of registration - Previous treatment with any anti-CD22 directed therapy - Patients with previous allogeneic stem cell transplant (SCT) if they meet either of the following criteria: - < 100 days from allogeneic SCT - Active acute or chronic graft-versus-host disease (GvHD), or - Receiving immunosuppressive therapy as treatment for GvHD within the last 7 days - Patients with uncontrolled active infections (viral, bacterial, or fungal) are not eligible - Active hepatitis B or C infection, or known seropositivity for human immunodeficiency virus (HIV) - Patients with liver cirrhosis or other serious active liver disease or with suspected alcohol abuse - History of autoimmune diseases (such as systemic lupus erythematosus [SLE], Wegener's, Wegener's granulomatosis, polyarteritis nodosa); Note: Prior autoimmune diseases are allowed as long as clinically stable - Prior chemotherapy/radiotherapy/investigational therapy within 2 weeks before the start of study drugs with the following exceptions: - To reduce the circulating lymphoblast count or palliation: steroids, hydroxyurea; no washout necessary for these agents - For ALL maintenance/CML treatment: mercaptopurine, methotrexate, vincristine, single-agent, single-dose of cytarabine and/or tyrosine kinase inhibitors; these agents should be discontinued at least 48 hours prior to start of study drugs; (Note: the interval of time from last dose of any approved tyrosine kinase inhibitor [TKI] to start of protocol treatment is 48 hours regardless of the indication for treatment with the TKI) - Patients who have not recovered from acute non hematologic toxicity (to =< grade 1) of all previous therapy prior to enrollment - Females who are pregnant or lactating - Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study - Patients previously exposed to bosutinib are eligible unless they carry T315I - Patients with T315I mutations will be excluded (this criteria is not applicable for the frontline Ph+ ALL or CML-LBC cohort) B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); --- T315I ---

Cox regression models will be used to determine the relationship with the time-to-events (e.g., OS) and the potential prognostic factors.. Inclusion Criteria: - Relapsed or refractory B-cell ALL or CML in lymphoid blast phase; Philadelphia chromosome must be present at screening (as determined by cytogenetic analysis, fluorescence in situ hybridization [FISH], or polymerase chain reaction [PCR] [i.e., BCR-ABL positive]); Note: patients with CML who have received treatment with tyrosine kinase inhibitors for their CML, and have progressed to lymphoid blast phase are eligible for frontline treatment; Frontline Ph+ ALL or CML-lymphoid blast phase (LBC) Cohort: Patients with newly-diagnosed Ph+ ALL or CML-LBC, who have received no or minimal treatment (minimal treatment is defined as treatment with steroids/hydroxyurea of =< 2 week duration; vincristine =< 2 doses; tyrosine kinase inhibitor of =< 4 week duration; =< 2 doses of cytarabine) and are >= 60 years or older are eligible; patients must have bone marrow blasts > 5% at the time of screening - Expression of CD-22 in >= 20% blasts - Eastern Cooperative Oncology Group (ECOG) performance status score of < or = 2 - Serum bilirubin < or = 2.0 mg/dl - Serum creatinine < or = 2.0 mg/dl - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < or = 3 x upper limit of normal (ULN) - Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (beta-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use one of the following effective contraception methods during the study and for 30 days following the last dose of study drug; effective methods of birth control include: birth control pills, shots, implants (placed under the skin by a health care provider) or patches (placed on the skin); intrauterine devices (IUDs); condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide; females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy - Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug - Patients or their legally authorized representative must provide written informed consent Exclusion Criteria: - History of another primary invasive malignancy that has not been definitively treated or in remission for at least 2 years; patients with non-melanoma skin cancers or with carcinomas in situ are eligible regardless of the time from diagnosis (including concomitant diagnoses) - Patients with active unstable angina, concomitant clinically significant active arrhythmias, myocardial infarction within 6 months, or congestive heart failure New York Heart Association class III-IV; patients with a cardiac ejection fraction (as measured by either multi gated acquisition scan [MUGA] or echocardiogram) < 40% are excluded - Known evidence of active cerebral/meningeal disease; patients may have history of central nervous system (CNS) leukemic involvement if definitively treated with prior therapy and no evidence of active disease (defined as >= 2 consecutive spinal fluid assessments with no evidence of disease) at that time of registration - Previous treatment with any anti-CD22 directed therapy - Patients with previous allogeneic stem cell transplant (SCT) if they meet either of the following criteria: - < 100 days from allogeneic SCT - Active acute or chronic graft-versus-host disease (GvHD), or - Receiving immunosuppressive therapy as treatment for GvHD within the last 7 days - Patients with uncontrolled active infections (viral, bacterial, or fungal) are not eligible - Active hepatitis B or C infection, or known seropositivity for human immunodeficiency virus (HIV) - Patients with liver cirrhosis or other serious active liver disease or with suspected alcohol abuse - History of autoimmune diseases (such as systemic lupus erythematosus [SLE], Wegener's, Wegener's granulomatosis, polyarteritis nodosa); Note: Prior autoimmune diseases are allowed as long as clinically stable - Prior chemotherapy/radiotherapy/investigational therapy within 2 weeks before the start of study drugs with the following exceptions: - To reduce the circulating lymphoblast count or palliation: steroids, hydroxyurea; no washout necessary for these agents - For ALL maintenance/CML treatment: mercaptopurine, methotrexate, vincristine, single-agent, single-dose of cytarabine and/or tyrosine kinase inhibitors; these agents should be discontinued at least 48 hours prior to start of study drugs; (Note: the interval of time from last dose of any approved tyrosine kinase inhibitor [TKI] to start of protocol treatment is 48 hours regardless of the indication for treatment with the TKI) - Patients who have not recovered from acute non hematologic toxicity (to =< grade 1) of all previous therapy prior to enrollment - Females who are pregnant or lactating - Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study - Patients previously exposed to bosutinib are eligible unless they carry T315I - Patients with T315I mutations will be excluded (this criteria is not applicable for the frontline Ph+ ALL or CML-LBC cohort) Inclusion Criteria: - Relapsed or refractory B-cell ALL or CML in lymphoid blast phase; Philadelphia chromosome must be present at screening (as determined by cytogenetic analysis, fluorescence in situ hybridization [FISH], or polymerase chain reaction [PCR] [i.e., BCR-ABL positive]); Note: patients with CML who have received treatment with tyrosine kinase inhibitors for their CML, and have progressed to lymphoid blast phase are eligible for frontline treatment; Frontline Ph+ ALL or CML-lymphoid blast phase (LBC) Cohort: Patients with newly-diagnosed Ph+ ALL or CML-LBC, who have received no or minimal treatment (minimal treatment is defined as treatment with steroids/hydroxyurea of =< 2 week duration; vincristine =< 2 doses; tyrosine kinase inhibitor of =< 4 week duration; =< 2 doses of cytarabine) and are >= 60 years or older are eligible; patients must have bone marrow blasts > 5% at the time of screening - Expression of CD-22 in >= 20% blasts - Eastern Cooperative Oncology Group (ECOG) performance status score of < or = 2 - Serum bilirubin < or = 2.0 mg/dl - Serum creatinine < or = 2.0 mg/dl - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < or = 3 x upper limit of normal (ULN) - Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (beta-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use one of the following effective contraception methods during the study and for 30 days following the last dose of study drug; effective methods of birth control include: birth control pills, shots, implants (placed under the skin by a health care provider) or patches (placed on the skin); intrauterine devices (IUDs); condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide; females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy - Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug - Patients or their legally authorized representative must provide written informed consent Exclusion Criteria: - History of another primary invasive malignancy that has not been definitively treated or in remission for at least 2 years; patients with non-melanoma skin cancers or with carcinomas in situ are eligible regardless of the time from diagnosis (including concomitant diagnoses) - Patients with active unstable angina, concomitant clinically significant active arrhythmias, myocardial infarction within 6 months, or congestive heart failure New York Heart Association class III-IV; patients with a cardiac ejection fraction (as measured by either multi gated acquisition scan [MUGA] or echocardiogram) < 40% are excluded - Known evidence of active cerebral/meningeal disease; patients may have history of central nervous system (CNS) leukemic involvement if definitively treated with prior therapy and no evidence of active disease (defined as >= 2 consecutive spinal fluid assessments with no evidence of disease) at that time of registration - Previous treatment with any anti-CD22 directed therapy - Patients with previous allogeneic stem cell transplant (SCT) if they meet either of the following criteria: - < 100 days from allogeneic SCT - Active acute or chronic graft-versus-host disease (GvHD), or - Receiving immunosuppressive therapy as treatment for GvHD within the last 7 days - Patients with uncontrolled active infections (viral, bacterial, or fungal) are not eligible - Active hepatitis B or C infection, or known seropositivity for human immunodeficiency virus (HIV) - Patients with liver cirrhosis or other serious active liver disease or with suspected alcohol abuse - History of autoimmune diseases (such as systemic lupus erythematosus [SLE], Wegener's, Wegener's granulomatosis, polyarteritis nodosa); Note: Prior autoimmune diseases are allowed as long as clinically stable - Prior chemotherapy/radiotherapy/investigational therapy within 2 weeks before the start of study drugs with the following exceptions: - To reduce the circulating lymphoblast count or palliation: steroids, hydroxyurea; no washout necessary for these agents - For ALL maintenance/CML treatment: mercaptopurine, methotrexate, vincristine, single-agent, single-dose of cytarabine and/or tyrosine kinase inhibitors; these agents should be discontinued at least 48 hours prior to start of study drugs; (Note: the interval of time from last dose of any approved tyrosine kinase inhibitor [TKI] to start of protocol treatment is 48 hours regardless of the indication for treatment with the TKI) - Patients who have not recovered from acute non hematologic toxicity (to =< grade 1) of all previous therapy prior to enrollment - Females who are pregnant or lactating - Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study - Patients previously exposed to bosutinib are eligible unless they carry T315I - Patients with T315I mutations will be excluded (this criteria is not applicable for the frontline Ph+ ALL or CML-LBC cohort) B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); --- T315I --- --- T315I ---

Cox regression models will be used to determine the relationship with the time-to-events (e.g., OS) and the potential prognostic factors.. Inclusion Criteria: - Relapsed or refractory B-cell ALL or CML in lymphoid blast phase; Philadelphia chromosome must be present at screening (as determined by cytogenetic analysis, fluorescence in situ hybridization [FISH], or polymerase chain reaction [PCR] [i.e., BCR-ABL positive]); Note: patients with CML who have received treatment with tyrosine kinase inhibitors for their CML, and have progressed to lymphoid blast phase are eligible for frontline treatment; Frontline Ph+ ALL or CML-lymphoid blast phase (LBC) Cohort: Patients with newly-diagnosed Ph+ ALL or CML-LBC, who have received no or minimal treatment (minimal treatment is defined as treatment with steroids/hydroxyurea of =< 2 week duration; vincristine =< 2 doses; tyrosine kinase inhibitor of =< 4 week duration; =< 2 doses of cytarabine) and are >= 60 years or older are eligible; patients must have bone marrow blasts > 5% at the time of screening - Expression of CD-22 in >= 20% blasts - Eastern Cooperative Oncology Group (ECOG) performance status score of < or = 2 - Serum bilirubin < or = 2.0 mg/dl - Serum creatinine < or = 2.0 mg/dl - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < or = 3 x upper limit of normal (ULN) - Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (beta-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use one of the following effective contraception methods during the study and for 30 days following the last dose of study drug; effective methods of birth control include: birth control pills, shots, implants (placed under the skin by a health care provider) or patches (placed on the skin); intrauterine devices (IUDs); condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide; females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy - Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug - Patients or their legally authorized representative must provide written informed consent Exclusion Criteria: - History of another primary invasive malignancy that has not been definitively treated or in remission for at least 2 years; patients with non-melanoma skin cancers or with carcinomas in situ are eligible regardless of the time from diagnosis (including concomitant diagnoses) - Patients with active unstable angina, concomitant clinically significant active arrhythmias, myocardial infarction within 6 months, or congestive heart failure New York Heart Association class III-IV; patients with a cardiac ejection fraction (as measured by either multi gated acquisition scan [MUGA] or echocardiogram) < 40% are excluded - Known evidence of active cerebral/meningeal disease; patients may have history of central nervous system (CNS) leukemic involvement if definitively treated with prior therapy and no evidence of active disease (defined as >= 2 consecutive spinal fluid assessments with no evidence of disease) at that time of registration - Previous treatment with any anti-CD22 directed therapy - Patients with previous allogeneic stem cell transplant (SCT) if they meet either of the following criteria: - < 100 days from allogeneic SCT - Active acute or chronic graft-versus-host disease (GvHD), or - Receiving immunosuppressive therapy as treatment for GvHD within the last 7 days - Patients with uncontrolled active infections (viral, bacterial, or fungal) are not eligible - Active hepatitis B or C infection, or known seropositivity for human immunodeficiency virus (HIV) - Patients with liver cirrhosis or other serious active liver disease or with suspected alcohol abuse - History of autoimmune diseases (such as systemic lupus erythematosus [SLE], Wegener's, Wegener's granulomatosis, polyarteritis nodosa); Note: Prior autoimmune diseases are allowed as long as clinically stable - Prior chemotherapy/radiotherapy/investigational therapy within 2 weeks before the start of study drugs with the following exceptions: - To reduce the circulating lymphoblast count or palliation: steroids, hydroxyurea; no washout necessary for these agents - For ALL maintenance/CML treatment: mercaptopurine, methotrexate, vincristine, single-agent, single-dose of cytarabine and/or tyrosine kinase inhibitors; these agents should be discontinued at least 48 hours prior to start of study drugs; (Note: the interval of time from last dose of any approved tyrosine kinase inhibitor [TKI] to start of protocol treatment is 48 hours regardless of the indication for treatment with the TKI) - Patients who have not recovered from acute non hematologic toxicity (to =< grade 1) of all previous therapy prior to enrollment - Females who are pregnant or lactating - Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study - Patients previously exposed to bosutinib are eligible unless they carry T315I - Patients with T315I mutations will be excluded (this criteria is not applicable for the frontline Ph+ ALL or CML-LBC cohort) Inclusion Criteria: - Relapsed or refractory B-cell ALL or CML in lymphoid blast phase; Philadelphia chromosome must be present at screening (as determined by cytogenetic analysis, fluorescence in situ hybridization [FISH], or polymerase chain reaction [PCR] [i.e., BCR-ABL positive]); Note: patients with CML who have received treatment with tyrosine kinase inhibitors for their CML, and have progressed to lymphoid blast phase are eligible for frontline treatment; Frontline Ph+ ALL or CML-lymphoid blast phase (LBC) Cohort: Patients with newly-diagnosed Ph+ ALL or CML-LBC, who have received no or minimal treatment (minimal treatment is defined as treatment with steroids/hydroxyurea of =< 2 week duration; vincristine =< 2 doses; tyrosine kinase inhibitor of =< 4 week duration; =< 2 doses of cytarabine) and are >= 60 years or older are eligible; patients must have bone marrow blasts > 5% at the time of screening - Expression of CD-22 in >= 20% blasts - Eastern Cooperative Oncology Group (ECOG) performance status score of < or = 2 - Serum bilirubin < or = 2.0 mg/dl - Serum creatinine < or = 2.0 mg/dl - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < or = 3 x upper limit of normal (ULN) - Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (beta-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use one of the following effective contraception methods during the study and for 30 days following the last dose of study drug; effective methods of birth control include: birth control pills, shots, implants (placed under the skin by a health care provider) or patches (placed on the skin); intrauterine devices (IUDs); condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide; females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy - Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug - Patients or their legally authorized representative must provide written informed consent Exclusion Criteria: - History of another primary invasive malignancy that has not been definitively treated or in remission for at least 2 years; patients with non-melanoma skin cancers or with carcinomas in situ are eligible regardless of the time from diagnosis (including concomitant diagnoses) - Patients with active unstable angina, concomitant clinically significant active arrhythmias, myocardial infarction within 6 months, or congestive heart failure New York Heart Association class III-IV; patients with a cardiac ejection fraction (as measured by either multi gated acquisition scan [MUGA] or echocardiogram) < 40% are excluded - Known evidence of active cerebral/meningeal disease; patients may have history of central nervous system (CNS) leukemic involvement if definitively treated with prior therapy and no evidence of active disease (defined as >= 2 consecutive spinal fluid assessments with no evidence of disease) at that time of registration - Previous treatment with any anti-CD22 directed therapy - Patients with previous allogeneic stem cell transplant (SCT) if they meet either of the following criteria: - < 100 days from allogeneic SCT - Active acute or chronic graft-versus-host disease (GvHD), or - Receiving immunosuppressive therapy as treatment for GvHD within the last 7 days - Patients with uncontrolled active infections (viral, bacterial, or fungal) are not eligible - Active hepatitis B or C infection, or known seropositivity for human immunodeficiency virus (HIV) - Patients with liver cirrhosis or other serious active liver disease or with suspected alcohol abuse - History of autoimmune diseases (such as systemic lupus erythematosus [SLE], Wegener's, Wegener's granulomatosis, polyarteritis nodosa); Note: Prior autoimmune diseases are allowed as long as clinically stable - Prior chemotherapy/radiotherapy/investigational therapy within 2 weeks before the start of study drugs with the following exceptions: - To reduce the circulating lymphoblast count or palliation: steroids, hydroxyurea; no washout necessary for these agents - For ALL maintenance/CML treatment: mercaptopurine, methotrexate, vincristine, single-agent, single-dose of cytarabine and/or tyrosine kinase inhibitors; these agents should be discontinued at least 48 hours prior to start of study drugs; (Note: the interval of time from last dose of any approved tyrosine kinase inhibitor [TKI] to start of protocol treatment is 48 hours regardless of the indication for treatment with the TKI) - Patients who have not recovered from acute non hematologic toxicity (to =< grade 1) of all previous therapy prior to enrollment - Females who are pregnant or lactating - Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study - Patients previously exposed to bosutinib are eligible unless they carry T315I - Patients with T315I mutations will be excluded (this criteria is not applicable for the frontline Ph+ ALL or CML-LBC cohort) B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); --- T315I --- --- T315I --- --- T315I ---

Cox regression models will be used to determine the relationship with the time-to-events (e.g., OS) and the potential prognostic factors.. Inclusion Criteria: - Relapsed or refractory B-cell ALL or CML in lymphoid blast phase; Philadelphia chromosome must be present at screening (as determined by cytogenetic analysis, fluorescence in situ hybridization [FISH], or polymerase chain reaction [PCR] [i.e., BCR-ABL positive]); Note: patients with CML who have received treatment with tyrosine kinase inhibitors for their CML, and have progressed to lymphoid blast phase are eligible for frontline treatment; Frontline Ph+ ALL or CML-lymphoid blast phase (LBC) Cohort: Patients with newly-diagnosed Ph+ ALL or CML-LBC, who have received no or minimal treatment (minimal treatment is defined as treatment with steroids/hydroxyurea of =< 2 week duration; vincristine =< 2 doses; tyrosine kinase inhibitor of =< 4 week duration; =< 2 doses of cytarabine) and are >= 60 years or older are eligible; patients must have bone marrow blasts > 5% at the time of screening - Expression of CD-22 in >= 20% blasts - Eastern Cooperative Oncology Group (ECOG) performance status score of < or = 2 - Serum bilirubin < or = 2.0 mg/dl - Serum creatinine < or = 2.0 mg/dl - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < or = 3 x upper limit of normal (ULN) - Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (beta-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use one of the following effective contraception methods during the study and for 30 days following the last dose of study drug; effective methods of birth control include: birth control pills, shots, implants (placed under the skin by a health care provider) or patches (placed on the skin); intrauterine devices (IUDs); condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide; females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy - Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug - Patients or their legally authorized representative must provide written informed consent Exclusion Criteria: - History of another primary invasive malignancy that has not been definitively treated or in remission for at least 2 years; patients with non-melanoma skin cancers or with carcinomas in situ are eligible regardless of the time from diagnosis (including concomitant diagnoses) - Patients with active unstable angina, concomitant clinically significant active arrhythmias, myocardial infarction within 6 months, or congestive heart failure New York Heart Association class III-IV; patients with a cardiac ejection fraction (as measured by either multi gated acquisition scan [MUGA] or echocardiogram) < 40% are excluded - Known evidence of active cerebral/meningeal disease; patients may have history of central nervous system (CNS) leukemic involvement if definitively treated with prior therapy and no evidence of active disease (defined as >= 2 consecutive spinal fluid assessments with no evidence of disease) at that time of registration - Previous treatment with any anti-CD22 directed therapy - Patients with previous allogeneic stem cell transplant (SCT) if they meet either of the following criteria: - < 100 days from allogeneic SCT - Active acute or chronic graft-versus-host disease (GvHD), or - Receiving immunosuppressive therapy as treatment for GvHD within the last 7 days - Patients with uncontrolled active infections (viral, bacterial, or fungal) are not eligible - Active hepatitis B or C infection, or known seropositivity for human immunodeficiency virus (HIV) - Patients with liver cirrhosis or other serious active liver disease or with suspected alcohol abuse - History of autoimmune diseases (such as systemic lupus erythematosus [SLE], Wegener's, Wegener's granulomatosis, polyarteritis nodosa); Note: Prior autoimmune diseases are allowed as long as clinically stable - Prior chemotherapy/radiotherapy/investigational therapy within 2 weeks before the start of study drugs with the following exceptions: - To reduce the circulating lymphoblast count or palliation: steroids, hydroxyurea; no washout necessary for these agents - For ALL maintenance/CML treatment: mercaptopurine, methotrexate, vincristine, single-agent, single-dose of cytarabine and/or tyrosine kinase inhibitors; these agents should be discontinued at least 48 hours prior to start of study drugs; (Note: the interval of time from last dose of any approved tyrosine kinase inhibitor [TKI] to start of protocol treatment is 48 hours regardless of the indication for treatment with the TKI) - Patients who have not recovered from acute non hematologic toxicity (to =< grade 1) of all previous therapy prior to enrollment - Females who are pregnant or lactating - Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study - Patients previously exposed to bosutinib are eligible unless they carry T315I - Patients with T315I mutations will be excluded (this criteria is not applicable for the frontline Ph+ ALL or CML-LBC cohort) Inclusion Criteria: - Relapsed or refractory B-cell ALL or CML in lymphoid blast phase; Philadelphia chromosome must be present at screening (as determined by cytogenetic analysis, fluorescence in situ hybridization [FISH], or polymerase chain reaction [PCR] [i.e., BCR-ABL positive]); Note: patients with CML who have received treatment with tyrosine kinase inhibitors for their CML, and have progressed to lymphoid blast phase are eligible for frontline treatment; Frontline Ph+ ALL or CML-lymphoid blast phase (LBC) Cohort: Patients with newly-diagnosed Ph+ ALL or CML-LBC, who have received no or minimal treatment (minimal treatment is defined as treatment with steroids/hydroxyurea of =< 2 week duration; vincristine =< 2 doses; tyrosine kinase inhibitor of =< 4 week duration; =< 2 doses of cytarabine) and are >= 60 years or older are eligible; patients must have bone marrow blasts > 5% at the time of screening - Expression of CD-22 in >= 20% blasts - Eastern Cooperative Oncology Group (ECOG) performance status score of < or = 2 - Serum bilirubin < or = 2.0 mg/dl - Serum creatinine < or = 2.0 mg/dl - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < or = 3 x upper limit of normal (ULN) - Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (beta-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use one of the following effective contraception methods during the study and for 30 days following the last dose of study drug; effective methods of birth control include: birth control pills, shots, implants (placed under the skin by a health care provider) or patches (placed on the skin); intrauterine devices (IUDs); condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide; females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy - Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug - Patients or their legally authorized representative must provide written informed consent Exclusion Criteria: - History of another primary invasive malignancy that has not been definitively treated or in remission for at least 2 years; patients with non-melanoma skin cancers or with carcinomas in situ are eligible regardless of the time from diagnosis (including concomitant diagnoses) - Patients with active unstable angina, concomitant clinically significant active arrhythmias, myocardial infarction within 6 months, or congestive heart failure New York Heart Association class III-IV; patients with a cardiac ejection fraction (as measured by either multi gated acquisition scan [MUGA] or echocardiogram) < 40% are excluded - Known evidence of active cerebral/meningeal disease; patients may have history of central nervous system (CNS) leukemic involvement if definitively treated with prior therapy and no evidence of active disease (defined as >= 2 consecutive spinal fluid assessments with no evidence of disease) at that time of registration - Previous treatment with any anti-CD22 directed therapy - Patients with previous allogeneic stem cell transplant (SCT) if they meet either of the following criteria: - < 100 days from allogeneic SCT - Active acute or chronic graft-versus-host disease (GvHD), or - Receiving immunosuppressive therapy as treatment for GvHD within the last 7 days - Patients with uncontrolled active infections (viral, bacterial, or fungal) are not eligible - Active hepatitis B or C infection, or known seropositivity for human immunodeficiency virus (HIV) - Patients with liver cirrhosis or other serious active liver disease or with suspected alcohol abuse - History of autoimmune diseases (such as systemic lupus erythematosus [SLE], Wegener's, Wegener's granulomatosis, polyarteritis nodosa); Note: Prior autoimmune diseases are allowed as long as clinically stable - Prior chemotherapy/radiotherapy/investigational therapy within 2 weeks before the start of study drugs with the following exceptions: - To reduce the circulating lymphoblast count or palliation: steroids, hydroxyurea; no washout necessary for these agents - For ALL maintenance/CML treatment: mercaptopurine, methotrexate, vincristine, single-agent, single-dose of cytarabine and/or tyrosine kinase inhibitors; these agents should be discontinued at least 48 hours prior to start of study drugs; (Note: the interval of time from last dose of any approved tyrosine kinase inhibitor [TKI] to start of protocol treatment is 48 hours regardless of the indication for treatment with the TKI) - Patients who have not recovered from acute non hematologic toxicity (to =< grade 1) of all previous therapy prior to enrollment - Females who are pregnant or lactating - Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study - Patients previously exposed to bosutinib are eligible unless they carry T315I - Patients with T315I mutations will be excluded (this criteria is not applicable for the frontline Ph+ ALL or CML-LBC cohort) B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); --- T315I --- --- T315I --- --- T315I --- --- T315I ---

Primary Outcomes

Description: Will be observed.

Measure: Maximum tolerated dose of bosutinib defined as the highest dose level in which < 2 patients of 6 develop first course dose limiting toxicity (Phase I)

Time: At day 28

Description: The response will be evaluated along with its 95% confidence interval.

Measure: Major hematologic response for relapsed Philadelphia positive acute lymphoblastic leukemia (MaHR) (Phase II)

Time: Up to 16 weeks (cycle 4 of treatment)

Description: Will be observed.

Measure: Complete response/complete response with incomplete bone marrow recovery for newly diagnosed Philadelphia positive acute lymphoblastic leukemia or chronic myeloid leukemia or chronic myeloid leukemia- lymphoid blast phase with age >= 60 (Phase II)

Time: Up to 1 year after completion of study treatment

Secondary Outcomes

Description: Will be observed.

Measure: Overall major hematologic response (Phase I)

Time: Up to 1 year after completion of study treatment

Description: Estimated using the method of Kaplan-Meier. Cox regression models will be used to determine the relationship with the time-to-events and the potential prognostic factors.

Measure: Duration of response (Phase I)

Time: Up to 1 year after completion of study treatment

Description: Estimated using the method of Kaplan-Meier. Cox regression models will be used to determine the relationship with the time-to-events (e.g., OS) and the potential prognostic factors.

Measure: Overall survival (OS) (Phase I)

Time: Up to 1 year after completion of study treatment

Description: Safety data will be summarized by category, severity and frequency.

Measure: Incidence and severity of adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (Phase II)

Time: Up to 1 year after completion of study treatment

Description: Estimated using the method of Kaplan-Meier. Cox regression models will be used to determine the relationship with the time-to-events and the potential prognostic factors.

Measure: Duration of response (Phase II)

Time: Up to 1 year after completion of study treatment

Description: Estimated using the method of Kaplan-Meier. Cox regression models will be used to determine the relationship with the time-to-events (e.g., OS) and the potential prognostic factors.

Measure: Overall survival (Phase II)

Time: Up to 1 year after completion of study treatment

54 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 ---

Primary Outcomes

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

Time: at 3 months of nilotinib treatment

55 Optimizing Ponatinib USe (OPUS). A GIMEMA Phase 2 Study of the Activity and Risk Profile of Ponatinib, 30 mg Once Daily, in Chronic Myeloid Leukemia (CML) Chronic Phase (CP) Patients Resistant to Imatinib

This study aims at evaluating the efficacy of treatment with ponatinib in patients with chronic myeloid leukemia who are in a chronic phase and who previously received treatment with imatinib but resulted to be resistant to it.

NCT02398825 Chronic Myeloid Leukemia Chronic Phase Adults Drug: Ponatinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Exclusion Criteria: 1. Accelerated or blastic phase CML 2. Patients previously treated with nilotinib or dasatinib 3. Patients with the T315I mutation 4. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis or of alcohol abuse 5. Patients with history of acute myocardial infarction (AMI), unstable angina or coronary heart disease (CHD), congestive heart failure, cerebrovascular events (CVE) (stroke or transitory ischemic attack), or peripheral artery occlusive disease (PAOD) 6. Compelled to take medications that are known to be associated with Torsades de Pointes and/or with significant QTc prolongation 7. Pregnant or breastfeeding 8. Any condition or illness that, in the opinion of the Investigator, would compromise patient safety or interfere with the evaluation of the drug 9. Lack of informed consent Inclusion Criteria: 1. Cytogenetic and/or molecular confirmed diagnosis of Ph+ and/or BCR-ABL1+ CML 2. Age ≥ 18 years 3. Chronic phase CML 4. Prior treatment with imatinib, any dose 5. Resistance to imatinib, as defined by any one of the ELN 2013 failure criteria, as follows: - no complete hematologic response (CHR) at 3 months - no cytogenetic response (CyR) (Ph+ > 95%) at 3 months - Less than partial CyR (PCyR, Ph+ > 35%) at 6 months - BCR-ABL1 > 10% at 6 months - Non complete CyR (CCyR) (Ph+ > 0%) at 12 months - BCR-ABL1 > 1% at 12 months - Loss of CHR, at any time - Loss of CCyR, at any time - Confirmed loss of major molecular response (MMR) (BCR-ABL1 bigger or equal to 0.1% in two consecutive tests, of which one bigger or equal to 1%), at any time - Any new BCR-ABL1 mutation, at any time 6. --- T315I ---

Exclusion Criteria: 1. Accelerated or blastic phase CML 2. Patients previously treated with nilotinib or dasatinib 3. Patients with the T315I mutation 4. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis or of alcohol abuse 5. Patients with history of acute myocardial infarction (AMI), unstable angina or coronary heart disease (CHD), congestive heart failure, cerebrovascular events (CVE) (stroke or transitory ischemic attack), or peripheral artery occlusive disease (PAOD) 6. Compelled to take medications that are known to be associated with Torsades de Pointes and/or with significant QTc prolongation 7. Pregnant or breastfeeding 8. Any condition or illness that, in the opinion of the Investigator, would compromise patient safety or interfere with the evaluation of the drug 9. Lack of informed consent Chronic Myeloid Leukemia Chronic Phase Adults Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Phase 2, single-arm, multicentre, open label. --- T315I ---

Primary Outcomes

Description: Cytogenetic response (CyR) is defined based on the percentage of Ph pos metaphases, as evaluated by chromosome banding analysis (CBA) of at least 20 marrow cell metaphases: Major Cytogenetic Response if Ph pos metaphases < 35% Complete (CCyR) if Ph pos metaphases 0 or FISH BCR-ABL1 nuclei minor or equal to 1% Partial (PCyR) if Ph pos metaphases 1-34% Minor (mCyR) if Ph pos metaphases 35-65% Minimal or none (min/none CyR) if Ph pos metaphases > 65% If marrow cell metaphases cannot be obtained or analysed, interphase fluorescence-in-situ-hybridization (FISH) can be used, but only to distinguish a CCyR (minor or equal to 1% positive nuclei out of at least 200 nuclei) from a non CCyR. FISH data cannot be used to classify a response as minimal, minor, or partial.

Measure: Number of patients with major cytogenetic response

Time: After 52 weeks of ponatinib treatment start

Secondary Outcomes

Measure: Number of Cardiovascular Adverse Events (AEs)

Time: After three years from ponatinib treatment start

Measure: Number of blood hypertension AEs

Time: After three years from ponatinib treatment start

Measure: Number of pancreatitis AEs

Time: After three years from ponatinib treatment start

Measure: Number of patients achieving Complete Cytogenetic Response (CCyR)

Time: After 52 weeks of ponatinib treatment start

Measure: Number of patients achieving major molecular response

Time: After 52 weeks of ponatinib treatment start

Measure: Number of patients with failure-free survival

Time: At 36 months from ponatinib treatment start

Measure: Number of patients with progression-free survival

Time: At 36 months from ponatinib treatment start

Measure: Number of patients in overal survival

Time: At 36 months from ponatinib treatment start

Measure: Number of patients in event-free survival

Time: At 36 months from ponatinib treatment start

Measure: Quality of Life patterns over time with the EORTC QLQ-C30 and the EORTC QLQ-CML24 questionnaires

Time: At baseline and at at weeks 4, 12, 24, 36 and 52

56 Radotinib Efficacy and Safety Validation in Chronic Phase Chronic Myeloid Leukemia Patients Who Are Intolerant or Resistant to at Least Two Tyrosine Kinase Inhibitors As a Third or Subsequent Line Therapy

The purpose of this study is to determine whether radotinib is effective and safe for patients with chronic myeloid leukemia, chronic phase who are intolerable or resistant to prior 2 or more tyrosine kinase inhibitors.

NCT02422719 Chronic Myeloid Leukemia Drug: Radotinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Exclusion Criteria: - T315I mutation - Prior exposure to radotinib - Accelerated or blastic phase - galactose intolerance, severe lactase deficiency or glucose galactose malabsorption - Prior history of intensive cytotoxic chemotherapy except for TKIs - Significant cardiac problem - QTcF > 450 msec - Pancreatitis history prior to study enrollment - Clinically significant malignant disease other than CML - Pregnant or breast feeding woman Inclusion Criteria: - Chronic myeloid leukemia chronic phase (CP-CML) patients who are not tolerable or resistant to prior 2 or more tyrosine kinase inhibitors (TKIs). --- T315I ---

Exclusion Criteria: - T315I mutation - Prior exposure to radotinib - Accelerated or blastic phase - galactose intolerance, severe lactase deficiency or glucose galactose malabsorption - Prior history of intensive cytotoxic chemotherapy except for TKIs - Significant cardiac problem - QTcF > 450 msec - Pancreatitis history prior to study enrollment - Clinically significant malignant disease other than CML - Pregnant or breast feeding woman Chronic Myeloid Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive The purpose of this study is to determine whether radotinib 400mg bid is effective and safe for patients with chronic myeloid leukemia, chronic phase who are intolerable or resistant to prior 2 or more tyrosine kinase inhibitors. --- T315I ---

Primary Outcomes

Description: The rate of achieving major cytogenetic response [35% or less t(9;22) chromosome by conventional banding technique] in bone marrow by 12 months after radotinib treatment will be the primary end point.

Measure: Rate of Major cytogenetic response

Time: by 12 months after radotinib treatment

Secondary Outcomes

Measure: Rate of Major Molecular response (MR3.0) on each time point

Time: up to 12 months

Measure: The number of Participants with Adverse Events

Time: 12 months

57 A Phase I - II Study to Assess Safety and Efficacy of the Combination of Ponatinib With High or Intermediate-Dose Cytarabine as Consolidation Therapy for Patients With Intermediate-Risk Cytogenetic FLT3-ITD AML iIn First Complete Remission

This project is part of a joint ALFA and GOELAM strategy aiming to improve the survival of patients with newly diagnosed Acute Myeloid Leukemia (AML) aged 18-70 years. The basis of this strategy is to evaluate intensified conventional chemotherapy and targeted drugs in selected disease-risk subgroups of adult patients with non promyelocytic AML. Participation will be proposed to almost all adult patients in France aged 18-70 years and diagnosed with AML. FLT3 genetic alterations include FLT3 somatic point mutations within the second tyrosine kinase domain and internal duplications of the juxta-membrane domain. This alteration is refered to as FLT3-ITD. The FLT3-ITD mutation is found in around 30% of patients with cytogenetically normal AML. Patients with the FLT3-ITD genotype have been reported to have a poor outcome when treated with conventional chemotherapy with an estimated 4-year relapse-free survival of 25% (Schlenk et al. N Engl J Med 2008). More recently, the prognostic relevance of FLT3-ITD has been studied in the context of integrated genetic profiling. This confirmed the genetic complexity of AML and also that FLT3-ITD was associated with reduced overall survival in intermediate-risk AML. A multivariate analysis of several genetic alterations revealed that FLT3-ITD was the primary predictor of patient outcome. FLT3-ITD mutations were classified in 3 categories: 1) FLT3-ITD with +8, TET2, DNMT3A or MLL-PTD mutations (3-year OS 14.5%); 2) FLT3-ITD with wild type CEBPA, TET2, DNMT3 and MLL-PTD (3-year OS 35.2%) and 3) FLT3-ITD with CEBPA mutations (3-year OS 42%) (Patel JP et al. N Engl J Med 2012). However, FLT3-ITD was not a predictor of response to induction therapy, allowing the introduction of targeted therapies after the induction course. Several FLT3 inhibitors have been evaluated or are currently being tested in the setting of relapsing AML. In most trials to date, patients were only eligible if the FLT3-ITD mutation was present. Disappointing results were reported with the first generation of FLT3 inhibitors, including lestaurtinib (CEP-701), midostaurin (PKC-412) and sorafenib. Second generation FLT3 inhibitors such as quizartinib (AC220) are currently under investigation with promising results. However, the hematologic toxicity of AC220 will likely present a major limitation in evaluating AC220 combined with standard or high-dose chemotherapy. Ponatinib (AP24534) is a third generation tyrosine kinase inhibitor targeting the BCR-ABL tyrosine kinase domain. Ponatinib was rationally designed with an extensive network of optimized molecular contacts and triple bonds to accommodate the T315I mutation, a major cause of resistance to tyrosine kinase inhibitors in chronic and advanced phase chronic myelogenous leukemia (CML). Ponatinib also inhibits SRC (IC50: 5.4 nM) and members of the VEGFR, FGFR, and PDGFR families of receptor tyrosine kinases (O'Hare T, Cancer Cell 2009). Despite low activity against FLT3 based on the IC50 value (FLT3 IC50: 12.6 nM compared to BCR IC50: 0.37 nM), ponatinib has recently been reported to have significant cellular activity against the MV4-11 cell line which harbors an FLT3-ITD activating mutation. Ponatinib-induced apoptosis was maximal at 10 nM in vitro and a single dose of 5 and 10 mg/kg had a strong inhibitory effect in vivo in mice bearing MV4-11 xenografts. Primary blast cells from 4 FLT3-ITD AML patients were also tested and ponatinib reduced their viability (IC50: 4 nM) whereas no activity was shown on FLT3-ITD-negative blast cells (Gozgit JM et al. Mol Cancer Ther 2011). Preliminary data from the phase I clinical trial showed that 15 mg ponatinib was associated with a Cmax of 51.1 nM. Cmax was increased to 111 nM and 149 nM in the 30 mg and 45 mg cohorts respectively. The trough concentrations were 55.3 nM and 61.9 nM for the 30 mg and 45 mg doses respectively (Ariad clinical investigator's brochure, version 3). Results from the ongoing phase II trial in CML patients suggest that the hematological toxicity profile of ponatinib is comparable with that of nilotinib or dasatinib, both of which have been successfully combined with conventional chemotherapy. Investigators thus aim to combine ponatinib with cytarabine in FLT3-ITD AML patients in first complete remission.

NCT02428543 Acute Myeloid Lukemia Drug: Ponatinib and Cytarabine

Ponatinib was rationally designed with an extensive network of optimized molecular contacts and triple bonds to accommodate the T315I mutation, a major cause of resistance to tyrosine kinase inhibitors in chronic and advanced phase chronic myelogenous leukemia (CML). --- T315I ---

Primary Outcomes

Description: assess the safety of increased doses of ponatinib in combination with high or intermediate -dose cytarabine in AML FLT3-ITD patients in first complete remission

Measure: dose-limiting toxicity (DLT) of ponatinib during consolidation 1 with HDAC or IDAC

Time: 12 months

Secondary Outcomes

Description: To determine disease-free survival from achievement of first complete remission

Measure: Overall survival

Time: 5 years

Description: To determine overall survival from achievement of first complete remission

Measure: Relapse-free survival

Time: 5 years

Description: To determine overall survival from diagnosis

Measure: Event-free survival

Time: 5 years

Description: To study minimal residual disease after induction and consolidation courses based on the quantification of the FLT3-ITD signal and /or WT1, NPM if available

Measure: Minimal residual disease based on FLT3-ITD quantification, WT1 expression and/or NPM1 mutation quantification

Time: 18 months

Description: To study the relationship between minimal residual disease and outcome

Measure: relationship between minimal residual disease and outcome

Time: 18 months

Description: To assess FLT3-ITD mutant before and after ponatinib treatment

Measure: To study ponatinib resistance mechanisms

Time: 18 months

58 A Randomized, Open-label, Phase 2 Trial of Ponatinib in Patients With Resistant Chronic Phase Chronic Myeloid Leukemia to Characterize the Efficacy and Safety of a Range of Doses

The purpose of this study is to characterize the efficacy of ponatinib administered in 3 starting doses (45 milligram [mg], 30 mg, and 15 mg daily) in participants with CP-CML who are resistant to prior tyrosine-kinase inhibitor (TKI) therapy or have T315I mutation, as measured by less than or equal to (<=) 1 percent (%) Breakpoint Cluster Region-Abelson Transcript Level using International Scale (BCR-ABL1IS) at 12 months.

NCT02467270 Myeloid Leukemia, Chronic, Chronic Phase Drug: Ponatinib 45 mg Drug: Ponatinib 30 mg Drug: Ponatinib 15 mg
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Ponatinib in Participants With Resistant Chronic Phase Chronic Myeloid Leukemia (CP-CML) to Characterize the Efficacy and Safety of a Range of Doses The purpose of this study is to characterize the efficacy of ponatinib administered in 3 starting doses (45 milligram [mg], 30 mg, and 15 mg daily) in participants with CP-CML who are resistant to prior tyrosine-kinase inhibitor (TKI) therapy or have T315I mutation, as measured by less than or equal to (<=) 1 percent (%) Breakpoint Cluster Region-Abelson Transcript Level using International Scale (BCR-ABL1IS) at 12 months. --- T315I ---

OS is defined as the interval between the first does of study treatment and death due to any cause, censored at the last contact date when the participant was alive.. Inclusion Criteria: 1. Have CP-CML and have received at least two prior TKI therapies and have demonstrated resistance to treatment OR have documented history of presence of T315I mutation after receiving any number of prior TKI. --- T315I ---

Inclusion Criteria: 1. Have CP-CML and have received at least two prior TKI therapies and have demonstrated resistance to treatment OR have documented history of presence of T315I mutation after receiving any number of prior TKI. --- T315I ---

Primary Outcomes

Measure: Percentage of Participants with <=1% BCR-ABL1IS at Month 12

Time: Month 12

Secondary Outcomes

Description: MMR is defined as percentage of participants with major molecular response.

Measure: Percentage of Participants With Major Molecular Response (MMR) at Months 12 and 24

Time: Months 12 and 24

Description: MCyR is defined as percentage of participants with complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). Cytogenetic response is the percentage of Philadelphia chromosome positive (Ph+) metaphases in bone marrow (BM). Response is further defined as MCyR: CCyR or PCyR, where CCyR: 0% Ph + metaphases; PCyR: greater than (>) 0 to 35% Ph + metaphases.

Measure: Major Cytogenetic Response (MCyR) Rates by Month 12

Time: Up to Month 12

Description: Duration of MMR is defined as the interval between the first assessment at which the criteria for <=1% MMR are met until the earliest date at which loss of <=1% MMR occurs, or the criteria for progression are met.

Measure: Duration of MMR

Time: Baseline up to Month 24

Description: Percentage of participants with adjusted incidence rates who developed AOEs and VTEs will be categorized according to arterial occlusive events (Cardiac occlusive/thrombotic events, cerebral occlusive/thrombotic events and peripheral occlusive/thrombotic events) and venous thrombotic events.

Measure: Percentage of Participants with Adjusted Incidence Rates for Arterial Occlusive Events (AOEs) and Venous Thrombotic Events (VTEs), Adverse Events (AEs), and Serious AEs (SAEs)

Time: Baseline up to Month 24

Description: Cytogenetic response is the percentage of Ph+ metaphases in bone marrow (peripheral blood may not be used), with a review of a minimum of 20 metaphases. CCyR is defined as 0% Ph+ metaphases.

Measure: Percentage of Participants With CCyR at Month 12

Time: Month 12

Description: MR4 is defined as <=0.01% BCR-ABL1IS. MR 4.5 is defined as <=0.0032% BCR-ALB1IS.

Measure: Percentage of Participants With Major Molecular Response (MMR), Molecular Response 4 (MR4) and Molecular Response (MR4.5)

Time: Baseline up to Month 24

Description: MR1 is defined as percentage of participants achieving a ratio of <=10% Breakpoint Cluster Region-abelson (BCR-ABL1) transcripts on the international scale.

Measure: Percentage of Participants With Molecular Response 1 (MR1) at Month 3

Time: Month 3

Description: CHR is defined as achieving all of the following measurements: white blood cells (WBC) <= institutional upper limit of normal (ULN), platelets less than (<) 450,000 per cubic millimeter (/mm^3), no blasts or promyelocytes in peripheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, and no extramedullary involvement (including no hepatomegaly or splenomegaly).

Measure: Percentage of Participants With Complete hematologic Response (CHR) at Month 3

Time: Month 3

Measure: Percentage of Participants with AEs Leading to Discontinuation and Dose Reduction

Time: Baseline up to Month 24

Measure: Percentage of Participants with Dose Interruptions

Time: Baseline up to Month 24

Description: Duration of <=1% BCR-ABL1IS is defined as the interval between the first assessment at which the criteria for <=1% BCR-ABL1IS are met until the earliest date at which loss of <=1% BCR-ABL1IS occurs, or the criteria for progression (progression to accelerated phase [AP] or blast phase [BP] of CML) are met. Loss of <=1% BCR-ABL1IS is an increase to >1% of BCR-ABL1IS. Progression to AP is defined as: greater than or equal to (>=) 15% and <30% blasts in peripheral blood or bone marrow or >=20% basophils in peripheral blood or bone marrow or >=30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*109 platelets per liter (/L) in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP is defined as: >=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.

Measure: Duration of Response (DOR) of <=1% BCR-ABL1 IS

Time: From the first assessment at which the criteria for <= 1% BCR-ABL1IS are met until the earliest date at which loss of <= 1% BCR-ABL1IS occurs, or the criteria for progression are met (up to 6.3 years)

Description: Duration of MMR is defined as the interval between the first assessment at which the criteria for MMR are met until the earliest date at which loss of MMR occurs, or the criteria for progression (progression to AP or BP of CML) are met. Participants remaining in MMR will be censored at the last date at which the criteria for MMR are met. Loss of MMR is an increase to >1% of BCR-ABL1IS. Progression to AP is defined as: >= 15% and <30% blasts in peripheral blood or bone marrow or >=20% basophils in peripheral blood or bone marrow or >=30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*109 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP is defined as: >=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.

Measure: DOR for MMR

Time: From the first assessment at which the criteria for MMR are met until the earliest date at which loss of MMR occurs, or the criteria for progression are met (up to 6.3 years)

Description: Responders are defined as those participants who meet all of the following: are randomized and treated, respond at 12 months after the initiation of study treatment, and undergo baseline polymerase chain reaction (PCR) assessment.

Measure: DOR in Responders

Time: Baseline up to 6.3 years

Measure: Time to Response

Time: Baseline up to 6.3 years

Description: Progression to AP is defined as: >=15% and <30% blasts in peripheral blood or bone marrow or >=20% basophils in peripheral blood or bone marrow or >=30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*109 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP is defined as: >=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.

Measure: Percentage of Participants With Progression to AP or BP CML

Time: From first dose date of study treatment until death due to any cause, censored at the last response assessment (up to 6.3 years)

Description: PFS is defined as the interval between the first dose date of study treatment and the first date at which the criteria for progression are met (progression to the AP or BP of CML), or death due to any cause, censored at the last response assessment. Progression to AP is defined as: >=15% and <30% blasts in peripheral blood or bone marrow or >=20% basophils in peripheral blood or bone marrow or >=30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*109 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP is defined as: >=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.

Measure: Progression-free Survival (PFS)

Time: From first dose date of study treatment until first date at which criteria for progression are met, or death due to any cause, censored at the last response assessment (up to 6.3 years)

Description: OS is defined as the interval between the first does of study treatment and death due to any cause, censored at the last contact date when the participant was alive.

Measure: Overall Survival (OS)

Time: From first dose date of study treatment until death due to any cause, censored at the last contact date when the participant was alive (up to 6.3 years)

59 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 --- --- V299L --- --- T315A --- --- T315I ---

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

60 Multi-center, Single Stage Phase II Study to Evaluate the Efficacy and Safety of Flumatinib in Accelerated or Blastic Phase Chronic Myelogenous Leukemia Patients

Multi-center, single stage, phase II study to evaluate the efficacy and safety of Flumatinib in accelerated or blastic Phase chronic myelogenous leukemia patients.

NCT02511340 Chronic Myelogenous Leukemia Drug: Flumatinib mesylate tablet 600 mg qd
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Exclusion Criteria: - Patients in Chronic and Blastic Phases; - Previously treated with Flumatinib; - Previously documented T315I mutations; - Previous therapy within protocol defined timeframe, including: - hydroxyurea within 24 hr, - Imatinib or Nilotinib or Dasatinib within 28 days) - Cardiac dysfunction ; - History of congenital or acquired bleeding disorders unrelated to CML; - Central nervous system leukemia; - Previous malignancy except CML; - Acute or chronic liver or severe kidney disease unrelated to CML; - Pregnant, breastfeeding, child bearing potential but failed to take effective contraception. --- T315I ---

Primary Outcomes

Measure: Confirmed overall hematologic response(OHR)at 6 months

Time: 6 months

61 A Phase II Study of Dose-Adjusted Etoposide, Prednisone, Vincristine, Cyclophosphamide, and Doxorubicin Plus Asparaginase (DA-EPOCH-A) for Adults With Acute Lymphoblastic Leukemia/Lymphoma

This phase II trial studies how well etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride with asparaginase work in treating patients with acute lymphoblastic leukemia or lymphoblastic lymphoma. Drugs used in chemotherapy, such as etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride, 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. Asparaginase breaks down the amino acid asparagine and may block the growth of tumor cells that need asparagine to grow. Giving combination chemotherapy with asparaginase may work better in treating patients with acute lymphoblastic leukemia or lymphoblastic lymphoma.

NCT02538926 B Acute Lymphoblastic Leukemia B Lymphoblastic Lymphoma Recurrent Adult Acute Lymphoblastic Leukemia Recurrent B Lymphoblastic Lymphoma Recurrent T Lymphoblastic Leukemia/Lymphoma Refractory B Lymphoblastic Lymphoma Refractory T Lymphoblastic Lymphoma T Acute Lymphoblastic Leukemia T Lymphoblastic Lymphoma Drug: Asparaginase Drug: Cyclophosphamide Drug: Doxorubicin Hydrochloride Drug: Etoposide Drug: Imatinib Mesylate Other: Laboratory Biomarker Analysis Drug: Prednisone Biological: Rituximab Drug: Vincristine Sulfate
MeSH:Lymphoma Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Lymphoma, Non-Hodgkin Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
HPO:Leukemia Lymphoid leukemia Lymphoma Non-Hodgkin lymphoma T-cell acute lymphoblastic leukemias

Inclusion Criteria: - Patients must have a confirmed diagnosis of either B- or T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma that is either: - Arm A: Initially diagnosed at age 40 or later, OR - Arm B: Relapsed after or failed to respond to >= 1 previous chemotherapy regimen - The regimen under study must constitute a reasonable therapeutic option - Presence of >= 5% abnormal blasts in the bone marrow - Patients with prior allogeneic hematopoietic cell transplantation (HCT) must be at least 90 days post-HCT and must be on =< 20 mg of prednisone (or equivalent dose of an alternative corticosteroid) for treatment/prevention of graft-vs-host disease - Total bilirubin =< 1.5 x institutional upper limit of normal (ULN; unless attributable to Gilbert's disease or other causes of inherited indirect hyperbilirubinemia, at which point total bilirubin must be =< 2.5 x ULN) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN - Note: Patients with liver test abnormalities attributable to hepatic involvement by ALL will be permitted if the total bilirubin is =< 3.0 x ULN and ALT/AST are =< 5.0 x ULN - Creatinine =< 1.5 mg/dL; however, patients with a creatinine > 1.5 mg/dL but with a calculated creatinine clearance of > 60 ml/min, as measured by the Modification of Diet in Renal Disease (MDRD) equation, will be eligible - Measurement of left ventricular ejection fraction (LVEF) should be performed in patients with prior anthracycline exposure or known history of arrhythmia or structural heart disease; in these cases, LVEF must be >= 40% - As patients with ALL frequently have cytopenias, no hematologic parameters will be required for enrollment or to receive the first cycle of treatment; however, adequate recovery of blood counts will be required to receive subsequent cycles - Per good clinical practice, any toxicity related to prior therapies that, in the opinion of the investigator, would potentially be worsened with DA-EPOCH-A +/- imatinib (imatinib mesylate) +/- rituximab, should be resolved to grade 1 or less - Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 - Women of childbearing potential must have a negative pregnancy test and must agree to the use of effective contraception while on treatment; men must also agree to the use of effective contraception while on treatment - Ability to give informed consent and comply with the protocol - Anticipated survival of at least 3 months Exclusion Criteria: - Patients with Burkitt lymphoma/leukemia - Patients must not have received chemotherapy within 14 days of enrollment, with the two following exceptions: - Routine systemic maintenance therapy (e.g., Abelson murine leukemia viral oncogene homolog 1 [ABL] kinase inhibitor, methotrexate, 6-mercaptopurine, vincristine, etc.) and intrathecal/intraventricular therapy - Systemic therapy for the acute management of hyperleukocytosis or acute symptoms (e.g., corticosteroids, cytarabine, etc.) - May not have prior malignancies unless the expected survival is at least 2 years - For patients with Philadelphia chromosome positive (Ph+) ALL, they must not have progressed within 3 months of receiving imatinib or have a documented ABL kinase mutation known to confer resistance to imatinib (e.g., T315I) - Patients with persistent grade 2 or higher peripheral sensory or motor neuropathy of any cause - Patients with isolated extramedullary disease or with parenchymal central nervous system (CNS) disease - Known hypersensitivity or intolerance to any of the agents under investigation - Human immunodeficiency virus (HIV) positive or evidence of infection with hepatitis B or C virus, as defined by any of the following criteria (if patients have not previously been tested for the following, these will be conducted during screening): - HIV antibody positive - Hepatitis B surface antigen or core antibody positive - Hepatitis C antibody positive - Other medical or psychiatric conditions that in the opinion of the investigator would preclude safe participation in the protocol - May not be pregnant or nursing Inclusion Criteria: - Patients must have a confirmed diagnosis of either B- or T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma that is either: - Arm A: Initially diagnosed at age 40 or later, OR - Arm B: Relapsed after or failed to respond to >= 1 previous chemotherapy regimen - The regimen under study must constitute a reasonable therapeutic option - Presence of >= 5% abnormal blasts in the bone marrow - Patients with prior allogeneic hematopoietic cell transplantation (HCT) must be at least 90 days post-HCT and must be on =< 20 mg of prednisone (or equivalent dose of an alternative corticosteroid) for treatment/prevention of graft-vs-host disease - Total bilirubin =< 1.5 x institutional upper limit of normal (ULN; unless attributable to Gilbert's disease or other causes of inherited indirect hyperbilirubinemia, at which point total bilirubin must be =< 2.5 x ULN) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN - Note: Patients with liver test abnormalities attributable to hepatic involvement by ALL will be permitted if the total bilirubin is =< 3.0 x ULN and ALT/AST are =< 5.0 x ULN - Creatinine =< 1.5 mg/dL; however, patients with a creatinine > 1.5 mg/dL but with a calculated creatinine clearance of > 60 ml/min, as measured by the Modification of Diet in Renal Disease (MDRD) equation, will be eligible - Measurement of left ventricular ejection fraction (LVEF) should be performed in patients with prior anthracycline exposure or known history of arrhythmia or structural heart disease; in these cases, LVEF must be >= 40% - As patients with ALL frequently have cytopenias, no hematologic parameters will be required for enrollment or to receive the first cycle of treatment; however, adequate recovery of blood counts will be required to receive subsequent cycles - Per good clinical practice, any toxicity related to prior therapies that, in the opinion of the investigator, would potentially be worsened with DA-EPOCH-A +/- imatinib (imatinib mesylate) +/- rituximab, should be resolved to grade 1 or less - Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 - Women of childbearing potential must have a negative pregnancy test and must agree to the use of effective contraception while on treatment; men must also agree to the use of effective contraception while on treatment - Ability to give informed consent and comply with the protocol - Anticipated survival of at least 3 months Exclusion Criteria: - Patients with Burkitt lymphoma/leukemia - Patients must not have received chemotherapy within 14 days of enrollment, with the two following exceptions: - Routine systemic maintenance therapy (e.g., Abelson murine leukemia viral oncogene homolog 1 [ABL] kinase inhibitor, methotrexate, 6-mercaptopurine, vincristine, etc.) and intrathecal/intraventricular therapy - Systemic therapy for the acute management of hyperleukocytosis or acute symptoms (e.g., corticosteroids, cytarabine, etc.) - May not have prior malignancies unless the expected survival is at least 2 years - For patients with Philadelphia chromosome positive (Ph+) ALL, they must not have progressed within 3 months of receiving imatinib or have a documented ABL kinase mutation known to confer resistance to imatinib (e.g., T315I) - Patients with persistent grade 2 or higher peripheral sensory or motor neuropathy of any cause - Patients with isolated extramedullary disease or with parenchymal central nervous system (CNS) disease - Known hypersensitivity or intolerance to any of the agents under investigation - Human immunodeficiency virus (HIV) positive or evidence of infection with hepatitis B or C virus, as defined by any of the following criteria (if patients have not previously been tested for the following, these will be conducted during screening): - HIV antibody positive - Hepatitis B surface antigen or core antibody positive - Hepatitis C antibody positive - Other medical or psychiatric conditions that in the opinion of the investigator would preclude safe participation in the protocol - May not be pregnant or nursing B Acute Lymphoblastic Leukemia B Lymphoblastic Lymphoma Recurrent Adult Acute Lymphoblastic Leukemia Recurrent B Lymphoblastic Lymphoma Recurrent T Lymphoblastic Leukemia/Lymphoma Refractory B Lymphoblastic Lymphoma Refractory T Lymphoblastic Lymphoma T Acute Lymphoblastic Leukemia T Lymphoblastic Lymphoma Lymphoma Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Lymphoma, Non-Hodgkin Precursor T-Cell Lymphoblastic Leukemia-Lymphoma PRIMARY OBJECTIVES: I. To determine the efficacy of dose-adjusted etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride plus asparaginase (DA-EPOCH-A) in adults with acute lymphoblastic leukemia/lymphoma (ALL). --- T315I ---

Inclusion Criteria: - Patients must have a confirmed diagnosis of either B- or T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma that is either: - Arm A: Initially diagnosed at age 40 or later, OR - Arm B: Relapsed after or failed to respond to >= 1 previous chemotherapy regimen - The regimen under study must constitute a reasonable therapeutic option - Presence of >= 5% abnormal blasts in the bone marrow - Patients with prior allogeneic hematopoietic cell transplantation (HCT) must be at least 90 days post-HCT and must be on =< 20 mg of prednisone (or equivalent dose of an alternative corticosteroid) for treatment/prevention of graft-vs-host disease - Total bilirubin =< 1.5 x institutional upper limit of normal (ULN; unless attributable to Gilbert's disease or other causes of inherited indirect hyperbilirubinemia, at which point total bilirubin must be =< 2.5 x ULN) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN - Note: Patients with liver test abnormalities attributable to hepatic involvement by ALL will be permitted if the total bilirubin is =< 3.0 x ULN and ALT/AST are =< 5.0 x ULN - Creatinine =< 1.5 mg/dL; however, patients with a creatinine > 1.5 mg/dL but with a calculated creatinine clearance of > 60 ml/min, as measured by the Modification of Diet in Renal Disease (MDRD) equation, will be eligible - Measurement of left ventricular ejection fraction (LVEF) should be performed in patients with prior anthracycline exposure or known history of arrhythmia or structural heart disease; in these cases, LVEF must be >= 40% - As patients with ALL frequently have cytopenias, no hematologic parameters will be required for enrollment or to receive the first cycle of treatment; however, adequate recovery of blood counts will be required to receive subsequent cycles - Per good clinical practice, any toxicity related to prior therapies that, in the opinion of the investigator, would potentially be worsened with DA-EPOCH-A +/- imatinib (imatinib mesylate) +/- rituximab, should be resolved to grade 1 or less - Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 - Women of childbearing potential must have a negative pregnancy test and must agree to the use of effective contraception while on treatment; men must also agree to the use of effective contraception while on treatment - Ability to give informed consent and comply with the protocol - Anticipated survival of at least 3 months Exclusion Criteria: - Patients with Burkitt lymphoma/leukemia - Patients must not have received chemotherapy within 14 days of enrollment, with the two following exceptions: - Routine systemic maintenance therapy (e.g., Abelson murine leukemia viral oncogene homolog 1 [ABL] kinase inhibitor, methotrexate, 6-mercaptopurine, vincristine, etc.) and intrathecal/intraventricular therapy - Systemic therapy for the acute management of hyperleukocytosis or acute symptoms (e.g., corticosteroids, cytarabine, etc.) - May not have prior malignancies unless the expected survival is at least 2 years - For patients with Philadelphia chromosome positive (Ph+) ALL, they must not have progressed within 3 months of receiving imatinib or have a documented ABL kinase mutation known to confer resistance to imatinib (e.g., T315I) - Patients with persistent grade 2 or higher peripheral sensory or motor neuropathy of any cause - Patients with isolated extramedullary disease or with parenchymal central nervous system (CNS) disease - Known hypersensitivity or intolerance to any of the agents under investigation - Human immunodeficiency virus (HIV) positive or evidence of infection with hepatitis B or C virus, as defined by any of the following criteria (if patients have not previously been tested for the following, these will be conducted during screening): - HIV antibody positive - Hepatitis B surface antigen or core antibody positive - Hepatitis C antibody positive - Other medical or psychiatric conditions that in the opinion of the investigator would preclude safe participation in the protocol - May not be pregnant or nursing Inclusion Criteria: - Patients must have a confirmed diagnosis of either B- or T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma that is either: - Arm A: Initially diagnosed at age 40 or later, OR - Arm B: Relapsed after or failed to respond to >= 1 previous chemotherapy regimen - The regimen under study must constitute a reasonable therapeutic option - Presence of >= 5% abnormal blasts in the bone marrow - Patients with prior allogeneic hematopoietic cell transplantation (HCT) must be at least 90 days post-HCT and must be on =< 20 mg of prednisone (or equivalent dose of an alternative corticosteroid) for treatment/prevention of graft-vs-host disease - Total bilirubin =< 1.5 x institutional upper limit of normal (ULN; unless attributable to Gilbert's disease or other causes of inherited indirect hyperbilirubinemia, at which point total bilirubin must be =< 2.5 x ULN) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN - Note: Patients with liver test abnormalities attributable to hepatic involvement by ALL will be permitted if the total bilirubin is =< 3.0 x ULN and ALT/AST are =< 5.0 x ULN - Creatinine =< 1.5 mg/dL; however, patients with a creatinine > 1.5 mg/dL but with a calculated creatinine clearance of > 60 ml/min, as measured by the Modification of Diet in Renal Disease (MDRD) equation, will be eligible - Measurement of left ventricular ejection fraction (LVEF) should be performed in patients with prior anthracycline exposure or known history of arrhythmia or structural heart disease; in these cases, LVEF must be >= 40% - As patients with ALL frequently have cytopenias, no hematologic parameters will be required for enrollment or to receive the first cycle of treatment; however, adequate recovery of blood counts will be required to receive subsequent cycles - Per good clinical practice, any toxicity related to prior therapies that, in the opinion of the investigator, would potentially be worsened with DA-EPOCH-A +/- imatinib (imatinib mesylate) +/- rituximab, should be resolved to grade 1 or less - Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 - Women of childbearing potential must have a negative pregnancy test and must agree to the use of effective contraception while on treatment; men must also agree to the use of effective contraception while on treatment - Ability to give informed consent and comply with the protocol - Anticipated survival of at least 3 months Exclusion Criteria: - Patients with Burkitt lymphoma/leukemia - Patients must not have received chemotherapy within 14 days of enrollment, with the two following exceptions: - Routine systemic maintenance therapy (e.g., Abelson murine leukemia viral oncogene homolog 1 [ABL] kinase inhibitor, methotrexate, 6-mercaptopurine, vincristine, etc.) and intrathecal/intraventricular therapy - Systemic therapy for the acute management of hyperleukocytosis or acute symptoms (e.g., corticosteroids, cytarabine, etc.) - May not have prior malignancies unless the expected survival is at least 2 years - For patients with Philadelphia chromosome positive (Ph+) ALL, they must not have progressed within 3 months of receiving imatinib or have a documented ABL kinase mutation known to confer resistance to imatinib (e.g., T315I) - Patients with persistent grade 2 or higher peripheral sensory or motor neuropathy of any cause - Patients with isolated extramedullary disease or with parenchymal central nervous system (CNS) disease - Known hypersensitivity or intolerance to any of the agents under investigation - Human immunodeficiency virus (HIV) positive or evidence of infection with hepatitis B or C virus, as defined by any of the following criteria (if patients have not previously been tested for the following, these will be conducted during screening): - HIV antibody positive - Hepatitis B surface antigen or core antibody positive - Hepatitis C antibody positive - Other medical or psychiatric conditions that in the opinion of the investigator would preclude safe participation in the protocol - May not be pregnant or nursing B Acute Lymphoblastic Leukemia B Lymphoblastic Lymphoma Recurrent Adult Acute Lymphoblastic Leukemia Recurrent B Lymphoblastic Lymphoma Recurrent T Lymphoblastic Leukemia/Lymphoma Refractory B Lymphoblastic Lymphoma Refractory T Lymphoblastic Lymphoma T Acute Lymphoblastic Leukemia T Lymphoblastic Lymphoma Lymphoma Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Lymphoma, Non-Hodgkin Precursor T-Cell Lymphoblastic Leukemia-Lymphoma PRIMARY OBJECTIVES: I. To determine the efficacy of dose-adjusted etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride plus asparaginase (DA-EPOCH-A) in adults with acute lymphoblastic leukemia/lymphoma (ALL). --- T315I --- --- T315I ---

Primary Outcomes

Description: A Simon two-stage optimum design will be used to define success of this treatment in the two subgroups of patients.

Measure: Complete minimal residual disease response rate

Time: Up to 5 years

Description: A Simon two-stage optimum design will be used to define success of this treatment in the two subgroups of patients.

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

Time: Up to 5 years

Description: A Simon two-stage optimum design will be used to define success of this treatment in the two subgroups of patients.

Measure: Overall survival

Time: From time of initiation of study therapy to up to 5 years

Description: A Simon two-stage optimum design will be used to define success of this treatment in the two subgroups of patients.

Measure: Progression-free survival

Time: From time of initiation of study therapy to up to 5 years

Secondary Outcomes

Measure: Incidence of adverse events, graded using the National Cancer Institute Common Terminology Criteria for Adverse Events

Time: Up to 30 days post-treatment, or until patient receives an alternative anti-cancer therapy, whichever date comes first

62 A Phase III Study, Randomized, to Evaluate the Reduction of Chemotherapy Intensity in Association With Nilotinib (Tasigna®) in Philadelphia Chromosome-positive (Ph+) ALL of Young Adults (18-59 Years Old) (GRAAPH-2014)

The Primary objective is to assess the non-inferiority of the experimental arm (arm B) compared to the control arm (arm A) in terms of Major Molecular Response (MMolR) after the 4th cycle (MRD4) in patients aged 18-59 years old with de novo Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL)

NCT02611492 Philadelphia Chromosome Positive Adult Acute Lymphoblastic Leukemia Drug: Nilotinib Drug: Methotrexate Drug: Aracytine (Ara C) Drug: Granulocyte Colony-Stimulating Factor (G-CSF) Drug: Depomedrol Drug: Dexamethasone Drug: Vincristine Drug: Imatinib Drug: 6 Mercaptopurine (6MP)
MeSH:Precursor Cell Lymphoblastic Leukemia-Lymphoma Philadelphia Chromosome

T315I mutation. --- T315I ---

Primary Outcomes

Description: defined as a breakpoint cluster region (BCR)-Abelson (ABL) ratio < 0.1% in the bone marrow sample of MRD4

Measure: Major Molecular Response (MMolR)

Time: 4 cycles (4 months)

Secondary Outcomes

Measure: Complete remission after cycle 1

Time: day 28

Measure: Cumulative incidence of treatment- and transplantation-related mortality

Time: 2 years

Measure: Cumulative incidence of relapse

Time: 10 years

Measure: Relapse free survival

Time: 10 years

Measure: Event-free survival

Time: 10 years

Measure: overall survival

Time: 10 years

Description: mutations will be assessed by Reverse transcription Quantitative Polymerase Chain Reaction (RQ-PCR) sequencing in case of progression or relapse

Measure: T315I mutation

Time: 10 years

Measure: Toxicity

Time: 12 months

63 Transplantation of Umbilical Cord Blood From Unrelated Donors in Patients With Hematological Diseases Using a Non-Myeloablative Preparative Regimen

This is a phase II trial using a non-myeloablative cyclophosphamide/ fludarabine/total body irradiation (TBI) preparative regimen with modifications based on factors including diagnosis, disease status, and prior treatment. Single or double unit selected according to current University of Minnesota umbilical cord blood graft selection algorithm.

NCT02722668 Acute Leukemia Acute Myeloid Leukemia Acute Lymphoblastic Leukemia/Lymphoma Burkitt's Lymphoma Natural Killer Cell Malignancies Chronic Myelogenous Leukemia Myelodysplastic Syndrome Large-cell Lymphoma Hodgkin Lymphoma Multiple Myeloma Relapsed Chronic Lymphocytic Leukemia Relapsed Small Lymphocytic Lymphoma Marginal Zone B-cell Lymphoma Follicular Lymphoma Lymphoplasmacytic Lymphoma Mantle-cell Lymphoma Prolymphocytic Leukemia Bone Marrow Failure Syndromes Myeloproliferative Neoplasms/Myelofibrosis Biphenotypic/Undifferentiated/Prolymphocytic Leukemias MRD Positive Leukemia Leukemia or MDS in Aplasia Relapsed T-Cell Lymphoma Relapsed Multiple Myeloma Plasma Cell Leukemia Drug: Fludarabine Drug: Cyclophosphamide Drug: MMF Drug: Sirolimus Radiation: TBI Biological: Umbilical cord blood cell infusion Biological: ATG
MeSH:Burkitt Lymphoma Lymphoma Leukemia Multiple Myeloma Neoplasms, Plasma Cell Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphocytic, Chronic, B-Cell Lymphoma, Mantle-Cell Leukemia, Myelogenous, Chronic, BCR-ABL Positive Lymphoma, B-Cell, Marginal Zone Leukemia, Prolymphocytic Waldenstrom Macroglobulinemia Leukemia, Plasma Cell Myelodysplastic Syndromes Myeloproliferative Disorders Pancytopenia Hematologic Diseases Syndrome
HPO:Abnormality of blood and blood-forming tissues Burkitt lymphoma Chronic lymphatic leukemia Chronic myelogenous leukemia Leukemia Lymphoma Monoclonal immunoglobulin M proteinemia Multiple myeloma Myelodysplasia Myeloproliferative disorder Pancytopenia

t(9;22), t(1;19), t(4;11), other MLL rearrangements, IKZF1 - 30 years of age or older at diagnosis - White blood cell counts of greater than 30,000/mcL (B-ALL) or greater than 100,000/mcL (T-ALL) at diagnosis - CNS leukemia involvement during the course of disease - Slow cytologic response (>10% lymphoblasts in bone marrow on Day 14 of induction therapy) - Evidence of persistent immonophenotypic or molecular minimal residual disease (MRD) at the end of induction and consolidation therapy - Biphenotypic/Undifferentiated/Prolymphocytic Leukemias in first or subsequent CR - Chronic myelogenous leukemia in chronic or accelerated phase, or CML blast crisis in morphological remission (<5% blasts): Chronic phase patients must have failed at least two tyrosine kinase inhibitors, been intolerant to all available TKIs, or have T315I mutation. --- T315I ---

Primary Outcomes

Description: Simple proportions will be used to estimate the probability of grade II-IV actue GVHD.

Measure: Probability of Acute Graft Versus Host Disease (GVHD)

Time: Day 100

Secondary Outcomes

Description: Percentage of patients with grade III-IV acute GVHD.

Measure: Incidence of Acute GVHD

Time: Day 100

Measure: Transplant related mortality

Time: 6 months post transplant

Description: Percentage of subjects with donor chimerism.

Measure: Chimerism

Time: Day 21

Description: Percentage of subjects with donor chimerism.

Measure: Chimerism

Time: Day 100

Description: Percentage of subjects with donor chimerism.

Measure: Chimerism

Time: Day 180

Description: Percentage of subjects with donor chimerism.

Measure: Chimerism

Time: 1 year post transplant

Description: Percentage of subjects with neutrophil engraftment.

Measure: Neutrophil Engraftment

Time: Day 42

64 Alternating or Combined Therapy With Axitinib and Bosutinib for Patients With Chronic Myeloid Leukemia in Chronic, Accelerated, or Blastic Phases

This phase I/II trial studies the side effects and best dose of axitinib and bosutinib and how well they work in treating patients with chronic, accelerated, or blastic phase chronic myeloid leukemia. Axitinib and bosutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

NCT02782403 Accelerated Phase Chronic Myelogenous Leukemia (CML) Blast Phase Chronic Myelogenous Leukemia (CML) Chronic Phase Phase Chronic Myelogenous Leukemia (CML) Philadelphia Chromosome Positive (Ph+) Phase Chronic Myelogenous Leukemia (CML) Drug: Axitinib Drug: Bosutinib Other: Laboratory Biomarker Analysis
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Blast Crisis Leukemia, Myeloid, Accelerated Phase Philadelphia Chromosome
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Following the analysis of each patient's mutation profile, the number of each somatic mutation identified will be reported.. Inclusion Criteria: - Diagnosis of Philadelphia chromosome positive (Ph+) (by cytogenetics or FISH) or BCR-ABL+ (by polymerase chain reaction [PCR]) CML in CP (cohort 1), AP (cohort 2) or BP (cohort 2) - Patients should have failed (demonstrated resistance, intolerance or treatment discontinuation for any other reason of) at least 3 Food and Drug Administration (FDA)-approved TKIs if in CP (cohort 1), or at least 1 FDA-approved TKI if in AP (cohort 2); resistance will be defined as meeting the criteria for failure or warning by the European Leukemia Net (ELN); no prior therapy is necessary for patients in BP (cohort 2); patients in CP who have failed < 3 TKIs, but are ineligible to receive other FDA-approved TKIs, may also be enrolled in cohort 1; at least 10 CP patients with the T315I mutation affecting the kinase domain of Bcr-Abl will be enrolled in cohort 1, as well as in the phase II portion of cohort 2 - Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 - Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless due to Gilbert syndrome, in which case it should be =< 3.0 x ULN) - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN - Serum creatinine =< 1.5 x ULN - Patients must sign the Institutional Review Board (IRB)-approved informed consent document for this trial - Reliable telephone access so as to be able to receive calls from an interactive voice response (IVR) system (only applicable to patients participating in the optional symptom burden assessment portion) - Women of childbearing potential (WOCBP) must practice 2 effective methods of birth control during the course of the study; male patients who are partners of WOCBP should also practice an effective method of contraception: postmenopausal women must be amenorrheic for >= 12 months to be considered of non-childbearing potential; women and men must continue birth control for the duration of the trial and >= 3 months after the last dose of study drug; all WOCBP MUST have a negative pregnancy test prior to first receiving study medication(s) - Patients should have discontinued therapy with imatinib, dasatinib, nilotinib, ponatinib, omacetaxine or other anti-leukemia therapy (except hydroxyurea) >= 48 hours prior to start of study therapy and recovered from any toxicity due to these therapies to grade =< 1; hydroxyurea may be received up to the time of enrollment and for the first 6 weeks of study treatment if necessary Exclusion Criteria: - Prior therapy with axitinib; prior therapy with bosutinib is allowed, except in the following circumstances: the subject is currently on bosutinib; bosutinib is the subject's most recent TKI for CML; the subject has a history of intolerance to bosutinib - Active gastrointestinal conditions that are expected to impair absorption of orally administered medications - Patients who currently have or have a history of the following within 6 months preceding study entry are not eligible: unstable angina (UA), myocardial infarction (MI), transient ischemic attack (TIA), stroke, deep vein thrombosis (DVT), acute peripheral or pulmonary arterial thromboembolism (PE); clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or torsades de pointes); New York Heart Association class III or IV heart failure - Patients with active, uncontrolled psychiatric disorders including: psychosis, major depressive, and bipolar disorders - Patients with uncontrolled hypertension (defined as sustained systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg) - Pregnant or breast-feeding women are excluded - Inability to understand a written informed consent document - Patients receiving anticoagulants that are unable to be discontinued - Patients with active, uncontrolled infection - Patients with a history of hypersensitivity to bosutinib or axitinib - Patients on proton pump inhibitors, potent CYP3A or P-glycoprotein substrates, inhibitors or inducers a minimum 7 day period washout required unless discontinuation or substitution is not in the best interests of the patient as determined by the investigator; in instances where use of these agents is felt to be required for optimal management, inclusion of such patients should be discussed with the principal investigator (PI) and the rationale documented; these patients, if enrolled on study, may require dose modifications for both axitinib and bosutinib Inclusion Criteria: - Diagnosis of Philadelphia chromosome positive (Ph+) (by cytogenetics or FISH) or BCR-ABL+ (by polymerase chain reaction [PCR]) CML in CP (cohort 1), AP (cohort 2) or BP (cohort 2) - Patients should have failed (demonstrated resistance, intolerance or treatment discontinuation for any other reason of) at least 3 Food and Drug Administration (FDA)-approved TKIs if in CP (cohort 1), or at least 1 FDA-approved TKI if in AP (cohort 2); resistance will be defined as meeting the criteria for failure or warning by the European Leukemia Net (ELN); no prior therapy is necessary for patients in BP (cohort 2); patients in CP who have failed < 3 TKIs, but are ineligible to receive other FDA-approved TKIs, may also be enrolled in cohort 1; at least 10 CP patients with the T315I mutation affecting the kinase domain of Bcr-Abl will be enrolled in cohort 1, as well as in the phase II portion of cohort 2 - Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 - Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless due to Gilbert syndrome, in which case it should be =< 3.0 x ULN) - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN - Serum creatinine =< 1.5 x ULN - Patients must sign the Institutional Review Board (IRB)-approved informed consent document for this trial - Reliable telephone access so as to be able to receive calls from an interactive voice response (IVR) system (only applicable to patients participating in the optional symptom burden assessment portion) - Women of childbearing potential (WOCBP) must practice 2 effective methods of birth control during the course of the study; male patients who are partners of WOCBP should also practice an effective method of contraception: postmenopausal women must be amenorrheic for >= 12 months to be considered of non-childbearing potential; women and men must continue birth control for the duration of the trial and >= 3 months after the last dose of study drug; all WOCBP MUST have a negative pregnancy test prior to first receiving study medication(s) - Patients should have discontinued therapy with imatinib, dasatinib, nilotinib, ponatinib, omacetaxine or other anti-leukemia therapy (except hydroxyurea) >= 48 hours prior to start of study therapy and recovered from any toxicity due to these therapies to grade =< 1; hydroxyurea may be received up to the time of enrollment and for the first 6 weeks of study treatment if necessary Exclusion Criteria: - Prior therapy with axitinib; prior therapy with bosutinib is allowed, except in the following circumstances: the subject is currently on bosutinib; bosutinib is the subject's most recent TKI for CML; the subject has a history of intolerance to bosutinib - Active gastrointestinal conditions that are expected to impair absorption of orally administered medications - Patients who currently have or have a history of the following within 6 months preceding study entry are not eligible: unstable angina (UA), myocardial infarction (MI), transient ischemic attack (TIA), stroke, deep vein thrombosis (DVT), acute peripheral or pulmonary arterial thromboembolism (PE); clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or torsades de pointes); New York Heart Association class III or IV heart failure - Patients with active, uncontrolled psychiatric disorders including: psychosis, major depressive, and bipolar disorders - Patients with uncontrolled hypertension (defined as sustained systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg) - Pregnant or breast-feeding women are excluded - Inability to understand a written informed consent document - Patients receiving anticoagulants that are unable to be discontinued - Patients with active, uncontrolled infection - Patients with a history of hypersensitivity to bosutinib or axitinib - Patients on proton pump inhibitors, potent CYP3A or P-glycoprotein substrates, inhibitors or inducers a minimum 7 day period washout required unless discontinuation or substitution is not in the best interests of the patient as determined by the investigator; in instances where use of these agents is felt to be required for optimal management, inclusion of such patients should be discussed with the principal investigator (PI) and the rationale documented; these patients, if enrolled on study, may require dose modifications for both axitinib and bosutinib Accelerated Phase Chronic Myelogenous Leukemia (CML) Blast Phase Chronic Myelogenous Leukemia (CML) Chronic Phase Phase Chronic Myelogenous Leukemia (CML) Philadelphia Chromosome Positive (Ph+) Phase Chronic Myelogenous Leukemia (CML) Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Blast Crisis Leukemia, Myeloid, Accelerated Phase Philadelphia Chromosome PRIMARY OBJECTIVES: I. To assess the rate of major cytogenetic response (MCyR) of an alternating schedule of axitinib and bosutinib in patients with chronic myeloid leukemia, chronic phase (CML-CP) after failure of/intolerance to >= 3 tyrosine kinase inhibitors (TKIs) using standard response criteria. --- T315I ---

Following the analysis of each patient's mutation profile, the number of each somatic mutation identified will be reported.. Inclusion Criteria: - Diagnosis of Philadelphia chromosome positive (Ph+) (by cytogenetics or FISH) or BCR-ABL+ (by polymerase chain reaction [PCR]) CML in CP (cohort 1), AP (cohort 2) or BP (cohort 2) - Patients should have failed (demonstrated resistance, intolerance or treatment discontinuation for any other reason of) at least 3 Food and Drug Administration (FDA)-approved TKIs if in CP (cohort 1), or at least 1 FDA-approved TKI if in AP (cohort 2); resistance will be defined as meeting the criteria for failure or warning by the European Leukemia Net (ELN); no prior therapy is necessary for patients in BP (cohort 2); patients in CP who have failed < 3 TKIs, but are ineligible to receive other FDA-approved TKIs, may also be enrolled in cohort 1; at least 10 CP patients with the T315I mutation affecting the kinase domain of Bcr-Abl will be enrolled in cohort 1, as well as in the phase II portion of cohort 2 - Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 - Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless due to Gilbert syndrome, in which case it should be =< 3.0 x ULN) - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN - Serum creatinine =< 1.5 x ULN - Patients must sign the Institutional Review Board (IRB)-approved informed consent document for this trial - Reliable telephone access so as to be able to receive calls from an interactive voice response (IVR) system (only applicable to patients participating in the optional symptom burden assessment portion) - Women of childbearing potential (WOCBP) must practice 2 effective methods of birth control during the course of the study; male patients who are partners of WOCBP should also practice an effective method of contraception: postmenopausal women must be amenorrheic for >= 12 months to be considered of non-childbearing potential; women and men must continue birth control for the duration of the trial and >= 3 months after the last dose of study drug; all WOCBP MUST have a negative pregnancy test prior to first receiving study medication(s) - Patients should have discontinued therapy with imatinib, dasatinib, nilotinib, ponatinib, omacetaxine or other anti-leukemia therapy (except hydroxyurea) >= 48 hours prior to start of study therapy and recovered from any toxicity due to these therapies to grade =< 1; hydroxyurea may be received up to the time of enrollment and for the first 6 weeks of study treatment if necessary Exclusion Criteria: - Prior therapy with axitinib; prior therapy with bosutinib is allowed, except in the following circumstances: the subject is currently on bosutinib; bosutinib is the subject's most recent TKI for CML; the subject has a history of intolerance to bosutinib - Active gastrointestinal conditions that are expected to impair absorption of orally administered medications - Patients who currently have or have a history of the following within 6 months preceding study entry are not eligible: unstable angina (UA), myocardial infarction (MI), transient ischemic attack (TIA), stroke, deep vein thrombosis (DVT), acute peripheral or pulmonary arterial thromboembolism (PE); clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or torsades de pointes); New York Heart Association class III or IV heart failure - Patients with active, uncontrolled psychiatric disorders including: psychosis, major depressive, and bipolar disorders - Patients with uncontrolled hypertension (defined as sustained systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg) - Pregnant or breast-feeding women are excluded - Inability to understand a written informed consent document - Patients receiving anticoagulants that are unable to be discontinued - Patients with active, uncontrolled infection - Patients with a history of hypersensitivity to bosutinib or axitinib - Patients on proton pump inhibitors, potent CYP3A or P-glycoprotein substrates, inhibitors or inducers a minimum 7 day period washout required unless discontinuation or substitution is not in the best interests of the patient as determined by the investigator; in instances where use of these agents is felt to be required for optimal management, inclusion of such patients should be discussed with the principal investigator (PI) and the rationale documented; these patients, if enrolled on study, may require dose modifications for both axitinib and bosutinib Inclusion Criteria: - Diagnosis of Philadelphia chromosome positive (Ph+) (by cytogenetics or FISH) or BCR-ABL+ (by polymerase chain reaction [PCR]) CML in CP (cohort 1), AP (cohort 2) or BP (cohort 2) - Patients should have failed (demonstrated resistance, intolerance or treatment discontinuation for any other reason of) at least 3 Food and Drug Administration (FDA)-approved TKIs if in CP (cohort 1), or at least 1 FDA-approved TKI if in AP (cohort 2); resistance will be defined as meeting the criteria for failure or warning by the European Leukemia Net (ELN); no prior therapy is necessary for patients in BP (cohort 2); patients in CP who have failed < 3 TKIs, but are ineligible to receive other FDA-approved TKIs, may also be enrolled in cohort 1; at least 10 CP patients with the T315I mutation affecting the kinase domain of Bcr-Abl will be enrolled in cohort 1, as well as in the phase II portion of cohort 2 - Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 - Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless due to Gilbert syndrome, in which case it should be =< 3.0 x ULN) - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN - Serum creatinine =< 1.5 x ULN - Patients must sign the Institutional Review Board (IRB)-approved informed consent document for this trial - Reliable telephone access so as to be able to receive calls from an interactive voice response (IVR) system (only applicable to patients participating in the optional symptom burden assessment portion) - Women of childbearing potential (WOCBP) must practice 2 effective methods of birth control during the course of the study; male patients who are partners of WOCBP should also practice an effective method of contraception: postmenopausal women must be amenorrheic for >= 12 months to be considered of non-childbearing potential; women and men must continue birth control for the duration of the trial and >= 3 months after the last dose of study drug; all WOCBP MUST have a negative pregnancy test prior to first receiving study medication(s) - Patients should have discontinued therapy with imatinib, dasatinib, nilotinib, ponatinib, omacetaxine or other anti-leukemia therapy (except hydroxyurea) >= 48 hours prior to start of study therapy and recovered from any toxicity due to these therapies to grade =< 1; hydroxyurea may be received up to the time of enrollment and for the first 6 weeks of study treatment if necessary Exclusion Criteria: - Prior therapy with axitinib; prior therapy with bosutinib is allowed, except in the following circumstances: the subject is currently on bosutinib; bosutinib is the subject's most recent TKI for CML; the subject has a history of intolerance to bosutinib - Active gastrointestinal conditions that are expected to impair absorption of orally administered medications - Patients who currently have or have a history of the following within 6 months preceding study entry are not eligible: unstable angina (UA), myocardial infarction (MI), transient ischemic attack (TIA), stroke, deep vein thrombosis (DVT), acute peripheral or pulmonary arterial thromboembolism (PE); clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or torsades de pointes); New York Heart Association class III or IV heart failure - Patients with active, uncontrolled psychiatric disorders including: psychosis, major depressive, and bipolar disorders - Patients with uncontrolled hypertension (defined as sustained systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg) - Pregnant or breast-feeding women are excluded - Inability to understand a written informed consent document - Patients receiving anticoagulants that are unable to be discontinued - Patients with active, uncontrolled infection - Patients with a history of hypersensitivity to bosutinib or axitinib - Patients on proton pump inhibitors, potent CYP3A or P-glycoprotein substrates, inhibitors or inducers a minimum 7 day period washout required unless discontinuation or substitution is not in the best interests of the patient as determined by the investigator; in instances where use of these agents is felt to be required for optimal management, inclusion of such patients should be discussed with the principal investigator (PI) and the rationale documented; these patients, if enrolled on study, may require dose modifications for both axitinib and bosutinib Accelerated Phase Chronic Myelogenous Leukemia (CML) Blast Phase Chronic Myelogenous Leukemia (CML) Chronic Phase Phase Chronic Myelogenous Leukemia (CML) Philadelphia Chromosome Positive (Ph+) Phase Chronic Myelogenous Leukemia (CML) Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Blast Crisis Leukemia, Myeloid, Accelerated Phase Philadelphia Chromosome PRIMARY OBJECTIVES: I. To assess the rate of major cytogenetic response (MCyR) of an alternating schedule of axitinib and bosutinib in patients with chronic myeloid leukemia, chronic phase (CML-CP) after failure of/intolerance to >= 3 tyrosine kinase inhibitors (TKIs) using standard response criteria. --- T315I --- --- T315I ---

Primary Outcomes

Measure: Rate of major cytogenetic response (MCyR) among patients with chronic myeloid leukemia, chronic phase status post (s/p) failure of/intolerance to >= 3 tyrosine kinase inhibitors treated with alternating axitinib and bosutinib (Chronic Phase Cohort)

Time: Up to 4 years

Measure: Maximum tolerated doses of the combination of axitinib and bosutinib among patients with chronic myeloid leukemia (CML)-advanced phase (AP) or -blast phase (BP) (AP patients must have received >= 1 prior TKI) (Advanced phase cohort - Phase I Portion)

Time: Up to 4 years

Measure: Complete hematologic response (CHR) rate to the combination of axitinib and bosutinib among patients with CML-AP or -BP (AP patients must have received >= 1 prior TKI) (Advanced phase cohort - Phase II Portion)

Time: Up to 4 years

Secondary Outcomes

Description: Rates of CHR, complete cytogenetic response (CCyR), major molecular response (MMR), molecular response 4-log (MR4), molecular response 4.5-log (MR4.5), complete molecular response (CMR), BCR-ABL/ABL =< 10% and =< 1%, duration of response (DOR), event-free survival (EFS), transformation-free survival (TFS), failure-free survival (FFS) and overall survival (OS) among patients with CML-CP after resistance and/or intolerance to >= 2 TKIs treated with alternating axitinib and bosutinib.

Measure: Clinical rates analysis (Chronic Phase Cohort)

Time: Up to 4 years

Description: Will be determined by history and physical examination and laboratory assessment, seen with the combination of axitinib and bosutinib among patients with CML-AP or -BP.

Measure: Incidence and severity of adverse events (AEs) (Advanced phase cohort - Phase I Portion)

Time: Up to 4 years

Measure: Rates of CHR, CCyR, MMR, MR4, MR4.5, CMR, BCR-ABL/ABL =< 10% and =< 1%, DOR, EFS, TFS, FFS and OS among patients with CML-AP or -BP receiving combined therapy with axitinib and bosutinib (Advanced phase cohort - Phase II Portion)

Time: Up to 4 years

Description: Measured by analysis of each patient's multigene profile using Next Generation Sequencing (NGS) panel and/or ABL kinase domain sequencing performed at baseline. Following the analysis of each patient's mutation profile, the number of each somatic mutation identified will be reported.

Measure: Percentage of participants with mutations in BCR-ABL and other genes in all patients receiving study drugs

Time: Baseline up to 4 years

65 Bosutinib Efficacy, Safety, Tolerability (BEST) Study in Elderly Chronic Myeloid Leukemia Patients Failing Front-line Treatment With Other Tyrosine Kinase Inhibitors

The objective of the present study is to evaluate a new drug called bosutinib as it is believed that this agent may be able to predict an excellent prognosis in patients that did not obtain any benefit with other drugs before. Still, this needs to be proved and we hope this study is able to do so.

NCT02810990 Chronic Myeloid Leukemia Drug: Bosutinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Exclusion Criteria: 1. Accelerated or blastic phase CML (according to ELN 2013 criteria) 2. Patients with the T315I or the V299L mutation 3. Patients previously treated with 2 TKIs or more 4. Compelled to take medications that are known to be associated with Torsades de Pointes and/or with significant QTc prolongation 5. Any condition or illness that, in the opinion of the Investigator, would compromise patient safety or interfere with the evaluation of the drug 6. --- T315I ---

Primary Outcomes

Measure: Number of patients who are in major molecular response (MMR)

Time: One year treatment

Secondary Outcomes

Measure: Number of patients who obtain molecular response

Time: At 6 and 12 months from treatment start

Measure: Number of patients discontinuing treatment for failure, adverse events or other reasons

Time: At 12 and 36 months

Measure: Number of Adverse Events (AEs)

Time: At 36 months

Measure: Number of patients alive

Time: At 36 months

Measure: Number of patients on treatment at 200, 300 and 400 mg or more daily

Time: At 6, 12 and 36 months

Measure: Number and type of BCR-ABL1 mutations

Time: At 36 months

Measure: Patient reported quality of life

Time: At 3, 6, and 12 months

66 Phase Ib Study of Nivolumab and Dasatinib in Patients With Relapsed/Refractory Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

The purpose of this research study is to determine the acceptable upper limit dose of nivolumab in combination with dasatinib that may be given to patients with relapsed/refractory philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Nivolumab is currently Food and Drug Administration (FDA) approved for other cancers, but has not yet been investigated in Ph+ ALL. Dasatinib is currently FDA approved for the treatment of Ph+ ALL, but has not yet been investigated in combination with nivolumab for this disease. There is evidence that dasatinib not only blocks the Philadelphia chromosome or breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL) mutation, but also increases the activity of cells in your immune system. Nivolumab increases T cells in your immune system, which allows your immune system to attack the cancer. We think the combination of these drugs will be more effective against your leukemia than either drug used alone.

NCT02819804 B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); BCR-ABL1 Recurrent Adult Acute Lymphoblastic Leukemia Recurrent Childhood Acute Lymphoblastic Leukemia Refractory Adult Acute Lymphoblastic Leukemia Refractory Childhood Acute Lymphoblastic Leukemia Drug: Dasatinib Other: Laboratory Biomarker Analysis Biological: Nivolumab Other: Pharmacological Study
MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Philadelphia Chromosome
HPO:Leukemia Lymphoid leukemia

Inclusion Criteria: - Patients must have a histologically confirmed diagnosis of Ph+ ALL - Detection of one of the following must be present: - t(9;22)(q34;q11) or 3-way variant by metaphase cytogenetics - Breakpoint cluster region (BCR)-Abelson (ABL) positive status by molecular analysis with qualitative polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) - Patients must have primary refractory ALL based on failure to achieve a hematologic or molecular remission after induction therapy with dasatinib and steroids or dasatinib and chemotherapy, or have relapsed after treatment with a tyrosine kinase inhibitor with or without chemotherapy - Note: Prior course of dasatinib and steroid induction therapy should have included dasatinib 140mg PO daily on days 1-84 and prednisone 60mg/m^2 (capped at 120mg, or equivalent steroid dose) on days 1-28; if patients were unable to tolerate full steroid dose during induction therapy they will still be eligible - Note: Patients with refractory or relapsed disease in the central nervous system will be eligible - Prior chemotherapy or tyrosine kinase inhibitor (TKI) treatment, aside from dasatinib, must be >= 7 days before first investigational agent dose - Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 - Patients must have adequate organ and bone marrow function prior to registration, as defined below: - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2 x institutional upper limit of normal (IULN) - Total bilirubin < 2.0 x IULN (unless Gilbert syndrome has been diagnosed); if leukemia infiltration of the liver is suspected to be causing liver function abnormalities the patient will still be eligible with principal investigator (PI) approval - Creatinine < 2 x IULN - Creatinine clearance > 40 mL/min (measured by Cockroft-Gault) - Females of child-bearing potential (FOCBP) must have a negative pregnancy test within 7 days of registration - Note: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: - Has not undergone a hysterectomy or bilateral oophorectomy - Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months) - Women must not be breastfeeding at the time of study registration - Women and men of reproductive potential should agree to use two effective means of birth control - For women, contraception should continue for 23 weeks after the last dose of nivolumab and 12 weeks after the last dose of dasatinib to allow complete clearance of drug and its principal metabolites from the body - For men, contraception should continue for 31 weeks after nivolumab and 12 weeks after dasatinib - Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study Exclusion Criteria: - Patients may not be receiving any other investigational agents within 5 half-lives of the drug (if known); if the half-life is not known, investigational agents should not be taken within two weeks - Patients are not eligible if they have an intolerance to most recent prior TKI (other than dasatinib) at the lowest possible effective dose, defined as a grade >= 3 toxicity considered at least possibly related to that TKI; patients are also excluded if they are intolerant or allergic to dasatinib and discontinued prior therapy due to a >= grade 2 treatment related adverse event - Patients must not have a history of a grade 4 anaphylactic reaction to monoclonal antibody therapy or known hypersensitivity reactions to drugs formulated with polysorbate 90 - Patients must not have had any prior therapy with an anti-PD-1, anti-programmed cell death 1 ligand 1 (PD-L1), anti-programmed cell death 1 ligand 2 (PD-L2), anti-cluster of differentiation (CD)137 or anti-cytotoxic t-lymphocyte-associated protein 4 ligand (CTLA-4) antibody (or any antibody or drug specifically targeting T-cell costimulation or checkpoint pathways; for questions or uncertainties, please contact the PI or quality assurance manager (QAM) - Patients who have had allogeneic hematopoietic stem cell transplant (HSCT) are not eligible if they meet any of the following: - transplant is within 2 months from cycle 1, day 1 (C1D1) - Has clinically significant graft-versus-host disease requiring treatment - Has >= grade 3 persistent non-hematological toxicity related to the transplant - Concomitant use of strong inhibitors of the cytochrome p450, family 3, subfamily a, polypeptide 4 (CYP3A4) isoenzyme is not permitted; must have wash-out period of 5 times the half-life of the compound before first dasatinib dose - Concomitant use of QT prolonging agents strongly associated with torsades de pointes is not permitted - Patients who have a known dasatinib-resistant ABL-kinase mutation such as T315I are not eligible; for confirmation, please contact PI - Patients who have any serious or uncontrolled medical disorder that would impair the ability of the subject to receive protocol therapy are not eligible; these include, but are not limited to: - Active infection that is not well controlled - Known pleural or pericardial effusion at baseline - Clinically significant gastrointestinal disease or digestive dysfunction compromising absorption of dasatinib - Pulmonary arterial hypertension - Uncontrolled or significant cardiovascular disease, including: - Myocardial infarction within 6 months of enrollment date - Uncontrolled angina or congestive heart failure within 3 months of enrollment date - Left ventricular ejection fraction (LVEF) < 40% - Significant cardiac conduction abnormality, including: - History of clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes) - History of second or third degree heart block (except for second degree type 1) - Corrected QT (QTc) interval > 500 msec, unless a cardiac pacemaker is present - Prior malignancy active within the previous 3 years, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancers, superficial bladder cancer, or carcinoma in situ of the prostate, cervix or breast - Subjects with active, known or suspected autoimmune disease; (Note: Subjects with vitiligo, type I diabetes mellitus, hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll) - Psychiatric illness/social situations that would limit compliance with study requirements - Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints - Female patients who are pregnant or nursing are not eligible - Patients are not eligible if they have a known positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (hepatitis C virus [HCV] antibody) indicating acute infection; Note: Patients with evidence of chronic hepatitis B infection will be allowed to enroll if on appropriate suppressive medications under the direction of a hepatologist and with PI approval - Patients who are known to be positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) are not eligible - Patients must not have live vaccine therapies for prevention of infectious diseases within 28 days of first nivolumab dose - Patients who are unable to swallow oral medication are not eligible - Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including chronic prolonged systemic corticosteroids (defined as corticosteroid use of duration one month or greater), should be excluded; these include but are not limited to patients with a history of: - Immune related neurologic disease - Multiple sclerosis - Autoimmune (demyelinating) neuropathy - Guillain-Barre syndrome - Myasthenia gravis - Systemic autoimmune disease such as systemic lupus erythematosus (SLE) - Connective tissue diseases - Scleroderma - Inflammatory bowel disease (IBD) - Crohn's - Ulcerative colitis - Patients with a history of toxic epidermal necrolysis (TEN) - Stevens-Johnson syndrome - Anti-phospholipid syndrome NOTE: Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll Inclusion Criteria: - Patients must have a histologically confirmed diagnosis of Ph+ ALL - Detection of one of the following must be present: - t(9;22)(q34;q11) or 3-way variant by metaphase cytogenetics - Breakpoint cluster region (BCR)-Abelson (ABL) positive status by molecular analysis with qualitative polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) - Patients must have primary refractory ALL based on failure to achieve a hematologic or molecular remission after induction therapy with dasatinib and steroids or dasatinib and chemotherapy, or have relapsed after treatment with a tyrosine kinase inhibitor with or without chemotherapy - Note: Prior course of dasatinib and steroid induction therapy should have included dasatinib 140mg PO daily on days 1-84 and prednisone 60mg/m^2 (capped at 120mg, or equivalent steroid dose) on days 1-28; if patients were unable to tolerate full steroid dose during induction therapy they will still be eligible - Note: Patients with refractory or relapsed disease in the central nervous system will be eligible - Prior chemotherapy or tyrosine kinase inhibitor (TKI) treatment, aside from dasatinib, must be >= 7 days before first investigational agent dose - Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 - Patients must have adequate organ and bone marrow function prior to registration, as defined below: - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2 x institutional upper limit of normal (IULN) - Total bilirubin < 2.0 x IULN (unless Gilbert syndrome has been diagnosed); if leukemia infiltration of the liver is suspected to be causing liver function abnormalities the patient will still be eligible with principal investigator (PI) approval - Creatinine < 2 x IULN - Creatinine clearance > 40 mL/min (measured by Cockroft-Gault) - Females of child-bearing potential (FOCBP) must have a negative pregnancy test within 7 days of registration - Note: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: - Has not undergone a hysterectomy or bilateral oophorectomy - Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months) - Women must not be breastfeeding at the time of study registration - Women and men of reproductive potential should agree to use two effective means of birth control - For women, contraception should continue for 23 weeks after the last dose of nivolumab and 12 weeks after the last dose of dasatinib to allow complete clearance of drug and its principal metabolites from the body - For men, contraception should continue for 31 weeks after nivolumab and 12 weeks after dasatinib - Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study Exclusion Criteria: - Patients may not be receiving any other investigational agents within 5 half-lives of the drug (if known); if the half-life is not known, investigational agents should not be taken within two weeks - Patients are not eligible if they have an intolerance to most recent prior TKI (other than dasatinib) at the lowest possible effective dose, defined as a grade >= 3 toxicity considered at least possibly related to that TKI; patients are also excluded if they are intolerant or allergic to dasatinib and discontinued prior therapy due to a >= grade 2 treatment related adverse event - Patients must not have a history of a grade 4 anaphylactic reaction to monoclonal antibody therapy or known hypersensitivity reactions to drugs formulated with polysorbate 90 - Patients must not have had any prior therapy with an anti-PD-1, anti-programmed cell death 1 ligand 1 (PD-L1), anti-programmed cell death 1 ligand 2 (PD-L2), anti-cluster of differentiation (CD)137 or anti-cytotoxic t-lymphocyte-associated protein 4 ligand (CTLA-4) antibody (or any antibody or drug specifically targeting T-cell costimulation or checkpoint pathways; for questions or uncertainties, please contact the PI or quality assurance manager (QAM) - Patients who have had allogeneic hematopoietic stem cell transplant (HSCT) are not eligible if they meet any of the following: - transplant is within 2 months from cycle 1, day 1 (C1D1) - Has clinically significant graft-versus-host disease requiring treatment - Has >= grade 3 persistent non-hematological toxicity related to the transplant - Concomitant use of strong inhibitors of the cytochrome p450, family 3, subfamily a, polypeptide 4 (CYP3A4) isoenzyme is not permitted; must have wash-out period of 5 times the half-life of the compound before first dasatinib dose - Concomitant use of QT prolonging agents strongly associated with torsades de pointes is not permitted - Patients who have a known dasatinib-resistant ABL-kinase mutation such as T315I are not eligible; for confirmation, please contact PI - Patients who have any serious or uncontrolled medical disorder that would impair the ability of the subject to receive protocol therapy are not eligible; these include, but are not limited to: - Active infection that is not well controlled - Known pleural or pericardial effusion at baseline - Clinically significant gastrointestinal disease or digestive dysfunction compromising absorption of dasatinib - Pulmonary arterial hypertension - Uncontrolled or significant cardiovascular disease, including: - Myocardial infarction within 6 months of enrollment date - Uncontrolled angina or congestive heart failure within 3 months of enrollment date - Left ventricular ejection fraction (LVEF) < 40% - Significant cardiac conduction abnormality, including: - History of clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes) - History of second or third degree heart block (except for second degree type 1) - Corrected QT (QTc) interval > 500 msec, unless a cardiac pacemaker is present - Prior malignancy active within the previous 3 years, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancers, superficial bladder cancer, or carcinoma in situ of the prostate, cervix or breast - Subjects with active, known or suspected autoimmune disease; (Note: Subjects with vitiligo, type I diabetes mellitus, hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll) - Psychiatric illness/social situations that would limit compliance with study requirements - Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints - Female patients who are pregnant or nursing are not eligible - Patients are not eligible if they have a known positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (hepatitis C virus [HCV] antibody) indicating acute infection; Note: Patients with evidence of chronic hepatitis B infection will be allowed to enroll if on appropriate suppressive medications under the direction of a hepatologist and with PI approval - Patients who are known to be positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) are not eligible - Patients must not have live vaccine therapies for prevention of infectious diseases within 28 days of first nivolumab dose - Patients who are unable to swallow oral medication are not eligible - Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including chronic prolonged systemic corticosteroids (defined as corticosteroid use of duration one month or greater), should be excluded; these include but are not limited to patients with a history of: - Immune related neurologic disease - Multiple sclerosis - Autoimmune (demyelinating) neuropathy - Guillain-Barre syndrome - Myasthenia gravis - Systemic autoimmune disease such as systemic lupus erythematosus (SLE) - Connective tissue diseases - Scleroderma - Inflammatory bowel disease (IBD) - Crohn's - Ulcerative colitis - Patients with a history of toxic epidermal necrolysis (TEN) - Stevens-Johnson syndrome - Anti-phospholipid syndrome NOTE: Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); --- T315I ---

Inclusion Criteria: - Patients must have a histologically confirmed diagnosis of Ph+ ALL - Detection of one of the following must be present: - t(9;22)(q34;q11) or 3-way variant by metaphase cytogenetics - Breakpoint cluster region (BCR)-Abelson (ABL) positive status by molecular analysis with qualitative polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) - Patients must have primary refractory ALL based on failure to achieve a hematologic or molecular remission after induction therapy with dasatinib and steroids or dasatinib and chemotherapy, or have relapsed after treatment with a tyrosine kinase inhibitor with or without chemotherapy - Note: Prior course of dasatinib and steroid induction therapy should have included dasatinib 140mg PO daily on days 1-84 and prednisone 60mg/m^2 (capped at 120mg, or equivalent steroid dose) on days 1-28; if patients were unable to tolerate full steroid dose during induction therapy they will still be eligible - Note: Patients with refractory or relapsed disease in the central nervous system will be eligible - Prior chemotherapy or tyrosine kinase inhibitor (TKI) treatment, aside from dasatinib, must be >= 7 days before first investigational agent dose - Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 - Patients must have adequate organ and bone marrow function prior to registration, as defined below: - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2 x institutional upper limit of normal (IULN) - Total bilirubin < 2.0 x IULN (unless Gilbert syndrome has been diagnosed); if leukemia infiltration of the liver is suspected to be causing liver function abnormalities the patient will still be eligible with principal investigator (PI) approval - Creatinine < 2 x IULN - Creatinine clearance > 40 mL/min (measured by Cockroft-Gault) - Females of child-bearing potential (FOCBP) must have a negative pregnancy test within 7 days of registration - Note: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: - Has not undergone a hysterectomy or bilateral oophorectomy - Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months) - Women must not be breastfeeding at the time of study registration - Women and men of reproductive potential should agree to use two effective means of birth control - For women, contraception should continue for 23 weeks after the last dose of nivolumab and 12 weeks after the last dose of dasatinib to allow complete clearance of drug and its principal metabolites from the body - For men, contraception should continue for 31 weeks after nivolumab and 12 weeks after dasatinib - Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study Exclusion Criteria: - Patients may not be receiving any other investigational agents within 5 half-lives of the drug (if known); if the half-life is not known, investigational agents should not be taken within two weeks - Patients are not eligible if they have an intolerance to most recent prior TKI (other than dasatinib) at the lowest possible effective dose, defined as a grade >= 3 toxicity considered at least possibly related to that TKI; patients are also excluded if they are intolerant or allergic to dasatinib and discontinued prior therapy due to a >= grade 2 treatment related adverse event - Patients must not have a history of a grade 4 anaphylactic reaction to monoclonal antibody therapy or known hypersensitivity reactions to drugs formulated with polysorbate 90 - Patients must not have had any prior therapy with an anti-PD-1, anti-programmed cell death 1 ligand 1 (PD-L1), anti-programmed cell death 1 ligand 2 (PD-L2), anti-cluster of differentiation (CD)137 or anti-cytotoxic t-lymphocyte-associated protein 4 ligand (CTLA-4) antibody (or any antibody or drug specifically targeting T-cell costimulation or checkpoint pathways; for questions or uncertainties, please contact the PI or quality assurance manager (QAM) - Patients who have had allogeneic hematopoietic stem cell transplant (HSCT) are not eligible if they meet any of the following: - transplant is within 2 months from cycle 1, day 1 (C1D1) - Has clinically significant graft-versus-host disease requiring treatment - Has >= grade 3 persistent non-hematological toxicity related to the transplant - Concomitant use of strong inhibitors of the cytochrome p450, family 3, subfamily a, polypeptide 4 (CYP3A4) isoenzyme is not permitted; must have wash-out period of 5 times the half-life of the compound before first dasatinib dose - Concomitant use of QT prolonging agents strongly associated with torsades de pointes is not permitted - Patients who have a known dasatinib-resistant ABL-kinase mutation such as T315I are not eligible; for confirmation, please contact PI - Patients who have any serious or uncontrolled medical disorder that would impair the ability of the subject to receive protocol therapy are not eligible; these include, but are not limited to: - Active infection that is not well controlled - Known pleural or pericardial effusion at baseline - Clinically significant gastrointestinal disease or digestive dysfunction compromising absorption of dasatinib - Pulmonary arterial hypertension - Uncontrolled or significant cardiovascular disease, including: - Myocardial infarction within 6 months of enrollment date - Uncontrolled angina or congestive heart failure within 3 months of enrollment date - Left ventricular ejection fraction (LVEF) < 40% - Significant cardiac conduction abnormality, including: - History of clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes) - History of second or third degree heart block (except for second degree type 1) - Corrected QT (QTc) interval > 500 msec, unless a cardiac pacemaker is present - Prior malignancy active within the previous 3 years, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancers, superficial bladder cancer, or carcinoma in situ of the prostate, cervix or breast - Subjects with active, known or suspected autoimmune disease; (Note: Subjects with vitiligo, type I diabetes mellitus, hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll) - Psychiatric illness/social situations that would limit compliance with study requirements - Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints - Female patients who are pregnant or nursing are not eligible - Patients are not eligible if they have a known positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (hepatitis C virus [HCV] antibody) indicating acute infection; Note: Patients with evidence of chronic hepatitis B infection will be allowed to enroll if on appropriate suppressive medications under the direction of a hepatologist and with PI approval - Patients who are known to be positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) are not eligible - Patients must not have live vaccine therapies for prevention of infectious diseases within 28 days of first nivolumab dose - Patients who are unable to swallow oral medication are not eligible - Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including chronic prolonged systemic corticosteroids (defined as corticosteroid use of duration one month or greater), should be excluded; these include but are not limited to patients with a history of: - Immune related neurologic disease - Multiple sclerosis - Autoimmune (demyelinating) neuropathy - Guillain-Barre syndrome - Myasthenia gravis - Systemic autoimmune disease such as systemic lupus erythematosus (SLE) - Connective tissue diseases - Scleroderma - Inflammatory bowel disease (IBD) - Crohn's - Ulcerative colitis - Patients with a history of toxic epidermal necrolysis (TEN) - Stevens-Johnson syndrome - Anti-phospholipid syndrome NOTE: Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll Inclusion Criteria: - Patients must have a histologically confirmed diagnosis of Ph+ ALL - Detection of one of the following must be present: - t(9;22)(q34;q11) or 3-way variant by metaphase cytogenetics - Breakpoint cluster region (BCR)-Abelson (ABL) positive status by molecular analysis with qualitative polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) - Patients must have primary refractory ALL based on failure to achieve a hematologic or molecular remission after induction therapy with dasatinib and steroids or dasatinib and chemotherapy, or have relapsed after treatment with a tyrosine kinase inhibitor with or without chemotherapy - Note: Prior course of dasatinib and steroid induction therapy should have included dasatinib 140mg PO daily on days 1-84 and prednisone 60mg/m^2 (capped at 120mg, or equivalent steroid dose) on days 1-28; if patients were unable to tolerate full steroid dose during induction therapy they will still be eligible - Note: Patients with refractory or relapsed disease in the central nervous system will be eligible - Prior chemotherapy or tyrosine kinase inhibitor (TKI) treatment, aside from dasatinib, must be >= 7 days before first investigational agent dose - Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 - Patients must have adequate organ and bone marrow function prior to registration, as defined below: - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2 x institutional upper limit of normal (IULN) - Total bilirubin < 2.0 x IULN (unless Gilbert syndrome has been diagnosed); if leukemia infiltration of the liver is suspected to be causing liver function abnormalities the patient will still be eligible with principal investigator (PI) approval - Creatinine < 2 x IULN - Creatinine clearance > 40 mL/min (measured by Cockroft-Gault) - Females of child-bearing potential (FOCBP) must have a negative pregnancy test within 7 days of registration - Note: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: - Has not undergone a hysterectomy or bilateral oophorectomy - Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months) - Women must not be breastfeeding at the time of study registration - Women and men of reproductive potential should agree to use two effective means of birth control - For women, contraception should continue for 23 weeks after the last dose of nivolumab and 12 weeks after the last dose of dasatinib to allow complete clearance of drug and its principal metabolites from the body - For men, contraception should continue for 31 weeks after nivolumab and 12 weeks after dasatinib - Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study Exclusion Criteria: - Patients may not be receiving any other investigational agents within 5 half-lives of the drug (if known); if the half-life is not known, investigational agents should not be taken within two weeks - Patients are not eligible if they have an intolerance to most recent prior TKI (other than dasatinib) at the lowest possible effective dose, defined as a grade >= 3 toxicity considered at least possibly related to that TKI; patients are also excluded if they are intolerant or allergic to dasatinib and discontinued prior therapy due to a >= grade 2 treatment related adverse event - Patients must not have a history of a grade 4 anaphylactic reaction to monoclonal antibody therapy or known hypersensitivity reactions to drugs formulated with polysorbate 90 - Patients must not have had any prior therapy with an anti-PD-1, anti-programmed cell death 1 ligand 1 (PD-L1), anti-programmed cell death 1 ligand 2 (PD-L2), anti-cluster of differentiation (CD)137 or anti-cytotoxic t-lymphocyte-associated protein 4 ligand (CTLA-4) antibody (or any antibody or drug specifically targeting T-cell costimulation or checkpoint pathways; for questions or uncertainties, please contact the PI or quality assurance manager (QAM) - Patients who have had allogeneic hematopoietic stem cell transplant (HSCT) are not eligible if they meet any of the following: - transplant is within 2 months from cycle 1, day 1 (C1D1) - Has clinically significant graft-versus-host disease requiring treatment - Has >= grade 3 persistent non-hematological toxicity related to the transplant - Concomitant use of strong inhibitors of the cytochrome p450, family 3, subfamily a, polypeptide 4 (CYP3A4) isoenzyme is not permitted; must have wash-out period of 5 times the half-life of the compound before first dasatinib dose - Concomitant use of QT prolonging agents strongly associated with torsades de pointes is not permitted - Patients who have a known dasatinib-resistant ABL-kinase mutation such as T315I are not eligible; for confirmation, please contact PI - Patients who have any serious or uncontrolled medical disorder that would impair the ability of the subject to receive protocol therapy are not eligible; these include, but are not limited to: - Active infection that is not well controlled - Known pleural or pericardial effusion at baseline - Clinically significant gastrointestinal disease or digestive dysfunction compromising absorption of dasatinib - Pulmonary arterial hypertension - Uncontrolled or significant cardiovascular disease, including: - Myocardial infarction within 6 months of enrollment date - Uncontrolled angina or congestive heart failure within 3 months of enrollment date - Left ventricular ejection fraction (LVEF) < 40% - Significant cardiac conduction abnormality, including: - History of clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes) - History of second or third degree heart block (except for second degree type 1) - Corrected QT (QTc) interval > 500 msec, unless a cardiac pacemaker is present - Prior malignancy active within the previous 3 years, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancers, superficial bladder cancer, or carcinoma in situ of the prostate, cervix or breast - Subjects with active, known or suspected autoimmune disease; (Note: Subjects with vitiligo, type I diabetes mellitus, hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll) - Psychiatric illness/social situations that would limit compliance with study requirements - Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints - Female patients who are pregnant or nursing are not eligible - Patients are not eligible if they have a known positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (hepatitis C virus [HCV] antibody) indicating acute infection; Note: Patients with evidence of chronic hepatitis B infection will be allowed to enroll if on appropriate suppressive medications under the direction of a hepatologist and with PI approval - Patients who are known to be positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) are not eligible - Patients must not have live vaccine therapies for prevention of infectious diseases within 28 days of first nivolumab dose - Patients who are unable to swallow oral medication are not eligible - Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including chronic prolonged systemic corticosteroids (defined as corticosteroid use of duration one month or greater), should be excluded; these include but are not limited to patients with a history of: - Immune related neurologic disease - Multiple sclerosis - Autoimmune (demyelinating) neuropathy - Guillain-Barre syndrome - Myasthenia gravis - Systemic autoimmune disease such as systemic lupus erythematosus (SLE) - Connective tissue diseases - Scleroderma - Inflammatory bowel disease (IBD) - Crohn's - Ulcerative colitis - Patients with a history of toxic epidermal necrolysis (TEN) - Stevens-Johnson syndrome - Anti-phospholipid syndrome NOTE: Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); --- T315I --- --- T315I ---

Primary Outcomes

Description: Determine the maximum tolerated dose (MTD) of nivolumab when given in combination with dasatinib, the MTD will be defined as the highest dose level at which ≤ 1 DLT occurs and will be assessed by the Common Terminology Criteria for Adverse Events version 4.03.

Measure: Incidence of Dose-Limiting Toxicity (DLT)

Time: Up to 28 days

Secondary Outcomes

Description: To evaluate the toxicity and safety of nivolumab and dasatinib in patients with relapsed/refractory Ph+ ALL. Adverse events will be assessed by number, frequency, and severity and will be graded according to the NCI's common terminology criteria, version 4.03.

Measure: Incidence of Adverse Events

Time: Up to 28-days after the last dose

Description: Determine the rate of complete hematologic remission (CR) after three cycles of nivolumab and dasatinib

Measure: Rate of Complete Hematologic Remission (CR)

Time: At 84 days (3 cycles)

Description: Determine the rate of molecular remission after three cycles of nivolumab and dasatinib.

Measure: Rate of Molecular Remission

Time: At 84 days (3 cycles)

Description: The serum level of dasatinib will be measured at 24 hours after the start of cycle 1 and on days 8, 15, and 22 prior to treatment during cycle 1.

Measure: Serum Level of Dasatinib

Time: 24 hours after the start of cycle 1 and days 8, 15, and 22 prior to treatment during cycle 1

Description: The serum level of nivolumab will be measured on days 8, 15, and 22 prior to treatment during cycle 1.

Measure: Serum Level of Nivolumab

Time: Days 8, 15, and 22 prior to treatment during cycle 1

Description: Peripheral blood will be evaluated to measure PD1 expression levels and saturation.

Measure: PD1 Expression Levels and Saturation Assessed in the Peripheral Blood

Time: Baseline to 28-days after the last dose

Description: Bone marrow will be assessed to measure PD1 expression levels and saturation.

Measure: PD1 Expression Levels and Saturation in Bone Marrow

Time: Baseline to 28-days after the last dose

Description: T-cell levels and activation will be measured in the peripheral blood after treatment.

Measure: Peripheral T-cell Levels and Activation in Response to Treatment

Time: At cycle 1 days: 1, 2, 8, 15, & 22 prior to dosing

Other Outcomes

Description: Number and percentage of patients that die within the first 30 days of initiating treatment.

Measure: The 30 Day Mortality Rate

Time: Up to 30 days

Description: OS is defined as the time from the initiation of study treatment until death from any cause, evaluated for up to 1 year.

Measure: Overall Survival (OS)

Time: Up to 1 year

Description: PFS is defined as the time from the initiation of study treatment until the time of disease progression or relapse.

Measure: Progression Free Survival (PFS)

Time: Up to 1 year

Description: Duration of remission is defined as the time from achieving complete response until the time of disease relapse.

Measure: Duration of Remission (DOR)

Time: Up to 1 year

Measure: Compare the OS Between Patients Who Receive a Hematopoietic Stem Cell Transplant and Those Who Receive no Further Therapy Following Remission

Time: Up to 1 year

Measure: Presence of Resistance Mutations in Bone Marrow at the Time of Disease Progression

Time: Up to 28-days after the last dose

67 A Multicenter, Open Label Cohort Phase 1 Dose Finding Study to Evaluate Tolerability, Safety, Pharmacokinetics and Preliminary Efficacy of PF-114 Mesylate for Oral Administration in Adult Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myeloid Leukemia (CML), Which is Resistant to the 2-nd Generation Bcr-Abl Inhibitors or Has T315I Mutation in the BCR-ABL Gene

A multicenter, open label cohort Phase 1 dose finding study to evaluate tolerability, safety, pharmacokinetics and preliminary efficacy of PF-114 for oral administration in adult patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML), which is resistant to the 2-nd generation Bcr-Abl inhibitors or has T315I mutation in the BCR-ABL gene.

NCT02885766 Chronic Myeloid Leukemia Leukemia, Myelogenous, Chronic, BCR-ABL Positive Drug: PF-114
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

A Multicenter, Open Label Cohort Phase 1 Dose Finding Study to Evaluate Tolerability, Safety, Pharmacokinetics and Preliminary Efficacy of PF-114 Mesylate for Oral Administration in Adult Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myeloid Leukemia (CML), Which is Resistant to the 2-nd Generation Bcr-Abl Inhibitors or Has T315I Mutation in the BCR-ABL Gene. --- T315I ---

Study to Evaluate Tolerability, Safety, Pharmacokinetics and Preliminary Efficacy of PF-114 for Oral Administration in Adults With Ph+ Chronic Myeloid Leukemia, Which is Resistant to the 2-nd Generation Bcr-Abl Inhibitors or Has T315I Mutation in the BCR-ABL Gene A multicenter, open label cohort Phase 1 dose finding study to evaluate tolerability, safety, pharmacokinetics and preliminary efficacy of PF-114 for oral administration in adult patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML), which is resistant to the 2-nd generation Bcr-Abl inhibitors or has T315I mutation in the BCR-ABL gene. --- T315I ---

Study to Evaluate Tolerability, Safety, Pharmacokinetics and Preliminary Efficacy of PF-114 for Oral Administration in Adults With Ph+ Chronic Myeloid Leukemia, Which is Resistant to the 2-nd Generation Bcr-Abl Inhibitors or Has T315I Mutation in the BCR-ABL Gene A multicenter, open label cohort Phase 1 dose finding study to evaluate tolerability, safety, pharmacokinetics and preliminary efficacy of PF-114 for oral administration in adult patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML), which is resistant to the 2-nd generation Bcr-Abl inhibitors or has T315I mutation in the BCR-ABL gene. --- T315I --- --- T315I ---

Inclusion Criteria: Patients must meet all of the following criteria in order to be eligible for participation in the study: 1. Able to give written informed consent; 2. Male or female patient ≥ 18 years old; 3. Confirmed diagnosis of CML in chronic or accelerated phase according to European LeukemiaNet guideline as of 2013; 4. Available information regarding resistance to the therapy with least one 2-nd generation Bcr-Abl inhibitor (dasatinib or nilotinib or bosutinib), or intolerance of approved Bcr-Abl inhibitors, or presence of T315I mutation irrespective of treatment history; 5. --- T315I ---

Preclinical in vitro and in vivo studies have demonstrated the ability of PF-114 to inhibit wild Bcr-Abl type and with T315I mutation, as well as other kinds of Bcr-Abl with mutations in kinase domain, including combined mutations. --- T315I ---

Indication: Adult patients with Ph+ CML in chronic phase (CP) or accelerated phase (AP) resistant to previous treatment with at least one 2-nd generation inhibitor of Bcr-Abl (dasatinib, nilotinib, bosutinib) or intolerant of approved Bcr-Abl inhibitors or with T315I mutation in the BCR-ABL gene --- T315I ---

Primary Outcomes

Description: To study the dose-limiting toxicities (DLTs) of PF-114 mesylate in the target patient population during the 1-st cycle of treatment

Measure: DLTs during the first cycle of therapy

Time: 1-st Cycle of Therapy - 28 days

Description: Primary Objectives: To determine the maximum tolerated dose (MTD) of PF-114 in the target patient population.

Measure: MTD

Time: 1-st Cycle of Therapy - 28 days

Secondary Outcomes

Description: To assess the safety and tolerability of PF-114 in the target patient population

Measure: The incidence of AEs

Time: through study completion, an average of 1 year

Measure: Cmax for oral PF-114 in the target patient population

Time: 31 days

Measure: Tmax for oral PF-114 in the target patient population

Time: 31 days

Measure: AUC0-t for oral PF-114 in the target patient population

Time: 31 days

Measure: AUC0-∞ for oral PF-114 in the target patient population

Time: 31 days

Measure: T1/2 for oral PF-114 in the target patient population

Time: 31 days

Measure: CL/F for oral PF-114 in the target patient population

Time: 31 days

Measure: Vd/F for single and multiple dosing for oral PF-114 in the target patient population

Time: 31 days

Measure: Ctrough for multiple dosing for oral PF-114 in the target patient population

Time: 31 days

Description: Hematological response is evaluated on Day 1 of each therapy cycle Full hematologic response: Leukocytes < 10 х 109 /L Basophils < 5 % Thrombocytes < 450 х 109 /L No myelocytes, promyelocyts, myeloblasts in the differential Absence of splenomegaly - spleen non palpable

Measure: Hematological response to the treatment based on European LeukemiaNet criteria, 2013.

Time: through study completion, an average of 1 year

Description: Molecular response is evaluated on Day 1 of Cycles 2, 4, 7, 10. For cycles > 12, the molecular response will be evaluated once in 3 months, where the procedure is carried out for the first time during Cycle 13.

Measure: Molecular response - the level of BCR-ABL transcripts in the peripheral blood, determined by the method of quantitative polymerase chain reaction (qPCR) using the international scale.

Time: through study completion, an average of 1 year

Description: Cytogenetic response is evaluated on Day 1, Cycles 4, 7, 13. Then if the level of BCR-ABL transcripts exceeds the level of 0.1% using the qPCR method using the international scale, cytogenetic response is evaluated no earlier than in 3 months after the previous cytogenetic analysis. After the complete cytogenetic response has been reached (CCyR), cytogenetic analysis will be carried out every 12 months.

Measure: Cytogenetic response evaluated using the chromosome banding method (in situ (FISH) fluorescence hybridization is allowed only if the chromosome banding method cannot provide enough information).

Time: through study completion, an average of 1 year

Other Outcomes

Description: To assess pharmacodynamic response to PF-114 mesylate in patients who are not in complete hematologic response upon enrollment into the study by measuring the difference of pCrkL levels in peripheral blood leukocytes (PBL) during therapy compared to baseline

Measure: Pharmacodynamic response criterion to PF-114 (change in the level of pCrkL in PBL during therapy compared to baseline level)

Time: 20 months

Measure: The number of patients who satisfy the pharmacodynamic response criterion depending on the mutation status of BCR-ABL

Time: 20 months

Measure: The number of patients who satisfy the hematologic response depending on the mutation status of BCR-ABL

Time: 20 months

Measure: The number of patients who satisfy the cytogenetic response depending on the mutation status of BCR-ABL

Time: 20 months

Measure: The number of patients who satisfy the molecular response depending on the mutation status of BCR-ABL

Time: 20 months

68 An Observatory for Patients Aged 55 Years and Over With Philadelphia Chromosome Positive (Ph+ or BCR-ABL+) Acute Lymphoblastic Leukemia (ALL) and Treated With the Combination of Tyrosine Kinase Inhibitors and Low Intensity Chemotherapy.

The use of imatinib in combination with chemotherapy is now considered as the gold standard for the treatment of Ph+ ALL. The complete remission (CR) rate is 90% versus 20% to 40% with chemotherapy alone. The combination of imatinib, vincristine and dexamethasone is a well tolerated regimen in aged patients and is also associated with a high CR rate of 80% to 90% in patient aged 55 years and over. 2. Dasatinib is indicated as first line therapy in Ph+ ALL. Results from the EWALLPH-01 are supporting the use of dasatinib in combination with low-intensity chemotherapy. A new EWALL-PH-02 study combining nilotinib in combination with low-intensity chemotherapy is currently initiated within the EWALL centers. 3. The EWALL-PH-01 trial is now closed after the recruitment of 71 patients. The activation of the EWALL-PH-02 trial is expected for Q1 2012. Based on the recruitment of the EWALL-PH-01 study it could be anticipated that 50 to 100 patients aged more than 55 years will be diagnosed during this 6 months period of time. In addition, all the EWALL centers are not participating to the EWALL-PH-02 study and thus these centers could be offered to treat patient following the EWALL backbone in addition to imatinib. 4. A minimum data set will be defined in order to collect the data of the patients treated following the EWALL-PH imatinib study. The main recommendation is to follow as close as possible the procedures of the EWALL-PH-01 trial (mutation analysis, MRD follow-up) in order to have a comparable data set. This imatinib treated cohort of patients would be of particular importance in order to better define the potential benefit of using one TKI compared to one other. From the end of the EWALL-PH-01 study recruitment to the initiation of the EWALL-PH-02 study, patients were treated following the common backbone schedule in combination with imatinib or others TKI. Patients not included in clinical trials for other reasons were also offered a treatment with the combination of TKIs and backbone low-intensity chemotherapy. The goal of this observatory retrospective and prospective is to describe the efficacy and the tolerance of the combination of tyrosine kinase inhibitors in combination with low intensity chemotherapy (EWALL backbone) in patients with Ph+ ALL aged 55 years and over.

NCT02888977 Lymphoblastic Leukemia, Acute
MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid
HPO:Leukemia Lymphoid leukemia

The proportion of Detection of a T315I or F317 BCR-ABL TK mutation. --- T315I ---

Primary Outcomes

Measure: The primary end-point will be Progression Free Survival (PFS) rate at 12 months

Time: 12 months

Secondary Outcomes

Measure: The proportion of Complete haematological remission

Time: 12 months

Measure: The proportion of Major molecular response defined by a BCR-ABL/ABL ≤ 0.1% in bone marrow

Time: 12 months

Measure: The proportion of Complete molecular response

Time: 12 months

Measure: Event free survival

Time: 12 months

Measure: Relapse free survival

Time: 12 months

Measure: Progression free survival

Time: 12 months

Measure: The proportion of Detection of a T315I or F317 BCR-ABL TK mutation

Time: 12 months

Measure: The proportion of molecular progression defined by the loss of major molecular response

Time: 12 months

Measure: Overall survival

Time: 12 months

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Time: 12 months

69 An Open Label Phase II Study to Evaluate the Efficacy and Safety of Induction and Consolidation Therapy With Dasatinib in Combination With Chemotherapy in Patients Aged 55 Years and Over With Philadelphia Chromosome Positive (Ph+ or BCR-ABL+) Acute Lymphoblastic Leukemia (ALL).

1. The use of imatinib in combination or in association with chemotherapy is now considered as the gold standard for the treatment of Ph+ ALL. The complete remission (CR) rate is 90% versus 20% to 40% with chemotherapy alone. The combination of imatinib, vincristine and dexamethasone is a well tolerated regimen in aged patients and is also associated with a high CR rate of 80% to 90% in patient aged 55 years and over. 2. However, despite high CR rates, the progression free survival rate at 12 months of patients treated with the combination of imatinib and chemotherapy is 30% to 50%. Relapses remain frequent and only patients intensified with allogenic haematopoietic stem cell transplantation are in long term remission. This strategy is not fully applicable to most patients aged 55 years and over. 3. Relapses after or during imatinib therapy in patients with Ph+ ALL are associated with BCR-ABL tyrosine kinase domain mutation in 80% of cases, predominantly of the p-loop. The exact incidence of the T315I mutation is controversial and can be estimated to be near 50%. Conversely, the detection of the T315I or F317 mutation in a patient is a very strong predictor of relapse. 4. Dasatinib is a potent SCR and BCR-ABL tyrosine kinase inhibitor with preserved in vitro activity in most of the BCR-ABL mutated cell lines, except for the T315I and F317 mutations. This is also the case in vivo, with patients harbouring BCR-ABL TK domain mutations remaining sensitive to dasatinib. The CHR rate in Ph+ ALL resistant to imatinib is 33% and the median progression-free survival is 3.7 months. Progression free survival (PFS) rate at 12 months is 22%. The goal of this trial is to evaluate the efficacy and the tolerance of the combination of dasatinib with chemotherapy in the front-line setting as induction and consolidation therapy in Ph+ ALL patient aged 55 years and over. A European consensus has been reached to adopt a common chemotherapeutic schedule for patients aged 55 years and over. This schedule will be used in this trial with the addition of dasatinib as concomitant therapy during induction and alternating with chemotherapy during consolidation and maintenance. A CR rate of 90% and a progression free survival of 60% at 12 months are expected. The patients will be prospectively monitored for minimal residual disease and mutation.

NCT02888990 Leukemia, Lymphoblastic, Acute Drug: Dasatinib
MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid
HPO:Leukemia Lymphoid leukemia

The exact incidence of the T315I mutation is controversial and can be estimated to be near 50%. --- T315I ---

Conversely, the detection of the T315I or F317 mutation in a patient is a very strong predictor of relapse. --- T315I ---

4. Dasatinib is a potent SCR and BCR-ABL tyrosine kinase inhibitor with preserved in vitro activity in most of the BCR-ABL mutated cell lines, except for the T315I and F317 mutations. --- T315I ---

The proportion of Detection of a T315I or F317 BCR-ABL TK mutation. --- T315I ---

Primary Outcomes

Measure: Progression free survival at 12 months

Time: 12 months

Secondary Outcomes

Measure: The proportion of Complete haematological remission

Time: 5 years

Measure: The proportion of Major molecular response defined by a BCR-ABL/ABL ≤ 0.1% in bone marrow

Time: 5 years

Measure: The proportion of Complete molecular response

Time: 5 years

Measure: Event free survival

Time: 5 years

Measure: Relapse free survival

Time: 5 years

Measure: Progression free survival

Time: 5 years

Measure: The proportion of Detection of a T315I or F317 BCR-ABL TK mutation

Time: 5 years

Measure: The proportion of Molecular progression

Time: 5 years

Measure: Overall survival

Time: 5 years

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Time: 5 years

Measure: Death during induction

Time: 2 months

Measure: Death in complete remission

Time: 5 years

70 An Open-Label Phase II Dose Optimization Study of Bosutinib at a Starting Dose of 300 Mg Daily for Adult Patients With Chronic Myeloid Leukemia (CML) in Chronic Phase Post Frontline TKI Failure

This phase II trial studies how well bosutinib works in treating patients with chronic myeloid leukemia in chronic phase after frontline tyrosine kinase inhibitor (TKI) failure. Bosutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

NCT02906696 Blasts Under 15 Percent of Bone Marrow Nucleated Cells Blasts Under 15 Percent of Peripheral Blood White Cells Blasts Under 30 Percent of Bone Marrow Nucle Blasts Under 30 Percent of Bone Marrow Nucleated Cells Blasts Under 30 Percent of Peripheral Blood White Cells Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Drug: Bosutinib Other: Laboratory Biomarker Analysis
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Cox proportional hazards regression models will be fit to assess the association between patient characteristics including ABL kinase domain mutation status.. Inclusion Criteria: - Patients with chronic myeloid leukemia (CML) in chronic phase who have resistance and/or intolerance to frontline TKI therapy; resistance is defined as lack (lack defined as response not achieved or lost by the given dates mentioned hereafter) of CHR (complete hematologic response) within 3 months, lack of major cytogenetic response (MCyR) within 6 months, and lack of CCyR within 12 months of therapy with frontline TKIs; in addition, loss of MCyR, CCyR or MMR at any time during the course of therapy is also considered resistance to therapy; intolerance is defined as persistent or severe toxicity that is unacceptable to the patient - Chronic phase disease is defined as: - < 15% blasts in peripheral blood and bone marrow; - < 30% blasts plus promyelocytes in peripheral blood and bone marrow; - < 20% basophils in peripheral blood; - >= 100 x 10^9/L platelets (>= 100,000/mm^3); - No evidence of extramedullary disease except hepatosplenomegaly; and - No prior diagnosis of accelerated phase (AP) or blastic phase-chronic myeloid leukemia (BP-CML); patients with clonal evolution but no other criteria for accelerated phase are eligible - Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 - Creatinine less than or equal to 2.0 mg/dl - Bilirubin less than or equal to 2.0 mg/dl - Alanine aminotransferase (ALT) less than or equal to 3 times institutional upper limit of normal - Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotrophin (beta-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use one of the following effective contraception methods during the study and for 30 days following the last dose of study drug; effective methods of birth control include: - Birth control pills, shots or implants (placed under the skin by a health care provider) or patches (placed on the skin); - Intrauterine devices (IUDs); - Condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide; females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy - Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug - Patients or their legally authorized representative must provide written informed consent Exclusion Criteria: - Women who are pregnant or lactating - Known to be human immunodeficiency virus (HIV)+ - Active and uncontrolled disease/infection that in the opinion of the treating physician and principal investigator may affect the ability to participate in the trial or put the patient at unduly high risk - Unable or unwilling to sign the informed consent document - Received no other investigational therapy within the past 14 days - Presence of T315I mutation by ABL1 sequencing - Patient is currently in complete cytogenetic remission (CCyR) Inclusion Criteria: - Patients with chronic myeloid leukemia (CML) in chronic phase who have resistance and/or intolerance to frontline TKI therapy; resistance is defined as lack (lack defined as response not achieved or lost by the given dates mentioned hereafter) of CHR (complete hematologic response) within 3 months, lack of major cytogenetic response (MCyR) within 6 months, and lack of CCyR within 12 months of therapy with frontline TKIs; in addition, loss of MCyR, CCyR or MMR at any time during the course of therapy is also considered resistance to therapy; intolerance is defined as persistent or severe toxicity that is unacceptable to the patient - Chronic phase disease is defined as: - < 15% blasts in peripheral blood and bone marrow; - < 30% blasts plus promyelocytes in peripheral blood and bone marrow; - < 20% basophils in peripheral blood; - >= 100 x 10^9/L platelets (>= 100,000/mm^3); - No evidence of extramedullary disease except hepatosplenomegaly; and - No prior diagnosis of accelerated phase (AP) or blastic phase-chronic myeloid leukemia (BP-CML); patients with clonal evolution but no other criteria for accelerated phase are eligible - Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 - Creatinine less than or equal to 2.0 mg/dl - Bilirubin less than or equal to 2.0 mg/dl - Alanine aminotransferase (ALT) less than or equal to 3 times institutional upper limit of normal - Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotrophin (beta-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use one of the following effective contraception methods during the study and for 30 days following the last dose of study drug; effective methods of birth control include: - Birth control pills, shots or implants (placed under the skin by a health care provider) or patches (placed on the skin); - Intrauterine devices (IUDs); - Condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide; females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy - Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug - Patients or their legally authorized representative must provide written informed consent Exclusion Criteria: - Women who are pregnant or lactating - Known to be human immunodeficiency virus (HIV)+ - Active and uncontrolled disease/infection that in the opinion of the treating physician and principal investigator may affect the ability to participate in the trial or put the patient at unduly high risk - Unable or unwilling to sign the informed consent document - Received no other investigational therapy within the past 14 days - Presence of T315I mutation by ABL1 sequencing - Patient is currently in complete cytogenetic remission (CCyR) Blasts Under 15 Percent of Bone Marrow Nucleated Cells Blasts Under 15 Percent of Peripheral Blood White Cells Blasts Under 30 Percent of Bone Marrow Nucle Blasts Under 30 Percent of Bone Marrow Nucleated Cells Blasts Under 30 Percent of Peripheral Blood White Cells Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase PRIMARY OBJECTIVES: I. To assess the response rate within 24 weeks in patients in chronic phase receiving bosutinib with the starting dose of 300 mg per day, with potential escalation to 400 mg, 500 mg and 600 mg per day. --- T315I ---

Cox proportional hazards regression models will be fit to assess the association between patient characteristics including ABL kinase domain mutation status.. Inclusion Criteria: - Patients with chronic myeloid leukemia (CML) in chronic phase who have resistance and/or intolerance to frontline TKI therapy; resistance is defined as lack (lack defined as response not achieved or lost by the given dates mentioned hereafter) of CHR (complete hematologic response) within 3 months, lack of major cytogenetic response (MCyR) within 6 months, and lack of CCyR within 12 months of therapy with frontline TKIs; in addition, loss of MCyR, CCyR or MMR at any time during the course of therapy is also considered resistance to therapy; intolerance is defined as persistent or severe toxicity that is unacceptable to the patient - Chronic phase disease is defined as: - < 15% blasts in peripheral blood and bone marrow; - < 30% blasts plus promyelocytes in peripheral blood and bone marrow; - < 20% basophils in peripheral blood; - >= 100 x 10^9/L platelets (>= 100,000/mm^3); - No evidence of extramedullary disease except hepatosplenomegaly; and - No prior diagnosis of accelerated phase (AP) or blastic phase-chronic myeloid leukemia (BP-CML); patients with clonal evolution but no other criteria for accelerated phase are eligible - Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 - Creatinine less than or equal to 2.0 mg/dl - Bilirubin less than or equal to 2.0 mg/dl - Alanine aminotransferase (ALT) less than or equal to 3 times institutional upper limit of normal - Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotrophin (beta-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use one of the following effective contraception methods during the study and for 30 days following the last dose of study drug; effective methods of birth control include: - Birth control pills, shots or implants (placed under the skin by a health care provider) or patches (placed on the skin); - Intrauterine devices (IUDs); - Condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide; females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy - Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug - Patients or their legally authorized representative must provide written informed consent Exclusion Criteria: - Women who are pregnant or lactating - Known to be human immunodeficiency virus (HIV)+ - Active and uncontrolled disease/infection that in the opinion of the treating physician and principal investigator may affect the ability to participate in the trial or put the patient at unduly high risk - Unable or unwilling to sign the informed consent document - Received no other investigational therapy within the past 14 days - Presence of T315I mutation by ABL1 sequencing - Patient is currently in complete cytogenetic remission (CCyR) Inclusion Criteria: - Patients with chronic myeloid leukemia (CML) in chronic phase who have resistance and/or intolerance to frontline TKI therapy; resistance is defined as lack (lack defined as response not achieved or lost by the given dates mentioned hereafter) of CHR (complete hematologic response) within 3 months, lack of major cytogenetic response (MCyR) within 6 months, and lack of CCyR within 12 months of therapy with frontline TKIs; in addition, loss of MCyR, CCyR or MMR at any time during the course of therapy is also considered resistance to therapy; intolerance is defined as persistent or severe toxicity that is unacceptable to the patient - Chronic phase disease is defined as: - < 15% blasts in peripheral blood and bone marrow; - < 30% blasts plus promyelocytes in peripheral blood and bone marrow; - < 20% basophils in peripheral blood; - >= 100 x 10^9/L platelets (>= 100,000/mm^3); - No evidence of extramedullary disease except hepatosplenomegaly; and - No prior diagnosis of accelerated phase (AP) or blastic phase-chronic myeloid leukemia (BP-CML); patients with clonal evolution but no other criteria for accelerated phase are eligible - Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 - Creatinine less than or equal to 2.0 mg/dl - Bilirubin less than or equal to 2.0 mg/dl - Alanine aminotransferase (ALT) less than or equal to 3 times institutional upper limit of normal - Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotrophin (beta-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use one of the following effective contraception methods during the study and for 30 days following the last dose of study drug; effective methods of birth control include: - Birth control pills, shots or implants (placed under the skin by a health care provider) or patches (placed on the skin); - Intrauterine devices (IUDs); - Condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide; females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy - Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug - Patients or their legally authorized representative must provide written informed consent Exclusion Criteria: - Women who are pregnant or lactating - Known to be human immunodeficiency virus (HIV)+ - Active and uncontrolled disease/infection that in the opinion of the treating physician and principal investigator may affect the ability to participate in the trial or put the patient at unduly high risk - Unable or unwilling to sign the informed consent document - Received no other investigational therapy within the past 14 days - Presence of T315I mutation by ABL1 sequencing - Patient is currently in complete cytogenetic remission (CCyR) Blasts Under 15 Percent of Bone Marrow Nucleated Cells Blasts Under 15 Percent of Peripheral Blood White Cells Blasts Under 30 Percent of Bone Marrow Nucle Blasts Under 30 Percent of Bone Marrow Nucleated Cells Blasts Under 30 Percent of Peripheral Blood White Cells Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase PRIMARY OBJECTIVES: I. To assess the response rate within 24 weeks in patients in chronic phase receiving bosutinib with the starting dose of 300 mg per day, with potential escalation to 400 mg, 500 mg and 600 mg per day. --- T315I --- --- T315I ---

Primary Outcomes

Description: Response is defined as follows: 1) For patients who do not currently have a partial cytogenetic response (PCyR), achievement of major cytogenetic response is considered a response. 2) For patients who are currently in PCyR, achievement of CCyR is considered a response. The Simon's optimal two-stage design will be used for interim futility monitoring. Will be estimated along with the 95% credible interval.

Measure: Response Rate

Time: Up to 6 months

Secondary Outcomes

Description: Will be summarized.

Measure: Number of Participants With Treatment Interruptions and Dose Reductions

Time: Up to 2 years

Description: Will be estimated along with the exact 95% confidence intervals. Molecular assessments are based on quantitative reverse transcriptase polymerase chain reaction for Bcr-Abl in peripheral blood. Molecular response is categorized as MMR (Bcr-Abl/Abl ratio of Measure: Rates of Major Molecular Response (MR), MR4, MR4.5 and Complete Molecular Response

Time: Up to 2 years

Description: Will be assessed using the international scale. Will be estimated along with the exact 95% confidence intervals.

Measure: Rates of BCR-ABL/ABL <10%

Time: At 3 months

Description: Will be assessed using the international scale. Will be estimated along with the exact 95% confidence intervals.

Measure: Rates of BCR-ABL/ABL < 1%

Time: At 6 months

Description: Will be assessed by Kaplan-Meier methods. Cox proportional hazards regression models will be fit to assess the association between patient characteristics including survival outcome. Time from date of treatment start until date of death due to any cause or last Follow-up.

Measure: Overall Survival

Time: Up to 2 years

Description: Time from date of treatment start until the date of first objective documentation of disease-relapse.

Measure: Event-free Survival

Time: Up to 2 years

Description: Will be assessed by Kaplan-Meier methods. Transformation-free survival is defined as the time from treatment initiation until either progression to AP/BP or death from any cause.

Measure: Transformation-free Survival

Time: Up to 2 years

Description: Will be summarized and its association with survival outcomes will be analyzed through landmark analyses. Cox proportional hazards regression models will be fit to assess the association between patient characteristics including ABL kinase domain mutation status.

Measure: Change of ABL Kinase Domain Mutation Status

Time: Baseline up to 2 years

71 A Phase Ib/IIa Single-arm, Open-label Clinical Trial to Evaluate the Safety, Pharmacokinetics, and Efficacy of BP1001 (a Liposomal Grb2 Antisense Oligonucleotide) in Combination With Dasatinib in Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia (CML) Including Chronic Phase Patients Who Have Failed Initial Tyrosine Kinase Inhibitor (TKI) Therapy, Accelerated or Blast Phase, Ph+ Acute Myeloid Leukemia (AML) or High-risk Ph+ Myelodysplastic Syndrome (MDS)

The primary objective of the Phase Ib study is to determine the dose-limiting toxicity (DLT) and maximal tolerated dose (MTD) of BP1001 in combination with dasatinib in patients with with Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia (CML) including chronic phase patients who have failed initial tyrosine kinase inhibitor (TKI) therapy, accelerated or blast phase, Ph+ Acute Myeloid Leukemia (AML) or High-risk Ph+ Myelodysplastic Syndrome (MDS). The primary objective of the Phase IIa study is to assess the efficacy of the combination of BP1001 and dasatinib in patients with Ph+ CML, Ph+AML, or high-risk Ph+ MDS.

NCT02923986 Chronic Myelogenous Leukemia, Ph1-Positive Acute Myeloid Leukemia Myelodysplastic Syndrome Drug: BP1001 (varying dose) Drug: BP1001 (fixed dose) Drug: Dasatinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Preleukemia Leukemia, Myelogenous, Chronic, BCR-ABL Positive Myelodysplastic Syndromes
HPO:Acute megakaryocytic leukemia Acute myeloid leukemia Chronic myelogenous leukemia Leukemia Myelodysplasia Myeloid leukemia

× 0.74 [if female] x 1.212 [if African American (AA)] - Creatinine clearance estimated by 24-hr urine collection for creatinine clearance 6. Documented Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 7. Recovered from the effects of any prior surgery, radiotherapy, or antineoplastic treatment (with the exception of alopecia), based on Investigator assessment 8. Willing and able to provide written informed consent Exclusion Criteria At the time of Screening, participants who meet any of the following criteria will be excluded from participating in the study: 1. Patients with T315I mutation will not be excluded, but their response will be analyzed separately. --- T315I ---

Primary Outcomes

Description: Phase 1b portion of the study: Determine the dose limiting toxicity of BP1001 in combination with Das

Measure: Dose Limiting Toxicity of BP1001 using non-hematologic and hematologic parameters per NCI CTCAE criteria

Time: 240 days

Description: Phase 1b portion of the study: Determine the maximum tolerated dose of BP1001 in combination with Das

Measure: Maximum Tolerated Dose of BP1001 using non-hematologic and hematologic parameters per NCI CTCAE criteria

Time: 240 days

Description: Phase IIa portion of the study: Assess the efficacy of the combination of BP1001 and Das

Measure: Efficacy of the combination of BP1001 and Das using hematologic response by bone marrow aspirate or biopsy and complete blood counts

Time: 240 days

Description: Phase IIa portion of the study: Assess the efficacy of the combination of BP1001 and Das

Measure: Efficacy of the combination of BP1001 and Das using cytogenetic response (karyotyping) by bone marrow aspirate or biopsy

Time: 240 days

Description: Phase IIa portion of the study: Assess the efficacy of the combination of BP1001 and Das

Measure: Efficacy of the combination of BP1001 and Das using molecular response (PCR) by bone marrow aspirate or biopsy

Time: 240 days

Secondary Outcomes

Description: Evaluate Safety of BP1001 in combination with Das

Measure: Safety of BP1001 in combination with Das using non-hematologic and hematologic parameters per NCI CTCAE criteria

Time: 30 days

Description: Determine whether the combination of BP1001 and Das provides greater efficacy (Hematologic Response) than Das alone (by historical comparison)

Measure: Efficacy of the combination of BP1001 and Das using hematologic response by bone marrow aspirate or biopsy and complete blood counts versus Das alone by historical outcome comparison

Time: 240 days

Description: Determine whether the combination of BP1001 and Das provides greater efficacy (Cytogenetic Response) than Das alone (by historical comparison)

Measure: Efficacy of the combination of BP1001 and Das using cytogenetic response (karyotyping) by bone marrow aspirate or biopsy versus Das alone by historical outcome comparison

Time: 240 days

Description: Determine whether the combination of BP1001 and Das provides greater efficacy (Molecular Response) than Das alone (by historical comparison)

Measure: Efficacy of the combination of BP1001 and Das using molecular response (PCR) by bone marrow aspirate or biopsy versus Das alone by historical outcome comparison

Time: 240 days

Description: Evaluate in vivo PK of BP1001 when given alone and in combination with Das

Measure: In vivo PK using plasma to compute half life and elimination

Time: 30 days

Description: Assess time to response from administration of BP1001 + Das to hematologic response

Measure: Time to Response using hematologic response using bone marrow biopsy or aspirate and complete blood counts

Time: 30 days

Description: Assess time to response from administration of BP1001 + Das to cytogenetic response

Measure: Time to Response using cytogenetic response (karyotyping) using bone marrow biopsy or aspirate

Time: 30 days

Description: Assess time to response from administration of BP1001 + Das to molecular response

Measure: Time to Response using molecular response (PCR) using bone marrow biopsy or aspirate

Time: 30 days

Description: Assess duration of response from day of response to day of disease progression

Measure: Duration of Response using hematologic response using bone marrow biopsy or aspirate and complete blood counts from day of response to day of disease progression

Time: 30 days

Description: Assess duration of response from day of response to day of disease progression

Measure: Duration of Response using cytogenetic response (karyotyping) using bone marrow biopsy or aspirate from day of response to day of disease progression

Time: 30 days

Description: Assess duration of response from day of response to day of disease progression

Measure: Duration of Response using molecular response (PCR) using bone marrow biopsy or aspirate from day of response to day of disease progression

Time: 30 days

Description: Assess overall survival from date of study entry to study closure

Measure: Overall Survival from date of study entry to study closure

Time: 240 days

72 Overall Survival With Ponatinib Versus Allogeneic Stem Cell Transplant in Philadelphia-positive Leukemias With the T315I Mutation

Effective treatment options for chronic myeloid leukemia (CML) or Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) patients with the T315I mutation are few. This study compared overall survival (OS) between CML and Ph+ ALL patients treated with ponatinib versus allogeneic stem cell transplantation (allo-SCT).

NCT02981784 Leukemia Drug: Ponatinib (Iclusig®) Procedure: allogeneic stem cell transplantation
MeSH:Leukemia
HPO:Leukemia

Overall Survival With Ponatinib Versus Allogeneic Stem Cell Transplant in Philadelphia-positive Leukemias With the T315I Mutation. --- T315I ---

Comparative Evaluation of Results of Allogeneic Hematopoietic Stem Cells Versus Ponatinib in CML Patients Carrying a Mutation T315I Effective treatment options for chronic myeloid leukemia (CML) or Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) patients with the T315I mutation are few. --- T315I ---

Comparative Evaluation of Results of Allogeneic Hematopoietic Stem Cells Versus Ponatinib in CML Patients Carrying a Mutation T315I Effective treatment options for chronic myeloid leukemia (CML) or Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) patients with the T315I mutation are few. --- T315I --- --- T315I ---

Inclusion Criteria: - CML any phase with T315I mutation - Ph+ ALL with a T315I mutation - Being treated in the PACE trial according to the criteria of this phase II trial - Or being allogeneic stem cell transplanted with any source of allogeneic cells and after any conditioning regimen. --- T315I ---

Inclusion Criteria: - CML any phase with T315I mutation - Ph+ ALL with a T315I mutation - Being treated in the PACE trial according to the criteria of this phase II trial - Or being allogeneic stem cell transplanted with any source of allogeneic cells and after any conditioning regimen. --- T315I --- --- T315I ---

Exclusion Criteria: - Ph negative patients - Patients under 18 years Inclusion Criteria: - CML any phase with T315I mutation - Ph+ ALL with a T315I mutation - Being treated in the PACE trial according to the criteria of this phase II trial - Or being allogeneic stem cell transplanted with any source of allogeneic cells and after any conditioning regimen. --- T315I ---

Exclusion Criteria: - Ph negative patients - Patients under 18 years Inclusion Criteria: - CML any phase with T315I mutation - Ph+ ALL with a T315I mutation - Being treated in the PACE trial according to the criteria of this phase II trial - Or being allogeneic stem cell transplanted with any source of allogeneic cells and after any conditioning regimen. --- T315I --- --- T315I ---

Primary Outcomes

Measure: Overall survival after either allogeneic stem cell transplantation or Ponatinib initiation. (Time between therapeutic intervention and death, in months)

Time: From date of inclusion until the date of death, assessed up to 180 months

73 Adoptive Transfer of T Regulatory Cell for Suppression of Acute Graft-vs-Host-Disease After an Umbilical Cord Blood Transplant for Hematologic Malignancies

This is a single center pilot study of a non-myeloablative umbilical cord blood transplant for the treatment of a hematological malignancy with a single infusion of T regulatory (Treg) given shortly after UCB transplantation.

NCT02991898 Acute Lymphoblastic Leukemia Burkitt Lymphoma Natural Killer Cell Malignancies Chronic Myelogenous Leukemia Myelodysplastic Syndromes Large-cell Lymphoma Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma Marginal Zone B-Cell Lymphoma Follicular Lymphoma Lymphoplasmacytic Lymphoma Mantle-Cell Lymphoma Prolymphocytic Leukemia Hodgkin Lymphoma Multiple Myeloma Acute Myelogenous Leukemia Biphenotypic Leukemia Undifferentiated Leukemia Biological: Infusion of Treg
MeSH:Burkitt Lymphoma Lymphoma Leukemia Multiple Myeloma Precursor Cell Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphocytic, Chronic, B-Cell Leukemia, Myeloid Lymphoma, Mantle-Cell Leukemia, Myelogenous, Chronic, BCR-ABL Positive Lymphoma, B-Cell, Marginal Zone Leukemia, Myeloid, Acute Leukemia, Prolymphocytic Waldenstrom Macroglobulinemia Myelodysplastic Syndromes Neoplasms
HPO:Acute megakaryocytic leukemia Acute myeloid leukemia Burkitt lymphoma Chronic lymphatic leukemia Chronic myelogenous leukemia Leukemia Lymphoma Monoclonal immunoglobulin M proteinemia Multiple myeloma Myelodysplasia Myeloid leukemia Neoplasm

Chronic phase patients must have failed at least two different tyrosine-kinase inhibitors (TKIs), or been intolerant to all available TKIs or have T315I mutation. --- T315I ---

Primary Outcomes

Description: Measured by the length of Treg survival after infusion of Treg

Measure: Efficacy of Intervention

Time: 2 years

Secondary Outcomes

Description: Probability of grade II-IV aGVHD

Measure: Grade II-IV aGVHD

Time: Assessed weekly until day 100, then day 180, 360

Description: Probability of grade III-IV aGVHD

Measure: Grade III-IV aGVHD

Time: Assessed weekly until day 100, then day 180, 360

Description: Evaluated with descriptive statistics and plots or cumulative incidence curves if enough evaluable patients are available for time-to-event endpoints.

Measure: Treatment related mortality (TRM)

Time: 6 months

Description: Evaluated with descriptive statistics and plots or cumulative incidence curves if enough evaluable patients are available for time-to-event endpoints.

Measure: Relapse

Time: 1 year

Description: Evaluated with descriptive statistics and plots or cumulative incidence curves if enough evaluable patients are available for time-to-event endpoints.

Measure: Incidence of viral and fungal infections

Time: 1 year

Description: The proportion of patients with detectable Treg cells at day 14 post infusion

Measure: Detectable Treg cells

Time: Day 14

Description: The proportion of patients with immune reconstitution. Continuous endpoints will be described by medians, ranges and interquartile ranges as well as means and standard deviations if normally distributed.

Measure: Immune reconstitution

Time: Assessed at Day 4, weekly for 8 weeks

Description: Incidence of Adverse Events

Measure: Treg Cell Infusion Toxicity

Time: 48 hours post infusion

Description: Length of Treg survival after infusion of Treg.

Measure: Treg Survival

Time: 24 hours post infusion

Description: The incidence of chimerism in patients treated

Measure: Chimerism

Time: Day +100

Description: The probability of survival, one year post-treatment

Measure: Survival

Time: 1 year

Description: The incidence of neutrophil recovery in treated patients

Measure: Neutrophil Recovery

Time: Day 42

Description: The incidence of platelet recovery in treated patients

Measure: Platelet Recovery

Time: 1 year

Description: The incidence of chronic GVHD in treated patients after one year

Measure: Chronic GVHD

Time: 1 year

74 Administration of Autologous CAR-T Cells Targeting the CD19 Antigen and Containing the Inducible caspase9 Safety Switch in Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

The body has different ways of fighting infection and disease. No single way is effective at fighting cancer. This research study combines two different ways of fighting disease: antibodies and T cells. Antibodies are proteins that protect the body from disease caused by bacteria or toxic substances. Antibodies work by binding those bacteria or substances, which stops them from growing and causing bad effects. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected. Both antibodies and T cells have been used to treat patients with cancers. They both have shown promise, but neither alone has been sufficient to cure most patients. This study combines both T cells and antibodies to try to create a more effective treatment. This investigational treatment is called autologous T lymphocyte chimeric antigen receptor cells targeted against the CD19 antigen (ATLCAR.CD19) administration. In previous studies, it has been shown that a new gene can be put into T cells that will increase their ability to recognize and kill cancer cells. A gene is a unit of DNA. Genes make up the chemical structure carrying your genetic information that may determine human characteristics (i.e., eye color, height and sex). The new gene that is put in the T cells makes a piece of an antibody called anti-CD19. This antibody can flow through the blood and can find and stick to leukemia cells because these leukemia cells have a substance on their surface called CD19. Anti-CD19 antibodies have been used to treat people with leukemia but have not been strong enough to cure most patients. For this study, the anti-CD19 antibody has been changed so that instead of floating free in the blood a piece of it is now joined to the surface of the T cells. Only the part of the antibody that sticks to the leukemia cells is attached to the T cells instead of the entire antibody. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These CD19 chimeric (combination) receptor-activated T cells kill some of the tumor, but they do not last very long in the body and so their chances of fighting the cancer are unknown. Preliminary results of giving ATLCAR.CD19 cells to leukemia patients have been encouraging; however, many subjects receiving this treatment have experienced unwanted side effects including neurotoxicity and/or cytokine release syndrome (also referred to as cytokine storm or an infusion reaction). Cytokines are small proteins that aract as e signals to other cells and are the way cells talk to one another. During cytokine release syndromesyndrome, too many cytokines are released and too many cells in your body react to their release. Symptoms resulting from cytokine release syndrome vary from flu-like symptoms to more severe side effects such as cardiac arrest, multi-system organ failure or death. We predict that about 50% of patients on this study will experience mild to severe cytokine release syndrome. To help reduce cytokine release syndrome symptoms in future patients, a safety switch has been added to the ATLCAR.CD19 cells that can cause the cells to become dormant or "go to sleep". The safety switch is called inducible caspase 9 or iC9. The modified ATLCAR.CD19 cells with the safety switch are referred to as iC9-CAR19 cells. The purpose of this study is to determine whether receiving the iC9-CAR19 cells is safe and tolerable (there are not too many unwanted effects). If you experience severe cytokine release syndrome or moderate to severe cytokine release syndrome that does not get better once you are given standard treatments, you may be given a second study drug called rimiducid. Similar studies showed that rimiducid can to turn on the safety switch, iC9 in other therapies. Using rimiducid to activate the safety switch may be done in addition to treating you according to hospital guidelines and making all efforts to immediately attend to your cytokine release syndrome symptoms

NCT03016377 Acute Lymphoblastic Leukemia Immune System Diseases Immunoproliferative Disorders Biological: iC9-CAR19 cells Drug: Rimiducid Drug: Cyclophosphamide Drug: Fludarabine
MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Immunoproliferative Disorders Immune System Diseases
HPO:Leukemia Lymphoid leukemia

Subject with the T315I ABL kinase point mutation eligible if have failed ponatinib-containing therapy, regardless of number of prior ABL TKIs - CD19 positivity of lymphoblasts confirmed by flow cytometry or IHC per institutional standards - Life expectancy ≥12 weeks - Demonstrate adequate renal and hepatic function as defined below: System Laboratory Value Renal*: Serum Creatinine (sCr) ≤ 1.5 × ULN Hepatic: Total bilirubin (tBili) ≤ 1.5 × ULN, unless attributed to Gilbert's Syndrome; Aspartate aminotransferase (AST) ≤ 3.0 × ULN; Alanine aminotransferase (ALT) ≤ 3.0 × ULN *For pediatric patients, adequate renal function defined below: Age: Maximum sCr (mg/dL) (Male, Female) 3 to <6 years: ≤0.8, ≤0.8; 6 to <10 years: ≤1, ≤1; 10 to <13 years: ≤1.2, ≤1.2; 13 to <16 years: ≤1.5, ≤1.4; 16 to <18 years: ≤1.7, ≤1.4 - Females of childbearing potential (WOCBP) must have a negative serum pregnancy test prior to procurement. --- T315I ---

Primary Outcomes

Description: Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (AEs) (CTCAE, version 5.0), a descriptive terminology which can be utilized for AE reporting. A grading (severity) scale is provided for each AE term/symptom: Grade 1 (Mild; asymptomatic); Grade 2 (Moderate; minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening; hospitalization indicated; disabling); Grade 4 (Life-threatening consequences; urgent intervention indicated); Grade 5 (Death related to AE). Immune effector cell-associated neurotoxicity syndrome (ICANS) symptoms will be graded according to the criteria outlined in the protocol on a scale from 1 (mild) to 4 (critical). Cytokine release syndrome (CRS) will be graded according to criteria outlined in the protocol on a scale from 1 (mild) to grade 5 (death).

Measure: Number of participants with adverse events as a measure of safety and tolerability of iC9-CAR19 T cells

Time: 4 weeks

Secondary Outcomes

Description: The recommended phase 2 dose of iC9-CAR19 cells in adult and pediatric subjects will be determined maximum dose at which no more than one out of six patients experiences a dose limiting toxicity (DLT). A DLT is defined according to protocol criteria using the NCI CTCAE, ICANS, and CRS criteria. In general, a DLT is any grade 3 or higher event that is at least possibly related to iC9-CAR19 T cells.

Measure: Incidence of dose limiting toxicity to identify recommended phase 2 dose (RP2D)

Time: 4 weeks

Description: Persistence of iC9-CAR19 T cells in vivo will be determined by quantitative polymerase chain reaction (PCR) and flow cytometry in samples of peripheral blood.

Measure: Changes in persistence of iC9-CAR19 T cells in vivo

Time: 15 years

Description: ORR (Complete Response/Complete Response with incomplete recovery of counts) to first iC9-CAR19 T cell therapy will be determined using National Comprehensive Cancer Network Response Criteria (NCCN) for acute lymphoblastic leukemia. Assessment of minimal residual disease will be included as criterion of response (ie, the percentage of subjects who achieve CRm [defined as minimal residual disease negative complete response] by either flow cytometry or PCR analysis will be determined)

Measure: Overall Response Rate (ORR)

Time: 15 years

Description: Overall survival will be measured from the date of administration of first iC9-CAR19 T cells to the date of death.

Measure: Overall survival after infusion of iC9-CAR19 T cells

Time: 15 years

Description: Event free survival rate applies to all subjects and will be measured from the date of administration of first iC9-CAR19 T cells to the date of signs and symptoms of treatment failure or relapse from complete response or complete response with incomplete recovery of counts, or death from any cause; subjects not known to have any of these events are censored on the date they were last examined.

Measure: Event-free survival rate

Time: 15 years

Description: Relapse-free survival rate will apply only to subjects achieving complete response or complete response with incomplete recovery of counts and measured from the date of achievement of a remission until the date of relapse or death from any cause; subjects not known to have relapsed or died at last follow-up are censored on the date they were last examined.

Measure: Relapse-free survival rate

Time: 15 years

Description: The NCI Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) is a patient-reported outcome measurement system developed to characterize the frequency, severity and interference of 78 symptomatic treatment toxicities.

Measure: Incidence of patient reported symptoms in adult patients using selected symptoms from the NCI PRO-CTCAE

Time: 15 years

Description: Patient reported physical functions in adult patients will be assessed per the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Score derived from the PROMIS Physical Function Short Form 20a v1.0. PROMIS is a set of person-centered measures, developed by the US Department of Health and Human Services, that evaluates and monitors physical, mental, and social health on a five point Likert scale with higher score indicating better functioning.

Measure: Changes in patient reported physical functions in adult patients

Time: 15 years

Description: Patient reported health-related quality of life will be assessed using the PROMIS (Patient-Reported Outcomes Measurement Information System) Global Health Score derived from the PROMIS Global Health Short Form v1.0-1.1. PROMIS is a set of person-centered measures, developed by the US Department of Health and Human Services, that evaluates and monitors physical, mental, and social health health on a five point Likert scale with higher score indicating better functioning.

Measure: Changes in patient reported health-related quality of life in adult patients

Time: 15 years

Description: Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (AEs) (CTCAE, version 5.0), a descriptive terminology which can be utilized for AE reporting. A grading (severity) scale is provided for each AE term/symptom: Grade 1 (Mild; asymptomatic); Grade 2 (Moderate; minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening; hospitalization indicated; disabling); Grade 4 (Life-threatening consequences; urgent intervention indicated); Grade 5 (Death related to AE). Immune effector cell-associated neurotoxicity syndrome (ICANS) symptoms will be graded according to the criteria outlined in the protocol on a scale from 1 (mild) to 4 (critical). Cytokine release syndrome (CRS) will be graded according to criteria outlined in the protocol on a scale from 1 (mild) to grade 5 (death).

Measure: Number of participants with adverse events as a measure of safety and tolerability of a second infusion of iC9-CAR19 T cells

Time: 4 weeks

Description: Rate of MRD clearance will be defined as the proportion of subjects who enter MRD-negative complete response (CRm) who are treated with one or two infusions of iC9 CAR19 T cells at the time of being in complete response (CR) or Complete Response with incomplete recovery of counts (CRi), but not CRm.

Measure: Rate of measurable residual disease (MRD) clearance in subjects who receive iC9-CAR19 T cells for MRD persistence or MRD-only relapse

Time: 8 weeks

75 A Phase 3, Multi-center, Open-label, Randomized Study of Oral ABL001 Versus Bosutinib in Patients With Chronic Myelogenous Leukemia in Chronic Phase (CML-CP), Previously Treated With 2 or More Tyrosine Kinase Inhibitors

The purpose of this pivotal study is to compare the efficacy of ABL001 with that of bosutinib in the treatment of patients with CML-CP having previously been treated with a minimum of two prior ATP-binding site TKIs. Patients intolerant to the most recent TKI therapy must have BCR-ABL1 ratio > 0.1% IS at screening and patients failing their most recent TKI therapy must meet the definition of treatment failure as per the 2013 ELN guidelines. Patients with documented treatment failure while on bosutinib treatment will have the option to switch to asciminib treatment within 96 weeks after the last patient has been randomized on study.

NCT03106779 Chronic Myelogenous Leukemia Drug: ABL001 Drug: Bosutinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

- Three months after the initiation of therapy: No CHR or > 95% Ph+ metaphases - Six months after the initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 65% Ph+ metaphases - Twelve months after initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 35% Ph+ metaphases - At any time after the initiation of therapy, loss of CHR, CCyR or PCyR - At any time after the initiation of therapy, the development of new BCR-ABL1 mutations which potentially cause resistance to study treatment - At any time after the initiation of therapy, confirmed loss of MMR in 2 consecutive tests, of which one must have a BCR-ABL1 ratio ≥ 1% IS - At any time after the initiation of therapy, new clonal chromosome abnormalities in Ph+ cells: CCA/Ph+ - Intolerance is defined as: - Non-hematologic intolerance: Patients with grade 3 or 4 toxicity while on therapy, or with persistent grade 2 toxicity, unresponsive to optimal management, including dose adjustments (unless dose reduction is not considered in the best interest of the patient if response is already suboptimal) - Hematologic intolerance: Patients with grade 3 or 4 toxicity (absolute neutrophil count [ANC] or platelets) while on therapy that is recurrent after dose reduction to the lowest doses recommended by manufacturer Exclusion Criteria: Known presence of the T315I or V299L mutation at any time prior to study entry Known second chronic phase of CML after previous progression to AP/BC Previous treatment with a hematopoietic stem-cell transplantation Patient planning to undergo allogeneic hematopoietic stem cell transplantation Cardiac or cardiac repolarization abnormality, including any of the following: - History within 6 months prior to starting study treatment of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG) - Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block) - QTcF at screening ≥450 msec (male patients), ≥460 msec (female patients) - Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: - Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia - Concomitant medication(s) with a known risk of Torsades de Pointes per www.crediblemeds.org that cannot be discontinued or replaced 7 days prior to starting study drug by safe alternative medication. --- T315I ---

Primary Outcomes

Description: To compare the MMR rate of ABL001 versus bosutinib

Measure: Major Molecular Response (MMR) rate

Time: at 24 weeks

Secondary Outcomes

Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Major Molecular Response (MMR) rate

Time: 96 weeks after the last patient received the first study dose

Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib. Cytogenic response will include Complete, Partial, Major, Minor, Minimal and no response.

Measure: Complete Cytogenetic response rate

Time: 96 weeks after the last patient received the first study dose

Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Time to MMR

Time: 96 weeks after the last patient received the first study dose

Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Duration of MMR

Time: 96 weeks after the last patient received the first study dose

Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Time to CCyR

Time: 96 weeks after the last patient received the first study dose

Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Duration of CCyR

Time: 96 weeks after the last patient received the first study dose

Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Time to treatment failure

Time: 96 weeks after the last patient received the first study dose

Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Progression free survival

Time: 96 weeks after the last patient received the first study dose

Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib

Measure: Overall survival

Time: 96 weeks after the last patient received the first study dose

Description: To characterize the PK of ABL001 in the CML-CP population

Measure: Trough plasma concentrations

Time: 96 weeks after the last patient received the first study dose

Description: To characterize the PK of ABL001 in the CML-CP population

Measure: PK parameter: Cmax,

Time: 96 weeks after the last patient received the first study dose

Description: To characterize the PK of ABL001 in the CML-CP population

Measure: PK parameter: Tmax

Time: 96 weeks after the last patient received the first study dose

Description: To characterize the PK of ABL001 in the CML-CP population

Measure: PK parameter: AUC0-12h

Time: 96 weeks after the last patient received the first study dose

Description: To characterize the PK of ABL001 in the CML-CP population

Measure: PK parameter: CL/F

Time: 96 weeks after the last patient received the first study dose

76 Multicenter, Open-label Single Arm Phase II Study Testing the Tolerability and the Efficacy of Bosutinib step-in Dosing in Chronic Phase CML Patients Intolerant or Refractory to Previous Imatinib, Nilotinib or Dasatinib Therapy

Bosutinib is a 2nd generation tyrosine kinase inhibitor that has shown promising results from first up to fourth line treatment in patients with in chronic phase of chronic myelogenous leukaemia. Most patients discontinuing the treatment with Bosutinib do so because of side effects occuring early after starting the treatment. A step in dosing scheme could improve these early toxicities. The aim of this study therefore is to demonstrate that temporary lowering of the Bosutinib dose during early treatment may help to reduce or prevent side effects while preserving efficacy.

NCT03205267 Chronic Myelogenous Leukaemia Drug: Bosulif
MeSH:Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase
HPO:Chronic myelogenous leukemia Myeloid leukemia

Exclusion Criteria: - Hypersensitivity against Bosutinib or other ingredients of the medicinal product - Evidence of features of accelerated (AP) or blast phase (BC) at any time before inclusion - Patients with BCR-ABL negative CML - Patients having received Imatinib for more than 6 weeks prior to initiation of 2nd generation TKI (either Nilotinib or Dasatinib) - Patients with known T315I or V299L mutation - Concomitant medications known to be strong inducers or inhibitors of P450 isoenzyme CYP3A4 - History of pancreatitis, inflammatory bowel disease requiring systemic or topical immunosuppressive therapy within the last 12 months - Impaired cardiac function, including any of the following: 1. History of or presence of complete left bundle branch block, right bundle branch block plus left anterior hemiblock, bifascicular block in screening ECG 2. ST depression of >1mm in 2 or more leads and/or T wave inversions in 2 or more contiguous leads in screening ECG 3. Congenital long QT syndrome 4. QTc> 450 msec in the screening ECG 5. QT-prolonging concomitant medication 6. History of or presence of significant ventricular or atrial tachyarrhythmias in screening ECG 7. History of or presence of clinically significant resting bradycardia (< 50 beats per minute) 8. Myocardial infarction within 6 months prior to inclusion 9. Unstable angina diagnosed or treated during the past 12 months 10. --- T315I ---

Primary Outcomes

Description: calculation of the incidence rate of grade 2 to 4 GI toxicity with and without regard to causality

Measure: Rate of GI-Toxicity (i.e. incidence and severity of grade 2 to 4 toxicities)

Time: within the first 6 months of treatment

Secondary Outcomes

Description: Apart from grade 2 to 4 GI toxicity, the occurrence of toxicity will be analyzed in general. This regards all grade toxicity, 2 to 4 grade and 3 to 4 grade toxicity (NCI CTCAE v4.0).

Measure: overall Tolerability (i.e. all grade, grade 2 to 4 and grade 3 and 4 toxicities)

Time: at month 6, 12 and 24

Description: Rating of CCyR, MMR, MR4 and MR4.5 after bone marrow aspiration and biopsy

Measure: Molecular response mesured by efficacy parametern

Time: at month 3, 6, 12, 18 and 24

Description: The EORTC QLQ-CML30 will be scored according to the respective user's guides.

Measure: Patient-reported outcome measures (QoL)

Time: at month 3 and 6

Description: Progression will be assessed according to the visit schedule at any visit.

Measure: Progression-free survival (PFS)

Time: at month 3, 6, 9, 12, 15, 18, 21 and 24

Description: Survival will be assessed according to the visit schedule at any visit.

Measure: Overall Survival (OS)

Time: at month 3, 6, 9, 12, 15, 18, 21 and 24

Description: The rate and type of mutations will be described. The rate will be given as percentage of patients developing mutations.

Measure: The rate of emerging mutations during Bosutinib treatment

Time: at month 3, 6, 9, 12, 15, 18, 21 and 24

Other Outcomes

Description: Ankle Brachial Index (ABI) will be prospectively evaluated followed by analysis of various biomarkers for vascular damage

Measure: Vascular biology substudy: analysis of clinical and laboratory vascular and metabolic risk factors

Time: baseline, at months 6, 12 and 24

Description: It is planned to analyze PK parameters sequentially by taking serum from PB and subsequent HPLC-MS/MS technology. Pharmacodynamics in different compartments will be analyzed by means of flow-cytometry of PB and BM samples.

Measure: Pharmacokinetic (PK), pharmacodynamic (PD) substudy

Time: at day 1, months 1, 2, 3, 12, 18, 24

Description: Assessment of telomere length in normal and leukemic cells as potential new biomarker for prognosis, prediction of response under Bosutinib

Measure: Telomere substudy

Time: at months 1, 2, 3, 12 and 24

Description: Documentation of subclone evolution or elimination during Bosutinib treatment

Measure: Ultra-deep next-generation sequencing (UD-NGS)

Time: at months 1, 2, 3, 12 and 24

Description: Documentation of patient´s comorbidity profile using 3 different comorbidity scales

Measure: Assessment of patients comorbidities and correlation to individual patient´s adverse side effect profile substudy

Time: through study completion, an average of 2 years

Description: Investigation the role of the 5-HT pathway in directing bosutinib induced diarrhea by assessment of 5-HT and certain cytokine levels and genetic analysis including SNP and GWAS

Measure: Transport mechanisms of Bosutinib and mechanisms of diarrhea substudy

Time: every 14 days month 1-3

77 A Phase 1A Dose Escalation and Phase 1B Expansion Study to Evaluate the Safety and Tolerability of ETC-1907206 in Combination With Dasatinib in Advanced Haematologic Malignancies

This study evaluates the use of ETC-1907206 in combination with dasatinib in certain types of blood cancers. The first phase of the study (1A) is designed to find the highest tolerated dose of ETC-1907206, while the second phase (1B) will assess the safety and tolerability of the recommended dose of ETC-1907206. ETC-1907206 has been designed to block the activity of an enzyme of the body known as Mnk kinase, which is thought to be involved in the development of a variety of cancers.

NCT03414450 Ph+ Acute Lymphoblastic Leukemia (Ph+ALL) Ph- Acute Lymphoblastic Leukemia (Ph-ALL) Chronic Myeloid Leukemia Accelerated Phase (CML-AP, Ph+) Chronic Myeloid Leukemia Blast Crisis (CML-BC, Ph+) Drug: ETC-1907206 Drug: dasatinib
MeSH:Leukemia Leukemia, Myeloid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Blast Crisis
HPO:Chronic myelogenous leukemia Leukemia Lymphoid leukemia Myeloid leukemia

3. Bone marrow (BM) cytogenetic analysis with at least 20 metaphase cells, confirmed advanced haematologic malignancies in any of the 4 following disease populations at Screening: - CML-AP, Ph+ - CML-BC, Ph+ - Ph+ ALL - Ph- ALL with relapsed and refractory disease who have exhausted all available therapy (for patients who develop T315I mutation related resistance, the definition requires failure of ponatinib treatment if drug is accessible). --- T315I ---

Primary Outcomes

Description: The MTD is defined as the highest possible dose with a predicted probability of having DLT not exceeding the target toxicity rate. The target toxicity rate (or the target predicted probability of DLT) for this study is set at 25%.

Measure: Maximum Tolerated Dose (MTD) (Phase 1A)

Time: the initial 28 days of treatment

Description: Incidence and Severity of AEs

Measure: Phase 1B Safety: Incidence of Adverse Events (AEs) during Phase 1B

Time: up to 44 months

Description: Single-dose PK measurement of AUC0-inf after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).

Measure: Phase 1B PK: Area under the drug concentration-time curve (AUC) from time zero to infinite time (AUC0-inf)

Time: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing

Description: Single-dose PK measurement of AUC0-t after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).

Measure: Phase 1B PK: AUC from time zero to the last measureable concentration (AUC0-t)

Time: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing

Description: Single-dose PK measurement of kel after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).

Measure: Phase 1B PK: First-order rate constant for elimination of drug (kel)

Time: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing

Description: Single-dose PK measurement of Tmax after dosing on Day 1 and Day 15 (Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).

Measure: Phase 1B PK: Time to reach maximum plasma concentration (Tmax)

Time: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing

Description: Single-dose PK measurement of Tlag after dosing on Day 1 and Day 15 (Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).

Measure: Phase 1B PK: Time between drug administration and first observed concentration above lower limit if quantitation in plasma (Tlag)

Time: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing

Description: Single-dose PK measurement of CL after dosing on Day 1 and Day 15 (Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).

Measure: Phase 1B PK: Total clearance (CL)

Time: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing

Description: Single-dose PK measurement of Vd after dosing on Day 1 and Day 15 (Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).

Measure: Phase 1B PK: Volume of distribution (Vd)

Time: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing

Description: Single-dose PK measurement of T1/2 after dosing on Day 1 and Day 15 (Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).

Measure: Phase 1B PK: Half-life (T1/2)

Time: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing

Secondary Outcomes

Description: Incidence and Severity of AEs

Measure: Phase 1A Safety: Incidence of Adverse Events (AEs) during Phase 1A

Time: up to 24 months

Description: Single-dose PK measurement of AUC0-inf after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).

Measure: Phase 1A PK: Area under the drug concentration-time curve (AUC) from time zero to infinite time (AUC0-inf)

Time: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing

Description: Single-dose PK measurement of AUC0-t after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).

Measure: Phase 1A PK: AUC from time zero to the last measureable concentration (AUC0-t)

Time: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing

Description: Single-dose PK measurement of kel after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).

Measure: Phase 1A PK: First-order rate constant for elimination of drug (kel)

Time: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing

Description: Single-dose PK measurement of Tmax after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).

Measure: Phase 1A PK: Time to reach maximum plasma concentration (Tmax)

Time: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing

Description: Single-dose PK measurement of Tlag after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).

Measure: Phase 1A PK: Time between drug administration and first observed concentration above lower limit if quantitation in plasma (Tlag)

Time: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing

Description: Single-dose PK measurement of CL after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).

Measure: Phase 1A PK: Total clearance (CL)

Time: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing

Description: Single-dose PK measurement of Vd after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).

Measure: Phase 1A PK: Volume of distribution (Vd)

Time: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing

Description: Single-dose PK measurement of T1/2 after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).

Measure: Phase 1A PK: Half-life (T1/2)

Time: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing

Description: The BOR for each patient is determined by the following hierarchical orders: For CML-AP Ph+, CML-BC Ph+ and Ph+ ALL: major molecular response, major cytogenetic response (complete response, partial response), major haematologic response (complete response, complete remission), minor haematologic response,cytogenetic response (minor response, minimal response, no response), progressive disease For Ph- ALL: complete haematologic response, complete response with partial haematologic recovery, progressive disease The response rate will be summarised and two-sided 95% confidence intervals (CIs) on the response rates will be calculated. The best overall response will be listed.

Measure: Phase 1B Clinical Activity: Best Overall Response (BOR)

Time: through study completion (44 months)

Measure: Phase 1B Clinical Activity: objective response rate (ORR)

Time: through study completion (44 months)

Measure: Phase 1B Clinical Activity: duration of objective response (DOR)

Time: through study completion (44 months)

Measure: Phase 1B Clinical Activity: duration of major molecular response (DOMMR)

Time: through study completion (44 months)

Measure: Phase 1B Clinical Activity: duration of complete haematologic response (DOCHR)

Time: through study completion (44 months)

Measure: Phase 1B Clinical Activity: duration of complete remission (DOCRe)

Time: through study completion (44 months)

Measure: Phase 1B Clinical Activity: duration of complete cytogenetic response (DOCCyR)

Time: through study completion (44 months)

Measure: Phase 1B Clinical Activity: time to objective response (TTR)

Time: through study completion (44 months)

Measure: Phase 1B Clinical Activity: time to major molecular response (TTMMR)

Time: through study completion (44 months)

Measure: Phase 1B Clinical Activity: time to complete haematologic response (TTCHR)

Time: through study completion (44 months)

Measure: Phase 1B Clinical Activity: time to complete remission (TTCRe)

Time: through study completion (44 months)

Measure: Phase 1B Clinical Activity: time to complete cytogenetic response (TTCCyR)

Time: through study completion (44 months)

Measure: Phase 1B Clinical Activity: progression-free survival (PFS)

Time: through study completion (44 months)

Measure: Phase 1B Clinical Activity: overall survival (OS)

Time: through study completion (44 months)

78 A Phase 3 Multinational, Multi-center, Single-arm, Open-label Study for the Efficacy and Safety of Radotinib in Ph+ Chronic Phase Chronic Myeloid Leukemia Patients With Failure or Intolerance to Previous TKIs Therapy Including Imatinib

In a multinational, multicenter, single-arm, open-label and Phase III Radotinib clinical study, chronic phase Ph+ chronic myeloid leukemia patients with failure or intolerance to previous TKIs therapy including Imatinib will be recruited. In this phase 3 study, 173 subjects are expected to be enrolled in a single arm with the administration of Radotinib 400mg twice daily, which includes 10% of dropout rate.

NCT03459534 Leukemia, Myeloid, Chronic Phase Drug: Radotinib HCl
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

- Medical history of clinically confirmed myocardial infarction - Medical history of unstable angina (within last 12 months) - Other clinically significant cardiac disease 4. Patients with T315I point mutations 5. Patients with central nervous system involvement as cytopathologically confirmed 6. Severe or uncontrolled chronic disease 7. Significant medical history of congenital or acquired bleeding disorders that are not related to leukemia 8. Patients who previously received radiotherapy to at least 25% of the bodies with high portion of bone marrow 9. Patients who received the major surgery within 4 weeks before the initiation of the IP administration or who failed to recover from the surgery that was performed before then. --- T315I ---

Primary Outcomes

Description: MCyR is defined as 0~35% CCyR+PCyR based on ≥20 metaphase myelocytes. Chromosome test results from <20 metaphase myelocytes will be excluded from the analysis.

Measure: Major Cytogenetic Response (MCyR)

Time: at month 6

Secondary Outcomes

Description: CCyR is defined as complete loss of Ph chromosome based on ≥20 metaphase myelocytes. Chromosome test results from <20 metaphase myelocytes will be excluded from the analysis.

Measure: Cytogenetic Response (CCyR)

Time: at month 12/24, by month 24

Description: MMR is defined as a ≥3-log reduction in BCR-ABL1 transcript level from the standardized reference or BCR-ABL1/ABL % of ≤0.1% according to the international reference when the level of BCR-ABL1 gene was measured by RQ-PCR, a standardized quantitative genetic method.

Measure: Major molecular response

Time: at month 12/24, by month 24

Description: OS is defined as the duration from the first day of Radotinib administration to the day of death for certain causes.

Measure: Overall Survival(OS)

Time: by month 24

Description: PFS is defined as the duration from the first day of Radotinib administration to the earliest day of disease progression or death for certain causes.

Measure: Progression Free Survival (PFS)

Time: by month 24

Other Outcomes

Description: Incidence rate of BCR-ABL1 point mutations that are newly found during the course of radotinib treatment

Measure: BCR-ABL1 point mutation

Time: up to month 24

Description: To measure the concentration of radotinib in blood

Measure: correlation between the concentration of radotinib in blood and the response (efficacy and safety)

Time: up to month 24

Description: Toxicities will be evaluated in all subjects treated with radotinib.

Measure: Incidence of Radotinib-Adverse Events

Time: up to month 24

79 Compassionate Use Administration of Autologous CAR T Cells Targeting the CD19 Antigen and Containing the Inducible Caspase 9 Safety Switch

This protocol for compassionate use combines 2 different ways of fighting disease: antibodies and T cells. Both antibodies and T cells have been used to treat patients with cancers, and both have shown promise, but neither alone has been sufficient to cure most patients. This protocol combines both T cells and antibodies to create a more effective treatment. The investigational treatment is called autologous T lymphocyte chimeric antigen receptor cells targeted against the CD19 antigen (ATLCAR.CD19) administration. Prior studies have shown that a new gene can be put into T cells and will increase their ability to recognize and kill cancer cells. The new gene that is put in the T cells in this study makes a piece of an antibody called anti-CD19. This antibody sticks to leukemia cells because they have a substance on the outside of the cells called CD19. For this protocol, the anti-CD19 antibody has been changed so that instead of floating free in the blood part of it is now joined to the T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These CD19 chimeric (combination) receptor-activated T cells seem to kill some of the tumor, but they do not last very long in the body and so their chances of fighting the cancer are unknown. Preliminary results have shown that many subjects receiving this treatment have experienced unwanted side effects including cytokine release syndrome. In this protocol, to help reduce cytokine release syndrome symptoms, the ATLCAR.CD19 cells have a safety switch that when active, can cause the cells to become dormant. These modified ATLCAR.CD19 cells with the safety switch are referred to as iC9-CAR19 cells. If the patient experiences moderate to severe cytokine release syndrome as a result of being given iC9-CAR19 cells, the patient can be given a dose of a second study drug, AP1903, if standard interventions fail to alleviate the symptoms of cytokine release syndrome. AP1903 activates the iC9-CAR19 safety switch, reducing the number of the iC9-CAR19 cells in the blood. The primary purpose of this protocol is to treat a single patient with a second dose of iC9-CAR19 T cells.

NCT03594162 Acute Lymphoblastic Leukemia Immune System Diseases Immunoproliferative Disorders Drug: iC9-CAR19 cells Drug: AP1903 Drug: Cyclophosphamide Drug: Fludarabine
MeSH:Precursor Cell Lymphoblastic Leukemia-Lymphoma Immunoproliferative Disorders Immune System Diseases

Patients with the T315I ABL kinase point mutation will be eligible if they have failed ponatinib-containing therapy, regardless of the number of prior ABL tyrosine kinase inhibitors. --- T315I ---


80 A Phase 1 Study of ABL001 in Combination With Dasatinib and Prednisone in Patients With BCR-ABL Positive (BCR-ABL+) B-cell Acute Lymphoblastic Leukemia (B-ALL) and Chronic Myeloid Leukemia (CML)

This research study is evaluating a drug called ABL001 taken in combination with dasatinib (Sprycel®) and prednisone (a steroid) as a possible treatment for B-cell Acute Lymphoblastic Leukemia that is BCR-ABL positive (BCR-ABL+ B-ALL) or Chronic Myeloid Leukemia (CML) in lymphoid blast crisis. BCR-ABL+ B-ALL is also called Philadelphia chromosome positive Acute Lymphoblastic Leukemia (Ph+ ALL). It is expected that 25-34 people will take part in this research study. - ABL001 - Dasatinib (Sprycel®) - Prednisone

NCT03595917 B-cell Acute Lymphoblastic Leukemia Chronic Myeloid Leukemia (CML) in Lymphoid Blast Crisis Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Ph+ ALL Drug: ABL001 Drug: Dasatinib Drug: Prednisone
MeSH:Leukemia Leukemia, Myeloid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Blast Crisis Philadelphia Chromosome
HPO:Chronic myelogenous leukemia Leukemia Lymphoid leukemia Myeloid leukemia

- Patients with a known ABL T315I mutation are excluded. --- T315I ---

Primary Outcomes

Description: To define the maximum tolerated dose (MTD) of ABL001 for participants with BCR-ABL positive (BCR-ABL+) B-cell acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) in lymphoid blast crisis.

Measure: Maximum tolerated dose (MTD) of ABL001

Time: 42 Days

Secondary Outcomes

Measure: Percentage for Participants Achieving Hematologic Remission

Time: 28 Days

Measure: Percentage for Participants Achieving Hematologic Remission

Time: 56 Days

Measure: Percentage for Participants Achieving Hematologic Remission

Time: 85 Days

Measure: Percentage of participants achieving cytogenetic response

Time: 28 Days

Measure: Percentage of participants achieving cytogenetic response

Time: 56 Days

Measure: Percentage of participants achieving cytogenetic response

Time: 85 Days

Measure: Percentage of participants achieving a minimal residual disease (MRD)-negative CR by flow cytometry

Time: 85 Days

Measure: Percentage of participants achieving a minimal residual disease (MRD)-negative CR by flow cytometry

Time: 28 Days

Measure: Percentage of participants achieving a minimal residual disease (MRD)-negative CR by flow cytometry

Time: 56 Days

Measure: Percentage of participants achieving molecular response

Time: 28 Days

Measure: Percentage of participants achieving molecular response

Time: 56 Days

Measure: Percentage of participants achieving molecular response

Time: 85 Days

81 Prospective Registry of Iclusig® (Ponatinib) Used in Clinical Practice for the Treatment of Patients With Chronic Myeloid Leukemia or Ph+ Acute Lymphoblastic Leukemia in Belgium

This prospective registry is initiated to follow up on the use of Iclusig® in patients with CML or Ph+ ALL in routine practice in Belgium.

NCT03678454 Chronic Myeloid Leukemia CML Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia Ph+ ALL
MeSH:Leukemia Leukemia, Myeloid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Philadelphia Chromosome
HPO:Chronic myelogenous leukemia Leukemia Lymphoid leukemia Myeloid leukemia

Costs associated with the treatment of Iclusig®-related adverse events reported during the registry.. Inclusion Criteria: - Patient with confirmed diagnosis of: - CML (chronic, accelerated or blast phase) who is resistant or intolerant to dasatinib or nilotinib; and for whom subsequent treatment with imatinib is not clinically appropriate; or who has the T315I mutation. --- T315I ---

- Ph+ ALL who is resistant or intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who has the T315I mutation. --- T315I ---

Inclusion Criteria: - Patient with confirmed diagnosis of: - CML (chronic, accelerated or blast phase) who is resistant or intolerant to dasatinib or nilotinib; and for whom subsequent treatment with imatinib is not clinically appropriate; or who has the T315I mutation. --- T315I ---

Primary Outcomes

Description: Prescribed dose of Iclusig® in milligrams.

Measure: Prescribed dose of Iclusig® in routine practice in Belgium

Time: Up to 3 years

Secondary Outcomes

Description: Includes treatment effectiveness, complete hematologic response, cytogenetic response, major molecular response.

Measure: Overall clinical benefit rate of Iclusig® based on response criteria for CML or Ph+ ALL in Belgium

Time: Up to 3 years

Description: Costs associated with the treatment of Iclusig®-related adverse events reported during the registry.

Measure: Estimate of additional health care utilization cost

Time: Up to 3 years

82 Phase 2 Study of Ponatinib (Iclusig) for Prevention of Relapse After Allogeneic Stem Cell Transplantation (Allo-SCT) in FLT3-ITD AML Patients: the PONALLO Trial."

Recent advances in acute myeloid leukemia (AML) have been characterized by a better understanding of disease biology. As such, FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) have been recognized as conferring a poor prognosis. The FLT3-ITD molecular mutation is observed in about one-quarter of patients diagnosed with AML. Patients presenting with this abnormality are referred for early allogeneic stem-cell transplantation (allo-SCT). However, some data suggest that FLT3-ITD remains associated with a poor prognosis even after allo-SCT because of higher risk of relapse and strategies for preventing relapse in the post-transplant setting are required (Hu et al, Expert Rev Hematol, 2014). For example, in a large cohort of patients (Brunet et al, JCO, 2012), the incidence of relapse for FLT3-ITD AML patients after allo-SCT was 30% at 2-years, significantly higher compared to FLT3-ITD negative patients (p=0.006). Ponatinib (Iclusig®) is an orally available, tyrosine kinase inhibitor with a unique binding mechanism allowing inhibition of BCR-ABL kinases, including those with the T315I point mutation. Ponatinib also has in vitro inhibitory activity against a discrete set of kinases implicated in the pathogenesis of other hematologic malignancies, including FLT3, KIT, fibroblast growth factor receptor 1 (FGFR1), and platelet derived growth factor receptor α (PDGFRα). In vitro activity of ponatinib in AML has been already demonstrated (Gozgit et al, Mol Cancer Ther, 2011; Smith et al, Blood 2013). If some trials are on-going to test ponatinib alone or in combination with chemotherapy in FLT3-ITD AML (Clinical.trials.gov), no study is dedicated to the use of ponatinib in the post-transplant setting in order to prevent relapse in these patients. The main goal of this study will be to determine the maximal tolerated dose (MDT) of ponatinib after allo-SCT in FLT3-ITD AML patients, then to investigate the efficacy of ponatinib in a larger cohort of patients

NCT03690115 Leukemia, Myeloid, Acute Drug: Ponatinib 30 MG
MeSH:Leukemia, Myeloid Leukemia, Myeloid, Acute
HPO:Acute megakaryocytic leukemia Acute myeloid leukemia Myeloid leukemia

Ponatinib (Iclusig®) is an orally available, tyrosine kinase inhibitor with a unique binding mechanism allowing inhibition of BCR-ABL kinases, including those with the T315I point mutation. --- T315I ---

Primary Outcomes

Measure: Relapse incidence at 2 years from transplant

Time: 2 years

Secondary Outcomes

Description: time interval from the graft (day 0) until the date of last follow-up or death

Measure: Overall survival

Time: 2 years

Description: time interval from the date of the graft (day 0) until the date of last follow-up, death or relapse

Measure: Leukemia free survival

Time: 2 years

Description: incidence of mortality due to all causes except relapse after transplant, considering that cause of death for patients having relapsed but dying from another cause is relapse

Measure: Non-relapse mortality (NRM)

Time: day 100

Description: NIH score

Measure: Acute and chronic GVHD

Time: 2 years

Description: an immunophenotype of PB lymphocytes will be performed by flow cytometry at +3, +6, +9 and +12 months post-transplant to study the reconstitutions of CD3, CD4 and CD8 T cells, B and NK cells. The results will be expressed as absolute counts (Giga/L). We want to establish the potential influence of ponatinib on the reconstitution of these cells

Measure: Influence of Ponatinib on Immune reconstitution PB lymphocyte cells

Time: 1 years

Description: Donor peripheral blood and CD3 T cells chimerism will be studied using molecular markers and RT-PCR at day +30, +60, +90, and +6, +12 months post-transplant. We want to establish the potential influence of ponatinib on the chimerism post-transplant.

Measure: Inflence of Ponatinib on Chimerism of Donor peripheral blood and CD3 T cells

Time: 1 years

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Time: 2 years

83 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 ---

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

84 A Randomized, Open, Double-crossing Trial to Evaluate the Effect of Fasting or High-fat Meals on the Pharmacokinetics of Single Oral Administration of HQP1351 Tablets on an Empty Stomach or a High-fat Meal in Patients With Chronic Myeloid Leukemia

The purpose of this study is to characterize the pharmacokinetics of HQP1351 in participants with resistant chronic myeloid leukemia (CML) in chronic phase (CP) after high-fat and fasting meals separately(Selection of high-fat meal spectrum:《The Food - Effect Bioavailability and Fed Bioequivalence Studies》high fat diet should be 800-1000 kcal heat.).

NCT03882281 Chronic Myeloid Leukemia, Chronic Phase Drug: HQP1351
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

3. Previously treated with and or developed resistance / intolerance to second generation tyrosine kinase inhibitors (TKIs) (dasatinib,nilotinib)or,been identified to have the T315I mutation at any time during treatment. --- T315I ---

Primary Outcomes

Description: Area under the plasma concentration-time curve from time zero extrapolated to infinity time of HQP1351.

Measure: Area under the curve from the time of dosing to infinity [AUC(0-inf)]

Time: 1-5 days after every drug administration

Description: Area under the plasma concentration-time curve from time zero to the last measurable time point of HQP1351.

Measure: Area under the curve from the time of dosing to the last measurable concentration [AUC(0-last)]

Time: 1-5 days after every drug administration

Description: Percentage of area under the concentration time curve from time zero extrapolated to infinite time obtained by extrapolation of HQP1351.

Measure: Percentage of AUC(0-inf)_obs due to extrapolation from the last measurable time point to infinity (AUC_%Extrap)

Time: 1-5 days after every drug administration

Description: Maximum observed plasma concentration of HQP1351.

Measure: Maximum observed concentration (Cmax)

Time: 1-5 days after every drug administration

Description: Time to maximum observed plasma concentration of HQP1351.

Measure: Time of maximum observed concentration (Tmax)

Time: 1-5 days after every drug administration

Description: Terminal elimination half life (T1/2) is defined as the duration until observation of half of the maximum concentration of HQP1351.

Measure: Terminal elimination half life (T1/2)

Time: 1-5 days after every drug administration

Description: Apparent clearance of HQP1351 following oral dosing. Clearance of a drug is a measure of rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose of HQP1351 (apparent oral clearance) is influenced by the fraction of dose absorbed.

Measure: Total body clearance for extravascular administration (CL/F)

Time: 1-5 days after every drug administration

Description: Apparent volume of distribution of HQP1351. Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution of HQP1351 after oral dose (Vz/F) is influenced by the fraction absorbed.

Measure: Volume of distribution based on the terminal phase for extravascular administration (Vz/F)

Time: 1-5 days after every drug administration

Secondary Outcomes

Description: Incidence of toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03

Measure: Incidence of toxicity

Time: up to 12 days

85 A Phase II Multi-center, Open Label Study of HQP1351 in Chinese Patients of Chronic Myeloid Leukemia With T315I Mutation in Chronic Phase

The purpose of this study is to evaluate the efficacy of HQP1351 in patients with chronic myeloid leukemia in chronic phase (CML-CP) harboring T315I mutation. The efficacy of HQP1351 was determined by evaluating the subjects' major cytogenetic response (MCyR).

NCT03883087 Chronic Myeloid Leukemia, Chronic Phase Drug: HQP1351
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

A Phase II Multi-center, Open Label Study of HQP1351 in Chinese Patients of Chronic Myeloid Leukemia With T315I Mutation in Chronic Phase. --- T315I ---

A Pivotal Study of HQP1351 in Patients of Chronic Myeloid Leukemia in Chronic Phase With T315I Mutation The purpose of this study is to evaluate the efficacy of HQP1351 in patients with chronic myeloid leukemia in chronic phase (CML-CP) harboring T315I mutation. --- T315I ---

A Pivotal Study of HQP1351 in Patients of Chronic Myeloid Leukemia in Chronic Phase With T315I Mutation The purpose of this study is to evaluate the efficacy of HQP1351 in patients with chronic myeloid leukemia in chronic phase (CML-CP) harboring T315I mutation. --- T315I --- --- T315I ---

After any targeted BCR-ABL1 tyrosine kinase inhibitors (TKI) treatment, CML-CP patients with T315I mutation. --- T315I ---

Chronic Myeloid Leukemia, Chronic Phase Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive This is an open, single-arm, multi-center phase 2 clinical study to evaluate the efficacy and safety of oral administrated HQP1351(40mg, QOD) in CML-CP patients with T315I mutation in China. --- T315I ---

Primary Outcomes

Description: MCyR is the proportion of patients achieving Complete cytogenetic response (CCyR: defined as 0% Philadelphia chromosome-positive [Ph+] metaphases by cytogenetic analysis of bone marrow) or Partial Cytogenetic Response (PCyR: defined as >0% to 35% Ph+ metaphases by cytogenetic analysis of bone marrow). It is defined as the best response obtained by the subjects during the whole treatment process of the study. And MCyR can only be considered as CCyR if the subject meets PCyR at baseline.

Measure: Major cytogenetic response (MCyR)

Time: By the end of Cycle 24 (each cycle is 28 days)

Secondary Outcomes

Description: CCyR is the proportion of patients achieving CCyR after being treated with HQP1351. It is defined as the best response obtained by the subjects during the whole treatment process of the study.

Measure: Complete cytogenetic response (CCyR)

Time: By the end of Cycle 24 (each cycle is 28 days)

Description: CHR requires that all of the following are present: white blood cell<10×10E9/ liter; blood platelet count<450×10E9/ liter; no medullary immature granulocytes in the peripheral blood (such as protocell, promyelocyte and myelocyte); basophils in peripheral blood are less than 5%; no disease symptoms, signs and palpable splenomegaly has disappeared; the duration of the above criteria is no less than 4 weeks. We will calculate the proportion of patients achieving CHR after being treated with HQP1351. It is defined as the best response obtained by the subjects during the whole treatment process of the study.

Measure: Complete hematologic response (CHR)

Time: By the end of Cycle 24 (each cycle is 28 days)

Description: MMR is the proportion of patients achieving a ratio of ≤0.1% breakpoint cluster region (BCR) abelson leukemia (ABL) to ABL transcripts on the international scale (≤0.1% BCR-ABL/ABL[IS]) after being treated with HQP1351. It is defined as the best response obtained by the subjects during the whole treatment process of the study.

Measure: Major molecular response (MMR)

Time: By the end of Cycle 24 (each cycle is 28 days)

Description: BCR-ABL1(IS) ≤1% is the proportion of patients achieving BCR-ABL1(IS) ≤1% by quantitative polymerase chain reaction detection. It is defined as the best response obtained by the subjects during the whole treatment process of the study.

Measure: BCR-ABL1(IS) transcript ≤1%

Time: By the end of Cycle 24 (each cycle is 28 days)

Description: The time to response is defined as the interval between the first use of HQP1351 and the first date at which the criteria for response are met. The subject who isn't met the response criteria will be censored at the last assessment time.

Measure: Time to response

Time: By the end of Cycle 24 (each cycle is 28 days)

Description: Duration of response is defined as the interval between the first assessment at which the criteria for response are met until the earliest date at which the criteria for progression are met, and the subject who isn't met the progression criteria will be censored at the last assessment time. The duration of response is calculated only for subjects who achieved response.

Measure: Duration of response

Time: By the end of Cycle 24 (each cycle is 28 days)

Description: PFS is defined as the interval between the first dose date of HQP1351 treatment and the first date at which the criteria for progression are met, or death. The subject who isn't progression or death will be censored at the last response assessment.

Measure: Progression free survival (PFS)

Time: By the end of Cycle 24 (each cycle is 28 days)

Description: OS is defined as the interval between the first dose date of HQP1351 treatment and date of death, censored at the last contact date to be alive.

Measure: Overall survive (OS)

Time: By the end of Cycle 24 (each cycle is 28 days)

Description: Patients with HQP1351 treatment related AE, SAE will be assessed according NCI CTCAE Version 5.0.

Measure: Safety: adverse events (AEs), and serious AEs (SAEs)

Time: By the end of Cycle 24 (each cycle is 28 days)

Other Outcomes

Description: During the course of HQP1351 therapy, the relationship between BCR-ABL1 kinase region/other mutations and drug resistance/disease progression will be measured.

Measure: The relationship between mutation and efficacy.

Time: By the end of Cycle 24 (each cycle is 28 days)

Description: Objects' quality of life will be measured during the course of HQP1351 therapy by European Organization for Research and Treatment quality of life questionnaire core-30 version3.

Measure: Quality of life (QOL)

Time: By the end of Cycle 24 (each cycle is 28 days)

86 A Phase II Multi-center, Open Label Study of HQP1351 in Chinese Patients of Chronic Myeloid Leukemia With T315I Mutation in Accelerated Phase

The purpose of this study is to evaluate the efficacy of HQP1351 in patients with chronic myeloid leukemia in accelerated phase (CML-AP) harboring T315I mutation. The efficacy of HQP1351 was determined by evaluating the subjects' major hematologic response (MaHR).

NCT03883100 Chronic Myeloid Leukemia - Accelerated Phase Drug: HQP1351
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positiv Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Accelerated Phase
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

A Phase II Multi-center, Open Label Study of HQP1351 in Chinese Patients of Chronic Myeloid Leukemia With T315I Mutation in Accelerated Phase. --- T315I ---

A Pivotal Study of HQP1351 in Patients of Chronic Myeloid Leukemia in Accelerated Phase With T315I Mutation The purpose of this study is to evaluate the efficacy of HQP1351 in patients with chronic myeloid leukemia in accelerated phase (CML-AP) harboring T315I mutation. --- T315I ---

A Pivotal Study of HQP1351 in Patients of Chronic Myeloid Leukemia in Accelerated Phase With T315I Mutation The purpose of this study is to evaluate the efficacy of HQP1351 in patients with chronic myeloid leukemia in accelerated phase (CML-AP) harboring T315I mutation. --- T315I --- --- T315I ---

After any targeted BCR-ABL1 tyrosine kinase inhibitors (TKI) treatment, CML-AP patients with T315I mutation. --- T315I ---

Chronic Myeloid Leukemia - Accelerated Phase Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positiv Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Accelerated Phase This is an open, single-arm, multi-center phase 2 clinical study to evaluate the efficacy and safety of oral administrated of HQP1351(40mg, QOD) in CML-AP patients with T315I mutation in China. --- T315I ---

Primary Outcomes

Description: MaHR is the proportion of patients achieving Complete hematologic response (CHR) or no evidence of leukemia (NEL). It is defined as the best response obtained by the subjects during the whole treatment process of the study.

Measure: Major hematologic response (MaHR)

Time: By the end of Cycle 24 (each cycle is 28 days)

Secondary Outcomes

Description: CHR is the proportion of patients achieving CHR after being treated with HQP1351. It is defined as the best response obtained by the subjects during the whole treatment process of the study.

Measure: CHR

Time: By the end of Cycle 24 (each cycle is 28 days)

Description: MCyR is the proportion of patients achieving Complete cytogenetic response (CCyR: defined as 0% Philadelphia chromosome-positive [Ph+] metaphases by cytogenetic analysis of bone marrow) or Partial Cytogenetic Response (PCyR: defined as >0% to 35% Ph+ metaphases by cytogenetic analysis of bone marrow). It is defined as the best response obtained by the subjects during the whole treatment process of the study.

Measure: Major cytogenetic response (MCyR)

Time: By the end of Cycle 24 (each cycle is 28 days)

Description: CCyR is the proportion of patients achieving CCyR after being treated with HQP1351. It is defined as the best response obtained by the subjects during the whole treatment process of the study.

Measure: CCyR

Time: By the end of Cycle 24 (each cycle is 28 days)

Description: MMR is the proportion of patients achieving a ratio of ≤0.1% breakpoint cluster region (BCR) abelson leukemia (ABL) to ABL transcripts on the international scale (≤0.1% BCR-ABL/ABL[IS]) after being treated with HQP1351. It is defined as the best response obtained by the subjects during the whole treatment process of the study.

Measure: Major molecular response (MMR)

Time: By the end of Cycle 24 (each cycle is 28 days)

Description: The time to response is defined as the interval between the first use of HQP1351 and the first date at which the criteria for response are met. The subject who isn't met the response criteria will be censored at the last assessment time.

Measure: Time to response

Time: By the end of Cycle 24 (each cycle is 28 days)

Description: Duration of response is defined as the interval between the first assessment at which the criteria for response are met until the earliest date at which the criteria for progression are met, and the subject who isn't met the progression criteria will be censored at the last assessment time. The duration of response is calculated only for subjects who achieved response.

Measure: Duration of response

Time: By the end of Cycle 24 (each cycle is 28 days)

Description: PFS is defined as the interval between the first dose date of HQP1351 treatment and the first date at which the criteria for progression are met, or death. The subject who isn't progression or death will be censored at the last response assessment.

Measure: Progression free survival (PFS)

Time: By the end of Cycle 24 (each cycle is 28 days)

Description: OS is defined as the interval between the first dose date of HQP1351 treatment and date of death, censored at the last contact date to be alive.

Measure: Overall survive (OS)

Time: By the end of Cycle 24 (each cycle is 28 days)

Description: Patients with HQP1351 treatment related AE, SAE will be assessed according NCI CTCAE Version 5.0.

Measure: Safety: adverse events (AEs), and serious AEs (SAEs)

Time: By the end of Cycle 24 (each cycle is 28 days)

Other Outcomes

Description: During the course of HQP1351 therapy, the relationship between BCR-ABL1 kinase region/other mutations and drug resistance/disease progression will be measured.

Measure: The relationship between mutation and efficacy.

Time: By the end of Cycle 24 (each cycle is 28 days)

Description: Objects' quality of life will be measured during the course of HQP1351 therapy by European Organization for Research and Treatment (EORTC) quality of life questionnaire core-30 version3 [QLQ-C30(V3) questionnaire].

Measure: Quality of life (QOL)

Time: By the end of Cycle 24 (each cycle is 28 days)

87 Preliminary Evaluation of TKI Exposure-response Relationships in Real World Patients (RWPs) With Chronic Myelogenous Leukemia (CML)

The purpose of this prospective, single-institution observational study is to evaluate associations between the pharmacokinetic (PK) parameters for tyrosine kinase inhibitors (TKIs) used to treat chronic phase chronic myeloid leukemia (CML) and clinical outcomes for up to 12 months. The study aims to identify associations between TKI clearance and/or exposure with demographic and clinical patient characteristics, CML milestones, medication toxicities, medication adherence, and germline genetic variants. Because this is an observational study, standard-of-care therapy will not be altered during the course of participation. Blood samples will be collected at each study visit (up to 6 visits) over the course of 12 months to evaluate TKI concentrations, and PK parameters. Blood will also be collected during the first visit to isolate DNA for next generation sequencing (NGS). Demographic information will be collected at baseline, while clinical and medication adherence information will be collected at baseline and then throughout the study. There will be no direct benefit to you for your participation. Risks are minor, but could include bruising, vein irritation, lightheadedness/dizziness, and/or infection from blood draws, as well as potential loss of confidentiality.

NCT03885830 CML, Chronic Phase CML (Chronic Myelogenous Leukemia CML - Philadelphia Chromosome Chronic Myeloid Leukemia Chronic Myeloid Leukemia, Chronic Phase Drug: Bosutinib Drug: Dasatinib Drug: Imatinib Drug: Nilotinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase Philadelphia Chromosome
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

4. Patients with a confirmed T315I point mutation in BCR-ABL and/or prescribed ponatinib. --- T315I ---

Primary Outcomes

Description: TKI exposure/clearance will be evaluated by measuring levels of TKI in the blood during the 12 month study period. BCR-ABL transcripts at 12 months will be compared against the TKI levels.

Measure: Correlation between TKI Exposure/Clearance and BCR-ABL transcript

Time: 12 months

Secondary Outcomes

Description: CHR at 1 month, defined as complete normalization of peripheral blood counts with leukocyte count < 10 x 1E9/L, platelet count < 450 x 1E9/L, no immature cells (such as myelocytes, promyelocytes, no blasts in peripheral blood, and no signs and symptoms of disease with disappearance of palpable splenomegaly.

Measure: Complete Hematologic Response (CHR)

Time: 1 month

Description: Incidence of EMR at 3 and 6 months, defined as BCR-ABL transcript ≤ 10%, will be evaluated, and will be compared against TKI levels at 3 and 6 months.

Measure: Correlation between Early Molecular Response (EMR) and TKI Exposure/Clearance

Time: 3 months, 6 months

Description: Incidence of MMR at 9 and 12 months, defined as BCR-ABL transcript ≤ 0.1%, will be evaluated, and will be compared against TKI levels at 9 and 12 months.

Measure: Correlation between Major Molecular response (MMR) and TKI Exposure/Clearance

Time: 9 months, 12 months

Description: BCR-ABL transcripts will be obtained at each time point. The Log10 change in BCR-ABL transcripts will be evaluated, and will be compared against TKI levels at each time point.

Measure: Correlation between Log10 change in BCR-ABL and TKI Exposure/Clearance

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

Description: Subject adherence will be evaluated at each time point during standard-of-care study visits. The Wilson's 3-item Adherence Score (WAS) tool will be administered to each subject at each visit in survey form. The WAS tool provides a score from 0-100 (0, worst; 100, best) to evaluate adherence to medications in the last 30 days.

Measure: Medication Adherence

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

Description: Associate TKI exposure/clearance with subject-reported toxicity assessments. Medication-induced toxicity assessments will be conducted at each study visit using the validated MD Anderson Symptom Inventory for CML (MDASI-CML) tool. The MDASI-CML tool asks subjects to rate symptom severity in the last 24 hours on a 0-10 scale (0, not present; 10, as bad as one can imagine). The MDASI-CML also evaluates symptom interference with daily activities in the same manner.

Measure: Correlation between Medication-induced Toxicities and TKi Exposure/Clearance

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

88 An Open-Label, Single-Arm, Phase 1/2 Study Evaluating the Safety and Efficacy of Ponatinib for the Treatment of Recurrent or Refractory Leukemias or Solid Tumors in Pediatric Participants

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and efficacy of ponatinib in children aged 1 to < 18 years with advanced leukemias, lymphomas, and solid tumors.

NCT03934372 Acute Myeloid Leukemia Accelerated Phase Chronic Myeloid Leukemia Blast Phase Chronic Myeloid Leukemia Chronic Phase Chronic Myeloid Leukemia Acute Lymphoblastic Leukemia Acute Lymphocytic Leukemia Leukemia Lymphoma Solid Tumors Drug: Ponatinib
MeSH:Leukemia Leukemia, Myeloid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Myelogenous, Chronic, BCR-ABL Positive Blast Crisis Leukemia, Myeloid, Chronic-Phase Leukemia, Myeloid, Accelerated Phase
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

- Phase 2 (CP-CML): Participants who are resistant to or intolerant of at least 1 prior BCR-ABL-targeted TKI therapy or have the T315I kinase domain mutation. --- T315I ---

Primary Outcomes

Description: Defined as the occurrence of any protocol-defined toxicities occurring after dosing and up to and including Day 28, except those toxicities with a clear alternative explanation.

Measure: Phase 1: Number of dose-limiting toxicities

Time: 28 days

Description: Defined as complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR) as assessed by conventional cytogenetics or fluorescence in situ hybridization (FISH).

Measure: Phase 2: Efficacy of ponatinib assessed by major cytogenetic response (MCyR) in participants with chronic-phase chronic myeloid leukemia (CP-CML)

Time: 12 months

Description: Assessed by polymerase chain reaction (PCR).

Measure: Phase 2: Efficacy of ponatinib assessed by major hematologic response (MaHR) or major molecular response (MMR) in participants with BCR-ABL-positive leukemias

Time: 3 months

Measure: Phase 2: Efficacy of ponatinib assessed by complete response (CR) in participants with leukemias other than BCR-ABL-positive leukemias to determine the efficacy of ponatinib

Time: 6 months

Description: Assessed by conventional cytogenetics, FISH, or PCR.

Measure: Phase 2: Efficacy of ponatinib assessed by incomplete complete response (iCR) in participants with leukemias other than BCR-ABL-positive leukemias

Time: 6 months

Description: According to Lugano criteria based on computed tomography (CT) or magnetic resonance imaging (MRI) (or positron emission tomography [PET]).

Measure: Phase 2: Efficacy of ponatinib assessed by CR in participants with lymphoma

Time: 6 months

Description: Defined as the percentage of participants having CR or PR, as determined by investigator assessment of radiographic disease per tumors per RANO for central nervous system (CNS) tumors or Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) for other solid tumors based on CT or MRI (or PET).

Measure: Phase 2: Efficacy of ponatinib assessed by overall response rate in participants with solid tumors

Time: 6 months

Secondary Outcomes

Measure: Phase 1: Number of treatment-emergent adverse events

Time: 6 months

Description: Time to maximum concentration.

Measure: Phase 1: Tmax of ponatinib

Time: 6 months

Description: Area under the steady-state plasma or serum concentration-time curve from Hour 0 to 24.

Measure: Phase 1: AUCss,0-24 of ponatinib

Time: 6 months

Description: Apparent terminal-phase disposition half-life.

Measure: Phase 1: t½ of ponatinib

Time: 6 months

Description: Apparent oral dose clearance at steady state.

Measure: Phase 1: CLss/F of ponatinib

Time: 6 months

Description: Apparent oral dose volume of distribution.

Measure: Phase 1: Vz/F of ponatinib

Time: 6 months

Description: Defined as CCyR or PCyR as assessed by conventional cytogenetics or FISH.

Measure: Phase 1: MCyR in participants with BCR-ABL-positive leukemias

Time: 3 months

Description: Assessed by quantitative PCR (q-PCR).

Measure: Phase 1: MMR in participants with BCR-ABL-positive leukemias

Time: 3 months

Measure: Phase 1 and Phase 2: Complete hematologic response (CHR) in participants with CP-CML

Time: 6 months

Measure: Phase 1 and Phase 2: CCyR in participants with CP-CML

Time: 12 months

Measure: Phase 1 and Phase 2: MMR in participants with CP-CML

Time: 12 months

Description: Defined as the interval from the date of the first dose of study treatment to first response.

Measure: Phase 1 and Phase 2: Time to response (TTR) in participants with CP-CML

Time: 6 months

Description: Defined as the interval between the first assessment at which the criteria for response are met until the criteria for progression are met.

Measure: Phase 1 and Phase 2: Duration of response (DOR) in participants with CP-CML

Time: 6 months

Description: Defined as the interval from the date of the first dose of study treatment until the date of progression of disease or the date of death from any cause, whichever is earlier.

Measure: Phase 1 and Phase 2: Progression-free survival (PFS) in participants with CP-CML

Time: 6 months

Description: Defined as the interval from the date of the first dose of study treatment until death from any cause.

Measure: Phase 1 and Phase 2: Overall survival (OS) in participants with CP-CML

Time: 6 months

Measure: Phase 1: CR in participants with leukemias other than BCR-ABL-positive leukemia or CP-CML.

Time: 6 months

Description: Assessed by conventional cytogenetics, FISH, or q-PCR.

Measure: Phase 1: CRi in participants with leukemias other than BCR-ABL-positive leukemia or CP-CML

Time: 6 months

Description: According to Lugano criteria based on CT or MRI (or PET).

Measure: Phase 1: CR in participants with lymphoma

Time: 6 months

Description: Defined as the percentage of participants having CR or PR, as determined by investigator assessment of radiographic disease per tumors per RANO for CNS tumors or RECIST v1.1 for other solid tumors based on CT or MRI (or PET).

Measure: Phase 1: Overall response rate in participants with solid tumors

Time: 6 months

Measure: Phase 2: Anticancer activity of ponatinib assessed by MaHR or MMR in participants with BCR-ABL-positive leukemias (AP-CML, BP-CML or Ph+ALL)

Time: 3 months

Measure: Phase 2: Anticancer activity of ponatinib assessed by CR in participants with leukemias other than BCR-ABL-positive leukemias

Time: 6 months

Description: Assessed by conventional cytogenetics, FISH, or PCR.

Measure: Phase 2: Anticancer activity of ponatinib assessed by CRi in participants with leukemias other than BCR-ABL-positive leukemias.

Time: 6 months

Description: According to Lugano criteria based on CT or MRI (or PET).

Measure: Phase 2: Anticancer activity of ponatinib assessed by CR in participants with lymphoma

Time: 6 months

Description: Defined as the percentage of participants having CR or PR, as determined by investigator assessment of radiographic disease per tumors per RANO for CNS tumors or RECIST v1.1 for other solid tumors based on CT or MRI (or PET).

Measure: Phase 2: Anticancer activity of ponatinib assessed by overall response rate in participants with solid tumors

Time: 6 months

Description: Defined as the interval from the date of the first dose of study treatment until death from any cause.

Measure: Phase 2: OS in participants with solid tumors

Time: 6 months

Description: Defined as the interval between the first assessment at which the criteria for response are met until the criteria for progression are met.

Measure: Phase 2: DOR in participants with solid tumors

Time: 6 months

Description: Defined as the interval from the date of the first dose of study treatment until the date of progression of disease or the date of death from any cause, whichever is earlier.

Measure: Phase 2: PFS in participants with solid tumors

Time: 6 months

Measure: Phase 2: Number of treatment-emergent adverse events

Time: 6 months

Measure: Phase 2: Clearance of pediatric-friendly formulation of ponatinib

Time: 6 months

Measure: Phase 2: Volume of distribution of pediatric-friendly formulation of ponatinib

Time: 6 months

Measure: Phase 2: AUC of pediatric-friendly formulation of ponatinib

Time: 6 months

89 Efficacy and Safety of Nilotinib as the First-line Treatment for Patients With Newly Diagnosed Chronic-phase Chronic Myeloid Leukemia: a Prospective Study

This is a phase IIIb, multi-centre, single-arm, open-label, prospective study investigating the efficacy and safety of nilotinib as the first-line treatment for the adult patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in China. Nilotinib 300 mg BID will be provided in this study. The assessment for the primary efficacy endpoint will be performed at 18 months and the rate of patients obtaining MR4.5 will be measured at this time point. Secondary endpoints include the complete hematologic response(CHR) and the rates of major molecular reactions (MMR) by 3, 6, 9,12,18 and 24 months; event free survival (EFS); overall survival (OS).

NCT03942094 Chronic Myeloid Leukemia, Chronic Phase Nilotinib Drug: Nilotinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Inclusion Criteria: - Male and female patients - Newly diagnosed CP-CML within 6 months prior to study entry, positive Philadelphia chromosome or positive BCR-ABL (M-bcr transcript) - Age ≥ 18 years old (no upper age limit given) - CML-CP defined by primordial cells in peripheral blood or bone marrow <20%, basophils in peripheral blood <20%, platelets ≥100 x 109/L(≥100,000/mm3), except for hepatosplenomegaly - Patient for whom treatment with Imatinib within 2 weeks is expected No other CML treatment except for hydroxyurea and/or anagrelide and/or IFN ECOG score 0 to 2 - Organ function defined by total serum bilirubin levels < 1.5 × the upper limit of the normal range (ULN), SGOT and SGPT < 2.5 UNL, creatinine < 1.5 × ULN, amylase and lipase ≤ 1.5 × ULN and alkaline phosphatase ≤ 2.5 × ULN not directly related to the CML - Laboratory values defined by potassium ≥ LLN, magnesium ≥ LLN, phosphate ≥ LLN, total calcium (correction for serum albumin) ≥ LLN - No planned allogeneic stem cell transplantation - Signed informed consent Exclusion Criteria: - Patients confirmed to have a T315I mutation - TKIs are not allowed to be treated prior to entering the study, unless the patient has an emergency pending the start of the study, and any dose of commercial imatinib may be used to the patient, but no more than 2 weeks - Treatment with IFN for more than 3 mouths - Impaired cardiac function including any of the following: 1. Complete left bundle branch block 2. Right bundle branch block plus left anterior hemiblock,bifascicular block 3. Use of a ventricular-paced pacemaker 4. Congenital long QT syndrome 5. Clinically significant ventricular or atrial tachyarrhythmias 6. Clinically significant resting bradycardia (<50 beats per minute) 7. QTcF >450 msec on screening ECG.If QTcF >450 msec and electrolytes are not within normal ranges before nilotinib dosing, electrolytes should be corrected and then the patient rescreened for QTcF criterion 8. Myocardial infarction within 12 months prior to starting nilotinib 9. Other clinical significant heart disease (e.g. --- T315I ---

uncontrolled diabetes, active or uncontrolled infections) - Congenital or acquired bleeding tendency - Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy - Received other study medications within 30 days (defined as drugs that cannot be used based on approved indications) - Patients unwilling or unable to comply with the protocol - Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention - Concomitant medications known to be strong inducers or inhibitors of the CYP450 Isoenzyme CYP3A4 (for example, erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, and midazolam) - Impaired gastrointestinal function or disease that may alter the absorption of study drug (e.g.ulcerative disease,uncontrolled nausea,vomiting and diarrhea,malabsorption syndrome,small bowel resection or gastric by-pass surgery) - History of acute pancreatitis within 12 months or chronic pancreatitis - History of acute or chronic diseases of Liver, pancreas or kidney - Concomitant medications with potential QT prolongation - Patients who are pregnant or breast feeding or women of reproductive potential not employing an effective method of birth control.Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to administration of nilotinib.Post menopausal women must be amenorrheic for at least 12 months in order to be considered of non-childbearing potential.Female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug Inclusion Criteria: - Male and female patients - Newly diagnosed CP-CML within 6 months prior to study entry, positive Philadelphia chromosome or positive BCR-ABL (M-bcr transcript) - Age ≥ 18 years old (no upper age limit given) - CML-CP defined by primordial cells in peripheral blood or bone marrow <20%, basophils in peripheral blood <20%, platelets ≥100 x 109/L(≥100,000/mm3), except for hepatosplenomegaly - Patient for whom treatment with Imatinib within 2 weeks is expected No other CML treatment except for hydroxyurea and/or anagrelide and/or IFN ECOG score 0 to 2 - Organ function defined by total serum bilirubin levels < 1.5 × the upper limit of the normal range (ULN), SGOT and SGPT < 2.5 UNL, creatinine < 1.5 × ULN, amylase and lipase ≤ 1.5 × ULN and alkaline phosphatase ≤ 2.5 × ULN not directly related to the CML - Laboratory values defined by potassium ≥ LLN, magnesium ≥ LLN, phosphate ≥ LLN, total calcium (correction for serum albumin) ≥ LLN - No planned allogeneic stem cell transplantation - Signed informed consent Exclusion Criteria: - Patients confirmed to have a T315I mutation - TKIs are not allowed to be treated prior to entering the study, unless the patient has an emergency pending the start of the study, and any dose of commercial imatinib may be used to the patient, but no more than 2 weeks - Treatment with IFN for more than 3 mouths - Impaired cardiac function including any of the following: 1. Complete left bundle branch block 2. Right bundle branch block plus left anterior hemiblock,bifascicular block 3. Use of a ventricular-paced pacemaker 4. Congenital long QT syndrome 5. Clinically significant ventricular or atrial tachyarrhythmias 6. Clinically significant resting bradycardia (<50 beats per minute) 7. QTcF >450 msec on screening ECG.If QTcF >450 msec and electrolytes are not within normal ranges before nilotinib dosing, electrolytes should be corrected and then the patient rescreened for QTcF criterion 8. Myocardial infarction within 12 months prior to starting nilotinib 9. Other clinical significant heart disease (e.g. --- T315I ---

Primary Outcomes

Measure: Molecular response (MR) 4.5 at 18 months of nilotinib 300 mg twice a day

Time: 18 months

Secondary Outcomes

Measure: Molecular Response 4.5 at 3, 6, 9, 12, 24 months of nilotinib

Time: 24 months

Measure: Major Molecular Response at 3, 6, 9, 12, 24 months of nilotinib

Time: 24 months

Measure: Rate of CCyR (complete cytogenetic responses: bone marrow Philadelphie positive at 0 % on at least 20 metaphases) at 3, 6, 9, 12, 24 months of nilotinib.

Time: 24 months

Description: Survival since randomization without any event defined as loss of CHR, loss of PCyR or CCyR, death from any cause, progression towards accelerated phase or blast crisis.

Measure: Event-free survival

Time: 24 months

Description: Survival without death from any cause

Measure: Overall survival

Time: 24 months

90 Effect of Omega-3 Fatty Acid, Eicosapentaenoic Acid, and Its Metabolites in Combination With Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia in Stable Chronic Phase

This is a Phase I/II single site, open label clinical trial. The purpose of the Phase I portion is to determine the safety, tolerability, and recommended Phase II dose of Eicosapentaenoic Acid (EPA) when given daily in combination with a Tyrosine Kinase Inhibitor (TKI) in subjects with Chronic Myeloid Leukemia (CML) in chronic stable phase. The recommended Phase II dose will be the maximum tolerated dose (MTD) of EPA as determined by the evaluation of dose-limiting toxicities (DLTs). The Phase II portion will subsequently examine the Anti-CML effects of EPA when administered with a TKI at the recommended Phase II dose. This efficacy objective will be done by evaluating BCR-ABL p210 quantitative PCR blood levels every 3 months to 1 year.

NCT04006847 Chronic Myeloid Leukemia, Chronic Phase Drug: Eicosapentaenoic Acid Drug: Tyrosine kinase inhibitor
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

- Known T315I mutation. --- T315I ---

Primary Outcomes

Description: Recommended Phase II dose of EPA will be established by using a standard 3 + 3 statistical design to determine the MTD as assessed by DLTs when administered orally in combination with a TKI in subjects with CML in stable chronic phase. Toxicity will be evaluated using the NCI Common Toxicity Criteria (CTC) version 5.0.

Measure: Phase I - Recommended Phase II dose of EPA

Time: 1 month

Description: BCR-ABL transcript levels will be assessed every 3 months post initiation of Eicosapentaenoic Acid to assess Anti-CML response.

Measure: Phase II - Anti-CML response to recommended Phase II dose Eicosapentaenoic Acid

Time: 1 year

Secondary Outcomes

Description: Using the NCI CTC Version 5.0, AEs will be assessed from the time of initiation of investigational medication

Measure: Number of subjects who experience treatment related Adverse Events (AEs)

Time: 2 years

Description: Using the NCI CTC Version 5.0, the highest grade of all treatment related AEs collected will be used to determine severity

Measure: Severity of AEs experienced by study subjects

Time: 2 years

Description: Proportion of protocol prescribed doses taken by subjects

Measure: Study subject compliance with investigational regimen

Time: 2 years

Description: Log reduction from stable molecular response with bcr-abl PCR at MR 3 or more to bcr-abl to major molecular response (MR 4.5) or complete molecular response

Measure: Molecular responses of CML

Time: 1 year

Description: Apoptosis will be analyzed by in vitro correlative studies using subject's plasma with effect on known leukemia cell line with CML leukemic stem cells. EPA metabolite will be examined by flow cytometry using Annexin V staining and adding serum from treated study subject to murine CML cells grown in vitro culture. The evaluation will be done at baseline, Month 1, and every 3 months up to year 2

Measure: Induction of apoptosis in CML leukemia stem cell by formation of Δ12-PGJ3 and other metabolites

Time: 2 years

91 A Clinical Study of CNCT19 Cells in the Treatment of CD19 Positive Relapsed or Refractory B Cell Malignancies

This is a single arm, open-label, single center study to determine the safety and efficacy of CNCT19 in adult patients with Relapsed or Refractory B cell Malignancies.

NCT04011293 Relapsed or Refractory Hematological Malignancies Biological: CNCT19
MeSH:Hematologic Neoplasms Neoplasms
HPO:Hematological neoplasm Leukemia Neoplasm

- Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are intolerant to or have failed 1generation and/or 2 generation of tyrosine kinase inhibitor therapy (TKI); no TKI salvage treatments if the patient has a BCR-ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) mutation. --- Thr315Ile ---

- Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are intolerant to or have failed 1generation and/or 2 generation of tyrosine kinase inhibitor therapy (TKI); no TKI salvage treatments if the patient has a BCR-ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) mutation. --- Thr315Ile --- --- T315I ---

Primary Outcomes

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

Time: 24 months

Measure: Overall remission rate (ORR)

Time: 3 months

Secondary Outcomes

Measure: Response at Day 28±3 days

Time: 1 month

Measure: Percentage of patients who achieve complete remission (CR) or complete remission with incomplete blood count recovery (CRi) (partial remission,PR) at month 6 without SCT between CNCT19 infusion and Month 6 response assessment.

Time: 6 months

Measure: Percentage of patients who achieve CR or CRi (PR) with minimal residual disease negative bone marrow.

Time: 6 months

Measure: Relapse-free survival

Time: 24 months

Measure: Progression-free survival

Time: 24 months

Measure: Percentage of patients who achieve best overall response (BOR)

Time: 24 months

Measure: Duration of remission (DOR)

Time: 24 months

Measure: Overall survival

Time: 24 months

Measure: Percentage of patient who achieve CR or CRi (PR) and then proceed to stem cell transplantation(SCT) while in remission.

Time: 24 months

Measure: Proportion of patients with detectable replication competent lentivirus (RCL) by vesicular stomatitis virus, glycoprotein (VSV-G)

Time: at Month 3 post treatment then Month 6 and Month12, yearly until year 15 if CD19 chimeric antigen receptor (CAR) transgene is still detected

92 a Feasibility and Safety Study of Bispecific CD19-CD22 CAR-T Cell in the Treatment of Relapsed or Refractory B-ALL

This is a single arm, open-label, single center study to determine the safety and efficacy of CD19-CD22 CAR-T cells in patients with CD19+CD22+ Leukemia.

NCT04034446 Relapsed or Refractory B Cell Acute Lymphoblastic Leukemia Biological: CD19-CD22 CAR-T cells
MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid
HPO:Leukemia Lymphoid leukemia

5. Without remission or relapse after any prior CD19 targeted therapy; 6. Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are intolerant to or have failed 2 lines of tyrosine kinase inhibitor therapy (TKI); no TKI salvage treatments if the patient has a BCR-ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) mutation. --- Thr315Ile ---

5. Without remission or relapse after any prior CD19 targeted therapy; 6. Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are intolerant to or have failed 2 lines of tyrosine kinase inhibitor therapy (TKI); no TKI salvage treatments if the patient has a BCR-ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) mutation. --- Thr315Ile --- --- T315I ---

Primary Outcomes

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

Time: 24 months

Measure: Overall remission rate (ORR)

Time: 3 months

Secondary Outcomes

Measure: Response at Day 28 days

Time: 1 month

Measure: Percentage of patients who achieve complete remission (CR) or complete remission with incomplete blood count recovery (CRi) at month 6 without SCT between CD19-CD22 CAR-T cells infusion and Month 6 response assessment.

Time: 6 months

Measure: Percentage of patients who achieve CR or CRi with minimal residual disease (MRD) negative bone marrow

Time: 6 months

Measure: Relapse-free survival (RFS)

Time: 24 months

Measure: Duration of remission (DOR)

Time: 24 months

Measure: Overall survival (OS)

Time: 24 months

93 A Pilot Study of Condensed Busulfan, Melphalan, and Fludarabine Conditioning Prior to Ex-vivo CD34+ Selected Allogeneic Hematopoietic Cell Transplantation

The purpose of this study is to see if a condensed version of the chemotherapy regimen busulfan, melphalan, fludarabine (bu/mel/flu) and the drug antithymocyte globulin (ATG—also referred to as rATG or thymoglobulin) can have the same or fewer number of severe side effects in people with various blood cancers 30 days after they receive an allogeneic hematopoietic cell transplantation.

NCT04098393 Hematologic Malignancies Drug: Busulfan 3.2 mg/kg/day Drug: Fludarabine Drug: Melphalan Drug: Antithymocyte globulin (ATG) Drug: Busulfan 0.8 mg/kg Procedure: Allogeneic hematopoietic cell transplantation (Allo-HCT)
MeSH:Hematologic Neoplasms
HPO:Hematological neoplasm Leukemia

- CML with BCR-ABL mutation consistent with poor response to TKIs (e.g., T315I mutation) - CML in accelerated phase or blast crisis with <10% blasts after therapy, or in second chronic phase. --- T315I ---

Primary Outcomes

Description: All grade 4 CTCAEv5.0 toxicities are included except for hematologic toxicities that are considered expected for patients receiving myeloablative conditioning.

Measure: the number of grade 4 toxicities

Time: in the first 30 days post-HCT

94 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 ---

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

95 A Clinical Trial of CNCT19 Cells in the Treatment of CD19 Positive Relapsed or Refractory Acute Lymphoblastic Leukemia

This is a single arm, open-label, non-randomized, dose-escalation, phase I study to determine the safety and efficacy of CNCT19 in adult patients with relapsed or refractory acute lymphoblastic leukemia.

NCT04230473 Relapsed or Refractory Acute Lymphoblastic Leukemia Biological: single dose of CNCT19
MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid
HPO:Leukemia Lymphoid leukemia

5. Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are intolerant to or have failed 1 generation and/or 2 generation of tyrosine kinase inhibitor therapy (TKI); no TKI salvage treatments if the patient has a T315I mutation. --- T315I ---

Primary Outcomes

Description: Determine the MTD and DLT of CNCT19 in the Treatment and recommend the dose for Phase II study.

Measure: Maximum Tolerated Dose (MTD), Dose Limiting Toxicity (DLT) and Recommended Phase II Dose (RP2D)

Time: 28 days

Description: Safety measures include adverse events as assessed by CTCAE v5.0.

Measure: Safety of CNCT19 therapy

Time: 24 months

Secondary Outcomes

Description: Efficacy of CNCT19 as measured by ORR during the 3 months after CNCT19 infusion, which includes CR and CRi.

Measure: Overall Remission Rate (ORR), which includes Complete Remission (CR) and Complete Remission with Incomplete Blood Count Recovery (CRi)

Time: 3 months

Description: Description: ORR includes CR and CRi.

Measure: Overall Remission Rate (ORR)

Time: 28 days

Description: MRD negative status as determined by central laboratory using multi-parameter flow cytometry.

Measure: Overall Remission Rate (ORR) with minimal residual disease (MRD) negative bone marrow

Time: 28 days

Description: MRD negative status as determined by central laboratory using multi-parameter flow cytometry.

Measure: Overall Remission Rate (ORR) with minimal residual disease (MRD) negative bone marrow

Time: 3 months

Description: ORR includes CR and CRi.

Measure: Overall Remission Rate (ORR)

Time: 6 months

Description: MRD negative status as determined by central laboratory using multi-parameter flow cytometry.

Measure: Overall Remission Rate (ORR) with minimal residual disease (MRD) negative bone marrow

Time: 6 months

Description: DOR is defined as the time from the first documented CR or Partial Remission (PR) to the date of the first documented progressive disease(PD) or death due to any cause.

Measure: Duration of remission (DOR)

Time: 24 months

Description: RFS is defined as the time from the documented CR or PR after the CNCT19 infusion to the date of the documented PD or death due to any cause.

Measure: Relapse-free survival (RFS)

Time: 24 Months

Description: OS is defined as the time from the signing of informed consent form to the date of the last survival follow-up or death due to any cause.

Measure: Overall survival (OS)

Time: 24 months

96 A Phase II Multi-center, Randomized, Open-label Study of Ponatinib in Chinese Patients With Chronic Myeloid Leukemia Who Have Failed Prior TKIs or With T315I Mutation, or Ph+ALL Who Have Failed Prior TKIs or With T315I Mutation

This protocol will allow ponatinib with refractory Chronic Myeloid Leukemia or Ph+ Acute Lymphoblastic Leukemia

NCT04233346 Chronic Myeloid Leukemia Acute Lymphoblastic Leukemia Drug: Ponatinib
MeSH:Leukemia Leukemia, Myeloid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

A Phase II Multi-center, Randomized, Open-label Study of Ponatinib in Chinese Patients With Chronic Myeloid Leukemia Who Have Failed Prior TKIs or With T315I Mutation, or Ph+ALL Who Have Failed Prior TKIs or With T315I Mutation. --- T315I ---

A Phase II Multi-center, Randomized, Open-label Study of Ponatinib in Chinese Patients With Chronic Myeloid Leukemia Who Have Failed Prior TKIs or With T315I Mutation, or Ph+ALL Who Have Failed Prior TKIs or With T315I Mutation. --- T315I --- --- T315I ---

The Study for CML Who Failed Prior TKIs or With T315I Mutation or Ph+ ALL Who Failed Prior TKIs or With T315I Mutation This protocol will allow ponatinib with refractory Chronic Myeloid Leukemia or Ph+ Acute Lymphoblastic Leukemia MCyR(Major Cytogenetic Response) of CP-CML patients. --- T315I ---

The Study for CML Who Failed Prior TKIs or With T315I Mutation or Ph+ ALL Who Failed Prior TKIs or With T315I Mutation This protocol will allow ponatinib with refractory Chronic Myeloid Leukemia or Ph+ Acute Lymphoblastic Leukemia MCyR(Major Cytogenetic Response) of CP-CML patients. --- T315I --- --- T315I ---

To confirm the efficacy of Ponatinib in Chinese patients with CML who have failed Dasatinib or Nilotinib or with T315I mutation, or Ph+ ALL who have failed prior TKIs or with T315I mutation as evidenced by cytogenetic responses. --- T315I ---

To confirm the efficacy of Ponatinib in Chinese patients with CML who have failed Dasatinib or Nilotinib or with T315I mutation, or Ph+ ALL who have failed prior TKIs or with T315I mutation as evidenced by cytogenetic responses. --- T315I --- --- T315I ---

To confirm the efficacy of Ponatinib in Chinese patients with CML who have failed Dasatinib or Nilotinib or with T315I mutation, or Ph+ ALL who have failed prior TKIs or with T315I mutation as evidenced by hematology responses. --- T315I ---

To confirm the efficacy of Ponatinib in Chinese patients with CML who have failed Dasatinib or Nilotinib or with T315I mutation, or Ph+ ALL who have failed prior TKIs or with T315I mutation as evidenced by hematology responses. --- T315I --- --- T315I ---

Inclusion Criteria: For CP-CML patients: 1. Patients with CP-CML Patients must either meet criterion 2 or 3: 2. Be previously treated with and resistant or intolerant to either Dasatinib or Nilotinib: 3. Develop the T315I mutation after any TKI therapy; 4. Must be ≥18 years old. 5. Provide written informed consent. --- T315I ---

Chronic Myeloid Leukemia Acute Lymphoblastic Leukemia Leukemia Leukemia, Myeloid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Myelogenous, Chronic, BCR-ABL Positive The purpose of this study is to determine the safety and efficacy of ponatinib in patients with chronic myeloid leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast phase (BP) or with Ph positive (Ph+) acute lymphoblastic leukemia (ALL) who either are resistant or intolerant to either dasatinib or nilotinib, or have the T315I mutation. --- T315I ---

Primary Outcomes

Description: To confirm the efficacy of Ponatinib in Chinese patients with CML who have failed Dasatinib or Nilotinib or with T315I mutation, or Ph+ ALL who have failed prior TKIs or with T315I mutation as evidenced by cytogenetic responses

Measure: MCyR(Major Cytogenetic Response) of CP-CML patients

Time: 12 months

Description: To confirm the efficacy of Ponatinib in Chinese patients with CML who have failed Dasatinib or Nilotinib or with T315I mutation, or Ph+ ALL who have failed prior TKIs or with T315I mutation as evidenced by hematology responses

Measure: MaHR(Major Hematologic Response) of AP-CML, BP-CML and Ph+ ALL patients by 6 months

Time: 6 months

Secondary Outcomes

Description: Assessment in the total patient population

Measure: Duration of response

Time: Up to 5 years

Description: Assessment in the total patient population

Measure: Progression-free survival (PFS)

Time: Up to 5 years

Description: Assessment in the total patient population

Measure: Overall survival (OS)

Time: Up to 5 years

Description: Assessment in the total patient population

Measure: Time to response (TTR)

Time: Up to 5 years

Description: Number of participants with adverse events as assessed by CTCAE v5.0

Measure: Adverse events

Time: Up to 5 years

Description: EORTC QLQ-C30 (version 3) score ranges from 1 to 4 or 1 to 7, A higher score represents a severer impressions or a best applies of patients.

Measure: EORTC QLQ-C30 (version 3)

Time: Up to 5 years

Description: Plasma concentration-time data for the population PK study

Measure: Maximum Plasma Concentration [Cmax]

Time: Up to 3 months

97 A Phase I/II Study of Bosutinib in Pediatric Patients With Newly Diagnosed Chronic Phase or Resistant/Intolerant Ph + Chronic Myeloid Leukemia", Study ITCC-054/COG-AAML1921

This is a Phase 1-2, multicenter, international, single-arm, open-label study designed to identify a recommended dose of bosutinib administered orally once daily in pediatric patients with newly diagnosed chronic phase Ph+ CML (ND CML) and pediatric patients with Ph+CML who have received at least one prior TKI therapy (R/I CML), to preliminary estimate the safety and tolerability and efficacy, and to evaluate the PK of bosutinib in this patient population.

NCT04258943 Philadelphia Chromosome Positive CML Accelerated Phase Chronic Myelogenous Leukemia Blastic Phase Chronic Myelogenous Leukemia Chronic Phase Chronic Myelogenous Leukemia Drug: Bosutinib
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase Blast Crisis Leukemia, Myeloid, Accelerated Phase Philadelphia Chromosome
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

4. Documented prior history of T315I or V299L BCR-ABL1 mutations (Note: BCR-ABL1 mutation testing will be performed at screening for a baseline assessment, but results are not used to determine eligibility. --- T315I ---

3. Documented prior history of T315I or V299L BCR-ABL1 mutations (Note: BCR-ABL1 mutation testing will be performed at screening for a baseline assessment, but results are not used to determine eligibility. --- T315I ---

Primary Outcomes

Description: Data from Phase 1; Dose-limiting toxicities determined as adverse events occurring in the first cycle (28 days) of treatment, which are attributable to bosutinib. Assessment will be done according the following DLT definition: Non-hematologic AEs: grade ≥3 toxicities, except those that have not been optimally treated; any grade ≥2 toxicity requiring discontinuation/interruption for ≥7 days during the first 28 days of treatment; clinically significant laboratory abnormalities grade ≥3 or lasting ≥7 days despite optimal treatment Hematologic AEs: grade 4 neutropenia or thrombocytopenia lasting ≥7 days (not explained by persistent leukemia).

Measure: 1. Incidence (and severity) of Dose-Limiting Toxicities (DLTs) assessed during the first 28 days of treatment.

Time: First 28 days of treatment (first cycle)

Description: Data from Phase 1; Maximum plasma concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time postdose and actual dose will be used for all calculations.

Measure: PK parameters of bosutinib: Maximum observed plasma concentration (Cmax)

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose and before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days); unexpected and/or serious bosutinib-related AEs: when AE is detected

Description: Data from Phase 1; Time to maximum plasma concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post dose and actual dose will be used for all calculations.

Measure: PK parameters of bosutinib:Time to Cmax (Tmax)

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected

Description: Data from Phase 1; Area under the plasma concentration versus time curve from time zero to the dosing interval calculated from the plasma concentration-time data by linear trapezoidal rule during the ascending phase and log trapezoidal rule during the descending phase.

Measure: PK parameters of bosutinib: Area under the plasma concentration versus time curve from time zero to the dosing interval (AUCτ)

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected

Description: Data from Phase 1; Pre-dose concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post dose and actual dose will be used for all calculations.

Measure: PK parameters of bosutinib: Pre-dose concentration (Ctrough)

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected

Description: Data from Phase 1; Apparent clearance of the drug from plasma after oral administration, calculated as Dose/AUCt.

Measure: PK parameters of bosutinib: Apparent clearance (CL/F).

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected

Description: Data from Phase 2; AEs will be graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and coded using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment emergent AEs (TEAEs) are defined as those with initial onset or increasing in severity after the first dose of study medication. Endpoints include maximum toxicity, time to first event (time from first dose to date of first event including only non-partial dates), duration of any stage/grade event (time from start date to stop date including only non-partial dates).

Measure: AEs, as characterized by type, frequency, severity (as graded using CTCAE version, v4.03), timing, seriousness, and relation to study therapy (pooled across ND and R/I CML patients and by line of therapy).

Time: AE's will be collected from signing informed consent continuously during the study until 28 days after last dose (on average, 2 years).

Description: Data from Phase 2; subset of newly diagnosed patients. Maximum plasma concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post-dose and actual dose will be used for all calculations.

Measure: PK parameters of bosutinib: Maximum observed plasma concentration (Cmax)

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose and before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 & and before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected

Description: Data from Phase 2; subset of newly diagnosed patients. Time to maximum plasma concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post-dose and actual dose will be used for all calculations.]

Measure: PK parameters of bosutinib:Time to Cmax (Tmax)

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected

Description: Data from Phase 2; subset of newly diagnosed patients. Area under the plasma concentration versus time curve from time zero to the dosing interval calculated from the plasma concentration-time data by linear trapezoidal rule during the ascending phase and log trapezoidal rule during the descending phase.

Measure: PK parameters of bosutinib: Area under the plasma concentration versus time curve from time zero to the dosing interval (AUCτ)

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected

Description: Data from Phase 2; subset of newly diagnosed patients. Pre-dose concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post-dose and actual dose will be used for all calculations.

Measure: PK parameters of bosutinib: Pre-dose concentration (Ctrough)

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected

Description: Data from Phase 2; subset of newly diagnosed patients. Apparent clearance of the drug from plasma after oral administration, calculated as Dose/AUCt.

Measure: PK parameters of bosutinib: Apparent clearance (CL/F).

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected

Description: Data from Phase1 and Phase 2. Population PK parameters of bosutinib including volume of distribution based on combined PK data from Phase 1 and Data from Phase1 and Phase 2. Volume of distribution are calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post-dose and actual dose will be used for all calculations.

Measure: Population PK parameters of bosutinib including volume of distribution based on combined PK data from Phase 1 and Phase 2

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing(each cycle is 28 days); for unexpected and/or serious bosutinib-related AEs: when AE is detected

Description: Data from Phase1 and Phase 2. Clearance is calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post-dose and actual dose will be used for all calculations

Measure: Population PK parameters of bosutinib including clearance based on combined PK data from Phase 1 and Phase 2

Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose and before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing(each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected

Secondary Outcomes

Description: Data from Phase 1. AEs will be graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and coded using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment emergent AEs (TEAEs) are defined as those with initial onset or increasing in severity after the first dose of study medication. Endpoints include maximum toxicity, time to first event (time from first dose to date of first event including only non-partial dates), duration of any stage/grade event (time from start date to stop date including only non-partial dates).]

Measure: AEs, as characterized by type, frequency, severity (as graded using CTCAE version, v4.03), timing, seriousness, and relation to study therapy;

Time: From signing informed consent, continuously during the study until 28 days after last dose (on average 2 years).

Description: Data from Phase 1. Test abnormalities in hematology, blood chemistry, liver functions, coagulation, HbsAg, urinalysis and pregnancy test will be recorded. Severity of laboratory test abnormalities will be graded using NCI CTCAE version, v4.03. For those laboratory abnormalities without CTCAE grade definitions, results will be categorized as normal, abnormal or not done. Coagulation and HBsAG only tested at screening. Urinalysis and pregnancy test and contraception check not tested at days 8, 14, 15 and 22 of cycle 1. Urinalysis not performed at beginning of cycles 2, 3, 5 and 6

Measure: Occurrence of laboratory abnormalities of hematology, blood chemistry, liver functions, coagulation, HbsAg, urinalysis and pregnancy tests values, as characterized by type, frequency, severity and timing summarized in an overview table

Time: Screening; cycle 1 days 1, 8, 14, 22; cycles 2 to 7: at start of every cycle; cycle 8 and higher: every 3 cycles; End of treatment: within 28 days after last dose (each cycle is 28 days)

Description: Data from Phase 1. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points. Kamofsky or Lansky performance score is collected to evaluate performance status.

Measure: ECG abnormalities: QT interval

Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)

Description: Data from Phase 1. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points.

Measure: ECG abnormalities: RR interval

Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)

Description: Data from Phase 1. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points.

Measure: ECG abnormalities: PR interval

Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)

Description: Data from Phase 1. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points.

Measure: ECG abnormalities: QRS duration

Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)

Description: Data from Phase 1. Kamofsky or Lansky (depending on age) performance score as assessed by physician is collected to evaluate performance status

Measure: Performance status abnormalities

Time: Screening; on day 1 of every subsequent cycle end of treatment (each cycle is 28 days)

Description: Data from Phase 1. MCyR is defined as complete cytogenetic response [CCyR] plus partial cytogenetic response [PCyR]. (definitions in appendix 2).]

Measure: Overall cumulative disease response: complete hematologic response (CHR), major cytogenetic response (MCyR), major molecular response (MMR) and deep molecular response

Time: Hematologic response:Screening; Cycles 2 to 7: start of every cycle; cycle 8 and higher: every 3 cycles; End of treatment: within 28 days after last dose (each cycle is 28 days).

Description: Data from Phase 2. MCyR is defined as complete cytogenetic response [CCyR] plus partial cytogenetic response [PCyR]. (definitions in appendix 2).

Measure: Overall cumulative disease response: complete hematologic response (CHR), major cytogenetic response (MCyR), major molecular response (MMR) and deep molecular response

Time: Screening; Cycles 2 to 7: start of every cycle; cycle 8 and higher: every 3 cycles; End of treatment: within 28 days after last dose (each cycle is 28 days).]

Description: Time to response is defined as the time period from start of treatment with bosutinib to first response, unconfirmed for molecular and cytogenetic and confirmed for hematologic. Patients without events are censored at the last molecular, cytogenetic, or hematologic assessment where response could be assessed for the respective endpoint

Measure: Time to the respective responses by line of therapy

Time: Through study completion, a maximum of around 10 years

Description: Data from Phase 2. Duration of response is defined is defined as the time period from the date of the earliest demonstration of a response until the earliest date of confirmed loss of that response.

Measure: Duration of the respective responses by line of therapy

Time: Through study completion, a maximum of around 10 years

Description: Data from Phase 2. EFS is defined as the interval from the date of first dose of bosutinib until the earlier date of EFS events. Patients without the event will be censored at the last evaluation date.

Measure: Event-free survival (EFS; including time to transformation to AP and BP CML) by line of therapy (definition in appendix 2).

Time: Through study completion, a maximum of around 10 years

Description: Data from Phase 2. OS or survival time is defined as the interval from the date of first dose of bosutinib until the date of death due to any cause. Patients without the event will be censored at the last evaluation date

Measure: Overall survival (OS) in pediatric patients with Ph+ CML by line of therapy

Time: Through study completion, a maximum of around 10 years

Description: Data from Phase 2. Pooled across ND and R/I CML and by line of therapy. Test abnormalities in hematology, blood chemistry, liver functions, coagulation, HbsAg, urinalysis and pregnancy test and contraception will be recorded. Severity of laboratory test abnormalities will be graded using NCI CTCAE version, v4.03. For those laboratory abnormalities without CTCAE grade definitions, results will be categorized as normal, abnormal or not done. Coagulation and HBsAG only tested at screening. Urinalysis and pregnancy test and contraception check not tested at days 8, 14, 15 and 22 of cycle 1. Urinalysis not performed at beginning of cycles 2, 3, 5 and 6

Measure: Occurrence of laboratory abnormalities of hematology, blood chemistry, liver functions, coagulation, HbsAg, urinalysis and pregnancy tests values, as characterized by type, frequency, severity and timing summarized in an overview table

Time: Screening; cycle 1 days 1, 8, 14, 22; cycles 2 to 7: at start of every cycle; cycle 8 and higher: every 3 cycles; End of treatment: within 28 days after last dose (each cycle is 28 days)

Description: Data from Phase 2. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points

Measure: ECG abnormalities: QT interval

Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)

Description: Data from Phase 2. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points

Measure: ECG abnormalities: RR interval

Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)

Description: Data from Phase 2. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points

Measure: ECG abnormalities: PR interval

Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)

Description: Data from Phase 2. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points

Measure: ECG abnormalities: QRS duration

Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)

Description: Data from Phase 2. Kamofsky or Lansky (depending on age) performance score as assessed by physician is collected to evaluate performance status.

Measure: Performance status abnormalities

Time: Screening; on day 1 of every subsequent cycle end of treatment (each cycle is 28 days)

Other Outcomes

Description: Data from Phase 1 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX). The analysis of bone age, pubertal status and results of serum chemistry tests will be descriptive. Height (cm), weight (kg), bone age (yr), Tanner stage, serum chemistry and bone densitometry scan results [Lumbar Spine (L1-L4) (g/cm2)] will be provided in listings and summarized by study visit (including change from baseline).

Measure: Parameters of bone metabolism and growth: linear growth

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

Description: Data from Phase 1 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Measure: Parameters of bone metabolism and growth: bone age

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

Description: Data from Phase 1 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Measure: Parameters of bone metabolism and growth: bone mineral density of lumbar spine

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

Description: Data from Phase 1 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Measure: Parameters of bone metabolism and growth: physical signs of pubertal maturation (Tanner stage and testicular volume of boys),

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

Description: Data from Phase 1 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Measure: Parameters of bone metabolism and growth: hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys)

Time: [Time Frame: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

Description: Data from Phase 1 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Measure: Parameters of bone metabolism and growth: markers of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

Description: Data from Phase 1. Pediatric quality of life inventory ™ (PedsQL) Gastrointestinal Symptom Scale questionnaires will be used to assess gastrointestinal symptoms. ON a scale of 0 to 4, with 0 being: 'never' and 4 being: 'almost always'

Measure: Patient and/or caregiver-reported assessments of gastrointestinal symptoms, as measured by selected domains from the Pediatric quality of life inventory ™ (PedsQL) Gastrointestinal Symptom Scale

Time: Through study completion, a maximum of around 10 years

Description: Data from Phase 1. A questionnaire with different kind of questions, using a 1 to 3 score on difficulty to swallow, with 1 being' difficult to swallow' and 3 being:' no trouble, easy to swallow' and a 1 to 5 score on assessment of taste and overall ease, with 1 being: 'dislike very much' and 5 being: ' like very much'.

Measure: Patient and/or caregiver-reported assessment of the taste and ability to swallow the medicine, as measured by the Palatability Questionnaire for Bosutinib in patients aged 4-18 years of age.

Time: Through study completion, a maximum of around 10 years

Description: Data from Phase 2 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX). The analysis of bone age, pubertal status and results of serum chemistry tests will be descriptive. Height (cm), weight (kg), bone age (yr), Tanner stage, serum chemistry and bone densitometry scan results [Lumbar Spine (L1-L4) (g/cm2)] will be provided in listings and summarized by study visit (including change from baseline).

Measure: Parameters of bone metabolism and growth: linear growth

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

Description: Data from Phase 2 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Measure: Parameters of bone metabolism and growth: bone age

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

Description: Data from Phase 2 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Measure: Parameters of bone metabolism and growth: bone mineral density of lumbar spine

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

Description: Data from Phase 2 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Measure: Parameters of bone metabolism and growth: physical signs of pubertal maturation (Tanner stage and testicular volume of boys

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

Description: Data from Phase 2 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Measure: Parameters of bone metabolism and growth: hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys)

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

Description: Data from Phase 2 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Measure: Parameters of bone metabolism and growth: markers of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).

Description: Data from Phase 2. Pediatric quality of life inventory ™ (PedsQL) Gastrointestinal Symptom Scale questionnaires will be used to assess gastrointestinal symptoms. On a scale of 0 to 4, with 0 being: 'never' and 4 being: 'almost always'

Measure: Patient and/or caregiver-reported assessments of gastrointestinal symptoms, as measured by selected domains from the Pediatric quality of life inventory ™ (PedsQL) Gastrointestinal Symptom Scale.

Time: Through study completion, a maximum of around 10 years

Description: Data from Phase 2 A questionnaire with different kind of questions, using a 1 to 3 score on difficulty to swallow, with 1 being' difficult to swallow' and 3 being:' no trouble, easy to swallow' and a 1 to 5 score on assessment of taste and overall ease, with 1 being: 'dislike very much' and 5 being: ' like very much'.

Measure: Patient and/or caregiver-reported assessment of the taste and ability to swallow the medicine, as measured by the Palatability Questionnaire for Bosutinib in patients aged 4-18 years of age.

Time: Through study completion, a maximum of around 10 years

98 A Phase IB Study of the Pharmacokinetics, Safety and Efficacy of Orally Administered HQP1351 in Subjects With Refractory Chronic Myeloid Leukemia (CML)

A multi-center, open-label, randomized, phase Ib study to evaluate the PK of HQP1351 and to determine the RP2D of HQP1351 in subjects with CML CP and AP, who have experienced resistance or intolerance to at least two TKIs.

NCT04260022 Leukemia, Myeloid, Chronic Myeloid Leukemia Chronic Myeloid Leukemia Drug: Ascentage Pharma HQP-1351 bioavailable inhibitor
MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Inclusion Criteria: - Patients must have CML in chronic phase (CP) or accelerated phase (AP) of any phenotype, with or without T315I mutation - Be previously treated with and developed resistance or intolerance to at least two TKIs (such as imatinib, dasatinib, nilotinib, bosutinib or ponatinib) 1. --- T315I ---

- Known allergy to any components in the study drug - Pregnant or lactating - Patients who have any conditions or illness that, according to the opinions of the investigator or the medical monitor, would comprise patient safety or interfere with the evaluation of safety and efficacy to the study drug Inclusion Criteria: - Patients must have CML in chronic phase (CP) or accelerated phase (AP) of any phenotype, with or without T315I mutation - Be previously treated with and developed resistance or intolerance to at least two TKIs (such as imatinib, dasatinib, nilotinib, bosutinib or ponatinib) 1. --- T315I ---

The randomization will be stratified to 3 groups: T315I mutated CML-CP and CML-AP, T315I un-mutated CML-CP, and T315I unmutated CML-AP to ensure that the subgroups are represented across all dose cohorts. --- T315I ---

The randomization will be stratified to 3 groups: T315I mutated CML-CP and CML-AP, T315I un-mutated CML-CP, and T315I unmutated CML-AP to ensure that the subgroups are represented across all dose cohorts. --- T315I --- --- T315I ---

The randomization will be stratified to 3 groups: T315I mutated CML-CP and CML-AP, T315I un-mutated CML-CP, and T315I unmutated CML-AP to ensure that the subgroups are represented across all dose cohorts. --- T315I --- --- T315I --- --- T315I ---

Primary Outcomes

Description: To evaluate the Maximum Plasma Concentration (Cmax) of HQP1351

Measure: Maximum Plasma Concentration (Cmax) of HQP1351

Time: 27 days

Description: To evaluate the Area Under the Curve (AUC) of HQP1351

Measure: Area Under the Curve (AUC) of HQP1351

Time: 27 days

99 Phase II Study of Blinatumomab and Concurrent Oral Tyrosine Kinase Inhibitor Therapy as Consolidation and Maintenance Therapy for Patients With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Following Chemotherapy-Sparing Induction

: The purpose of this study is to test whether blinatumomab in combination with TKI therapy (such as dasatinib) is an effective treatment for people with Ph+ ALL. Researchers want to improve the response to standard-of-care treatment of corticosteroids + TKI therapy by adding the study drug, blinatumomab.

NCT04329325 Acute Lymphoblastic Leukemia Philadelphia Chromosome-Positive Biological: Blinatumomab Drug: dasatinib Drug: dexamethasone Drug: methotrexate
MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-L Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Philadelphia Chromosome
HPO:Leukemia Lymphoid leukemia

- Presence of known ABL kinase mutations conferring resistance to dasatinib at time of study entry, including T315I mutation. --- T315I ---

Primary Outcomes

Description: (MRD negativity by flow cytometry and quantitative PCR of BCR-ABL transcripts) at any time during TKI + corticosteroid induction or consolidation with up to 3 cycles of blinatumomab in combination with TKI.

Measure: Proportion of evaluable patients achieving complete molecular response

Time: 7 months

Secondary Outcomes

Description: assessed by NCI CTCAE v5.0 and rates of blinatumomab discontinuation due to toxicity among all patients beginning the consolidation portion of the study on dasatinib. The window for toxicity evaluation for this objective extends from the beginning of consolidation of the study until completion of maintenance or removal from study, whichever is sooner."

Measure: Frequency, severity, and co-occurrence of treatment-related grade 3-4 toxicities

Time: 13 months

Measure: Proportion of evaluable patients with CMR or molecular MRD positivity with MRD negativity by flow cytometry at any time during induction or consolidation.

Time: 7 months

Measure: Duration of CMR among patients achieving MRD negativity after TKI + corticosteroid induction, followed by 1-3 cycles of blinatumomab in combination with an oral TKI.

Time: 2 years

Measure: Cumulative incidence of morphologic and molecular relapse following consolidative therapy with blinatumomab in combination with an oral TKI

Time: 2 years

Measure: Event-free survival following consolidative therapy with blinatumomab in combination with an oral TKI.

Time: 2 years

Measure: Overall survival following consolidative therapy with blinatumomab in combination with an oral TKI.

Time: 2 years

Measure: The proportion of patients first achieving CMR at any point during induction and proportion of patients not achieving CMR in Part 1 who subsequently achieved CMR at any point during consolidation.

Time: 7 months

Other Outcomes

Description: As assessed by sequencing of the ABL kinase gene in bone marrow or peripheral blood, observed in patients experiencing progression of B-ALL following consolidative therapy with blinatumomab in combination with an oral TKI.

Measure: Frequency, type, and co-occurrence of ABL kinase mutations

Time: 2 years

Description: As assessed by next-generation sequencing of bone marrow or peripheral blood, in patients experiencing progression of B-ALL following consolidative therapy with blinatumomab in combination with an oral TKI.

Measure: Frequency, type, and co-occurrence of new somatic mutations

Time: 2 years

100 Managed Access Program (MAP) to Provide Access to Asciminib for Patients With CML in Chronic Phase, With or Without Documented T315I Mutation, Without Comparable or Satisfactory Alternative Therapy to Treat the Disease

This program provides access to asciminib for patients with CML in chronic phase, with or without documented T315I mutation, without comparable or satisfactory alternative therapy to treat the disease

NCT04360005 Chronic Myeloid Leukemia Drug: Asciminib
MeSH:Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Myeloid leukemia

Managed Access Program (MAP) to Provide Access to Asciminib for Patients With CML in Chronic Phase, With or Without Documented T315I Mutation, Without Comparable or Satisfactory Alternative Therapy to Treat the Disease. --- T315I ---

Managed Access Program (MAP)* to Provide Access to Asciminibfor Patients With CML in Chronic Phase This program provides access to asciminib for patients with CML in chronic phase, with or without documented T315I mutation, without comparable or satisfactory alternative therapy to treat the disease Inclusion Criteria: Patients eligible for inclusion in this treatment plan have to meet all of the following criteria: Written patient informed consent must be obtained prior to start of treatment, including all necessary consents (or their legal representatives, where applicable). --- T315I ---

- Male or female patients ≥ 18 years of age - Patients with CML in chronic phase with or without T315I mutation, who were previously treated with all commercially available tyrosine kinase inhibitors (TKIs) for the specific market and are relapsed, refractory to or intolerant of TKIs as determined by the treating physician or for whom the treatment with one or more available TKIs is contraindicated based on approved label - Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 - Patient is deemed by the treating physician to have the initiative and means to be compliant with treatment and follow-up requested - Adequate end organ function, within 14 days before the first dose of asciminib treatment, as defined by: - Total bilirubin ≤ 1.5 x ULN except for patients with Gilbert's syndrome who may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN - Aspartate transaminase (AST) ≤ 3.0 x ULN - Alanine transaminase (ALT) ≤ 3.0 x ULN - Serum lipase ≤ 1.5 x ULN. --- T315I ---



HPO Nodes


HP:0002664: Neoplasm
Genes 1489
WHCR ATP7A PHOX2B KRT17 IL2RG HMGA2 PORCN KRAS TET2 IDH2 FLT3 ERCC4 AR BRCA1 BRCA2 GATA1 TCF4 TCTN3 GPR101 SMAD7 KRT6B PIK3CA KCNJ10 MAP2K2 REST TTC37 MC2R TRPS1 SIX6 ALX4 PIK3CA BRAF TP53 STK11 TSR2 EXT2 EDN1 RNF43 TRNL1 ATM SDHC EXT1 BCL10 BAP1 NF1 OCRL TP53 CHD7 TINF2 ERCC6 NF1 MAFA PMS2 ASXL1 PHOX2B CTNNB1 CR2 RET TCTN3 C11ORF95 PTPN3 PIEZO2 ABCB11 SETBP1 PDCD10 LRP5 LMOD1 MALT1 ASXL1 LZTR1 TINF2 RAD51C RECQL4 MAP2K1 FOXO1 PTCH2 RPS20 FLI1 BMPR1A SMARCAD1 BMPR1A MAP3K8 DNASE1L3 SUFU TP53 FOXP1 PTCH1 PDGFRB ND1 PIK3CA ZSWIM6 SETD2 INS NRAS HBB MEN1 AIP CLCNKB RPS10 HFE COX2 TSC2 DHH CTRC MEN1 EYA1 BRCA1 GINS1 MSH3 GLI2 TRNS1 HABP2 SSX1 SUFU PRKN CD81 TNFSF12 MYH11 KIT VEGFC WWOX H19 SDHD FGF3 TNFRSF1B RMRP XRCC2 HRAS MTM1 EPHB2 PLCD1 NBN CDKN1B TUBB RECQL4 EDNRB VHL ACAN MSH6 CDKN2B DCC TJP2 HRAS CDKN2A VHL REST NKX2-1 ANTXR1 RPL35 DNM2 FGFR3 SNAI2 NLRP1 ACTG2 GNB1 EWSR1 CBFB NSD1 FLCN ERBB2 MLH1 H19 EIF2AK4 RPL10 TMEM107 TRNK RAD54L RAD51C INPP5E NFKB1 CDKN1A KDM6B F13B SLC26A2 TRNS1 RPL26 CYLD H19 PTEN PTPN11 DCLRE1C MPL FLCN NEK1 MITF MSH3 NUTM1 IL7 STAT3 TRNS2 TG ERCC3 MNX1 NRAS MLH3 TSC1 GLI3 CDK4 SDHC NF1 BRCA2 CIB1 ATRX BRCA2 ADAMTS3 ZFPM2 COL2A1 TET2 ZIC2 SLCO2A1 BLM GJA1 MAP3K1 PIK3CA SDHA RTEL1 CDK4 KCNH1 SH2B3 APC ESCO2 FANCC TERT USP9X APC RAD54B NF2 SDHB RPS14 PPP2R1B RPS19 RPL35A MSH2 WRAP53 RASA1 LMNA ACVRL1 POLH SDHB DIS3L2 PIGA GNPTAB CXCR4 MSH2 SLC25A13 BMP2 NNT PSENEN FOXI1 APC IL1RN MITF ACD PTEN MPL RUNX1 ERCC3 ERCC4 DLEC1 CHEK2 BRCA2 JAK2 SBDS BRCA1 SDHD SEMA3D MSH6 HFE TREM2 APC CCDC22 MINPP1 DISP1 FAM20C MAP2K1 ALK BRCA1 STIM1 SLC25A13 RFWD3 HRAS GLI1 TET2 DVL3 COL7A1 HMBS TFAP2A ICOS CALR PTEN UROD DKC1 FDPS LIG4 TXNRD2 SRSF2 ND5 SDHD CHEK2 NRAS BCL6 GPC3 XPC MEN1 ERCC2 AXIN2 MYC RAD51 GBA KIF1B SDHB EXT2 EXT2 NTHL1 SRY RPGRIP1L MPL MTOR CASP8 RB1CC1 IGF2 FANCC ERCC4 WRN PGM3 VHL ING1 PLAG1 WT1 MYLK KLLN PIK3CA G6PC RPS7 MCM4 ANTXR1 POLH BRCA2 DLL1 OGG1 WRN F13A1 SBDS EFL1 TAF15 GLI3 GPC3 KRAS CDKN2B MAPK1 DIS3L2 GPR101 NRTN DKC1 KLLN NSUN2 MAP3K1 ERBB2 PHKG2 SRGAP1 CYLD NBN ALK MAX WT1 ACTB PALB2 TBX18 FIBP CASP10 DVL1 TYR MSH2 RECQL4 PIGL EDN3 WT1 ATP7B RPL27 RET USP8 FGFR2 PDGFRL H19 CCND1 ATM AXIN2 COL7A1 AKT1 TERT MUTYH HOXD13 DICER1 THPO GDF5 CEL SDHB EXT2 SRP72 TERT TRNF TP53 LIN28B APC NPM1 FGFR3 PTEN SMPD1 SLC22A18 SDHC PRDM16 KIT STK11 RPL11 LETM1 CALR SDHC RB1 PIK3CA PLCB4 COL4A5 CASP8 SKI H19 COL1A1 CC2D2A CASP10 GCGR GLI3 PIK3CA RPS29 RSPO1 PTEN MYSM1 BAP1 SRY UBE2T BRCA1 USP8 COL7A1 RNASEH2B KIF1B MN1 RELA SMAD4 VHL SH3KBP1 BCR CD79B SRP54 SRP54 SSX2 CHRNG RPL18 NF1 WWOX RERE LZTS1 WT1 MSH3 TYROBP ASCL1 IKBKG ABCC6 FAH KIT GDNF FANCE TERT BIN1 FANCL KIF11 SDHB WDPCP SLC6A17 TP53 HNF1A KEAP1 POLE HSPA9 SMO PTCH2 PTCH1 PMS1 ELMO2 BCL2 NSD2 EXT1 SRD5A3 STAT6 MVD TERC SF3B1 MNX1 FGFR1 CYSLTR2 POU2AF1 SMARCB1 NOD2 GJB2 SDHC FLT4 KRT9 CDH1 IRF1 SEC23B MYCN MGMT RPL10 RPL5 KIF7 TCF3 KRAS MUTYH TMEM127 KRAS IGH CTSC GNAS CD28 WWOX HNF1A BUB1B MC1R WNT10A CBL WT1 BRAF ADAR GAS1 GTF2E2 SMARCB1 RPS17 PARN TMEM127 BRIP1 SHH SRC GNAI3 STAR GDNF SLC22A18 FOXH1 SNAI2 GPC4 TNFRSF13C KARS1 TBC1D24 BMPR1A TET2 CD27 CASP8 DHCR7 KDSR HNF1A SH3GL1 PNP USB1 TSC2 TRIP13 TMEM67 EDN3 PMS1 PTPN11 GNA11 CREB1 ADA RAG2 PRSS1 KCNQ1 GPR101 PRF1 MTAP FANCA MSH6 TRNQ BRCA2 KRT1 RNASEL POU6F2 ACD SCN9A APC NSD2 INTU BRAF POU6F2 BRCA2 RB1 GTF2H5 PIK3CA FANCM TARS1 BRAF CASR RET VHL GPR143 TRNP GCM2 TMEM231 CPLANE1 RPS15A SOX9 GFI1B EPCAM MEN1 TERT KRAS SDHAF2 NF1 TRIP13 GATA2 SLC26A4 APC MPLKIP SAMD9L IL6 GNAS IGH AKT1 FANCD2 ESR1 SDHA APC MYF6 RASGRP1 SMAD4 MLLT10 LIG4 CPLANE1 BRCA2 MC1R MRE11 DLST SUFU LMO1 SDHB ABCA5 RMRP SDHC NUP214 AKT1 SMARCD2 DLC1 C1S TRNW THPO CHEK2 KIT SLC37A4 BCHE KCNJ11 ARID1B APC2 SAMD9 TMC6 SLX4 TNFRSF13B FGFR1 TRNH RAD21 KCNN3 DKC1 VANGL1 AXIN2 TCOF1 RPS19 SLC26A2 GPR35 CR2 TFAP2A KRAS FGFR3 PRKCD JAK2 EGFR AIP CTNNB1 KCNJ10 FANCI LYST TET2 SLC25A11 TP53 TCTN3 MUTYH ANTXR2 SEMA3C MMP1 AKT1 PDX1 JAK2 TCIRG1 PTCH1 MUC5B EXT1 DNMT3A BMPR1A SERPINA1 FAN1 CDC73 PTCH2 PIK3CA H19 FERMT1 GPC3 RET RET APC PALLD LPP BRD4 GNAS BMPR1B MAPRE2 DICER1 CTC1 TAL1 DICER1 STK11 HRAS GATA1 BCL10 KCNE3 XRCC4 HNF4A BDNF KLF11 SF3B1 MLH3 GNAQ TRPV3 IGLL1 PAX7 CRKL GDNF GATA2 ARL6IP6 ENG PTCH1 NEK9 TSC1 RNF139 ERCC3 PDGFRA IL2RG CTHRC1 WT1 BAP1 ATP7A SRP54 ABCC8 ESCO2 GPC4 OFD1 TNFSF15 APPL1 RNF6 CTSA TNFRSF1B TP53 PHOX2B DCLRE1C DDB2 BCL10 BCR KRT14 ALX3 EVC2 CD70 SMARCB1 AHCY SDHAF2 RAD51D SPINK1 SDHD ATM GABRD WT1 FASLG CTBP1 NOTCH1 NF2 DPM1 ERCC6 STS PHOX2B BUB1 FLT4 L2HGDH LAMC2 NTHL1 STAG3 ENG SDHD CTNNB1 DAXX NRAS MST1 MSTO1 SLC26A4 RAF1 STS FGFR3 EXOC6B VAMP7 NELFA HRAS ANTXR2 LEMD3 TNFSF12 GPC4 MLH1 SMAD4 RAD50 SUFU TRIP13 REST GNAS CBL RHBDF2 ASXL1 SMAD4 TCF4 ERCC6 WT1 BRAF APC TRIM28 TERT DNAJC21 RPL15 PAX3 SETBP1 CDH1 GNAS SMARCB1 AKT1 ASCL1 KRAS NAB2 ERCC5 RECQL4 KRAS DNMT3A EDN3 POLD1 FAM149B1 CDKN1C KRAS TP53 SMARCE1 PTEN PALB2 SEMA4A TEK NBN NHP2 GPC3 ETV6 FGF8 COL11A2 SMAD4 RNASEH2A NRAS MC1R TDGF1 FGFRL1 FGFR1 CTNNB1 IGH DNAJC21 CCND1 RET DIS3L2 DHCR24 CARD14 BRCA2 SQSTM1 NFKB2 TRNQ NDP SFTPA2 PAX4 COL7A1 TP53 RSPRY1 IFNG HMMR PALB2 FAT4 MBTPS2 MDM2 KRAS GNAS C2CD3 POT1 ABL1 WNT5A FANCE ABL1 ICOS SDHD RAD21 NSD1 SOS1 IL12A LIG4 PIK3CA TBXT RAD51 EWSR1 FZD2 FLNA BRCA2 NRAS TWIST1 TET2 TSC1 INHBA CAT CTNNB1 PIGL IRF1 PTCH2 TRNH MLH1 GFI1 CDC73 RET FANCD2 EVC NF2 TNPO3 SOX2 DYNC2H1 HRAS NEK1 CCND1 KRT10 AKT1 KIT PALB2 VHL CYLD IL1B GJC2 MLH1 SDHC FGFR2 CYP2A6 FOXE1 ARMC5 ERCC2 SLC25A11 LAMA3 FLCN BRCA1 BIRC3 MVK TOP2A PDGFB TCF4 RFWD3 ATP6V1B2 GDNF GATA4 CTNNB1 CDKN1B C2CD3 BRCA2 FUZ STK11 AKT1 FGFR2 SHOX TGFBR1 BTK LEMD3 FIBP SF3B1 SUFU PRLR NR5A1 FN1 ERBB2 CD19 RNR1 PTPN11 KIT RAD51 WAS PTEN TGFBR2 RPS24 CYLD RNF113A MYO1H ALX3 JAK2 BLM CTNNB1 CDKN2A PARN SH2B3 POLD1 CHEK2 COX1 KRT1 EXT1 BRAF PRCC MSH2 GATA2 REST NRAS RB1 TINF2 BMPR1A NR4A3 AGGF1 SIX3 RAG1 ND4 COL2A1 CDKN2A SDHD TREX1 WNT10A SEC23B XPA MET TP53 CDKN1B RPS27 PCNA HMBS RPS26 KIT FGFR2 TRIM37 HPGD ERCC5 PAX6 SLX4 PICALM PSAP FCN3 BMPR1A USF3 XPC DNAJC21 KRT16 BUB3 H19-ICR GPC6 STAC3 RPS28 FANCA RNF43 AP2S1 PDGFB DYNC2LI1 CYP11B1 ABCA5 PTCH1 TERF2IP KRAS DYNC2LI1 CDH1 CDC73 TERC SPRED1 PDGFB TRNF MTMR14 MAD2L2 FOXI1 ERCC2 GJB4 KAT6B MSH6 FASLG KRAS SEC23A RUNX1 CD19 WASHC5 KIT HLA-DRB1 WRAP53 FLT3 CEP57 KDR TREX1 TMEM216 PDGFRA ERCC3 KIT NOTCH3 WIPF1 TERC CTLA4 NQO2 CDKN2A RSPO1 STK4 PTPN11 GJB2 KRAS MET SPINK1 PDGFRB RHOH BUB1 ND6 CDKN2C TFE3 EP300 CHIC2 HNF1B NUMA1 BRCA1 SRY FLCN MLH3 SCN10A GNPTAB KRAS NODAL TGFBR2 PPM1D DOCK8 EPAS1 PHOX2B OCA2 KCNQ1OT1 CYP2D6 ITK DICER1 PRKCD ASPSCR1 SUFU IDH1 RUNX1 ATRX FOXC2 MFN2 SAMD9L SCN4A KIF1B DHH POLE VHL POLR1D KCNAB2 BRAF SLC12A3 CARMIL2 ENPP1 NRAS LRRC8A KIT SH2B3 MST1R CEBPA NRAS MRAP TP53 ND5 FH LAMB3 CALR SLC37A4 PERP KLHDC8B FH SFTPC TGIF1 CHEK2 SLC17A9 SLC22A18 TERT CDH23 MDH2 KRT17 PTEN FGFR3 RB1 YY1 ELANE EP300 SPRTN GJB3 XPA IDH2 MAGT1 ATR GNA14 OFD1 IL7R GREM1 ESCO2 HRAS PRKAR1A MMP1 TP53 KRT17 COL14A1 RHBDF2 MPL OFD1 RYR1 IFIH1 SCN11A IDH1 JAK2 WT1 TP53 ARSA LIG4 CCBE1 FANCG KCNH1 ELANE COL18A1 HACE1 NUP214 MYC CD79A AR CDH1 BRIP1 WT1 BCR BUB1B ERCC3 KRIT1 NBN IGF2 FANCF PDGFRA BLNK PCGF2 MSH6 MEN1 FAS BRIP1 PTH1R SIX1 RNF6 BRAF DHCR7 BMPER BUB1B TP53 RET CTLA4 HABP2 ARHGAP26 DLST GCK ERCC2 RAD54L POLE HSPG2 GNA11 ADA SMAD4 BCL10 RB1 STAT1 TAF1 RPS14 BCR IL12RB1 IRF5 TMC8 TNFRSF13B CYP26C1 CALR POT1 MINPP1 POLR1C CD28 ATP7A HNF1B ERCC2 ACVR1 RPL31 VANGL1 TP63 ERCC4 SLC45A2 OFD1 LMX1B PIK3CA ASCC1 TET2 IGF2R BARD1 TUBB IGF2 BTK MSTO1 CIB1 PHB CDKN2A TNFRSF10B KIAA0753 TBX2 FOXE1 EPCAM TNFRSF13C SLC26A2 ATRX MGAT2 SKIV2L CXCR4 PIK3R1 RTEL1 TSC1 HAX1 SDHB PRKAR1A DDB2 GFI1 CDH23 XRCC3 PMVK TP53 PIK3CA GJB2 NF2 KLF6 AR ZSWIM6 SDHB CDC73 PIK3CA CCND1 GJB6 ATM SOS1 NOTCH3 DDX41 TSC2 FLT4 FGFR3 RASA1 GDF2 F5 PMS2 PTEN HBB TSC2 CASP10 ADA2 AIP WT1 LETM1 PNP COMP TRIM28 TP53 PALB2 RAD51C CCL2 CDC73 SH2D1A COX3 ZAP70 PIK3CA CYP11B2 PDGFRB PTPN11 PHOX2B FH KIT HNF4A RNASEH2C MYD88 PDE6D JAG1 TYR SEC23A FH NPM1 PHKA2 DICER1 PIK3CA HFE GNAQ DMRT3 MS4A1 MYH8 VANGL2 SHOX PUF60 GATA2 BAP1 B3GALT6 TRNS2 HRAS HDAC4 FANCG SAMHD1 GATA2 LIG4 AXIN1 TNFRSF4 OPCML PRKN FGFR2 ECM1 TGFBR2 LMNA WDPCP KCNQ1OT1 BLK GCM2 ALX1 NRAS KIT AAGAB FAH MAX RARA NEUROD1 TGFBR2 MYD88 PHF21A IDH1 MLH1 FANCB CPLX1 SMARCA4 EXTL3 AIP TERT BCL10 XIAP IGF2 SASH1 PIK3R1 PTEN NAGS TMC6 NBEAL2 NOP10 JAK2 SDHB MSH2 ECE1 BARD1 APC PMS2 CCM2 JAK2 MMEL1 RET SDHA SDHD IGHM CACNA1S FAS NR0B1 POT1 SPIB TAL2 NF2 CDON WT1 TET2 PTPRJ CD96 TRNL1 DOCK8 DCC MPL GNAQ CREBBP CDKN2A TRNK MSR1 KRT5 PRKAR1A ERBB3
HP:0001871: Abnormality of blood and blood-forming tissues
Genes 1877
TCAP CTC1 KLKB1 TET2 RPS27 MYH9 SLC25A38 COL1A1 COL5A1 TCF4 RPS24 SERPINF2 ALX4 MPL TSR2 EXT2 EFL1 ATM CAP2 SDHC BCL10 OTULIN CD8A OCRL CHD7 FOXP3 PROS1 ASXL1 PRKCD PLEKHM1 SETBP1 FCGR2C GCDH MALT1 PKLR SERPINC1 THBD SLC4A1 ERAP1 FLI1 CYB5R3 F5 GGCX DNASE1L3 SUFU FOXP1 TGFB3 PIEZO1 VWF KLF1 PGK1 VPS13B LOX CTRC EGLN1 SOS1 GINS1 EIF2AK3 MECOM FASLG GP9 F2 TNFSF12 KIT LMNB2 NDUFS3 AEBP1 GNE XRCC2 SLC29A3 EPO COX6B1 SPTB VHL SGPL1 GNB1 SRD5A3 CBFB SPARC MLH1 AEBP1 EPHB2 TGFBR3 NHP2 CLPX NFKB1 FCGR2B F13B TRNS1 PTEN PTPN11 MPL PRLR NUTM1 STAT3 TEK SERPINF2 FBN1 STAT3 SSR4 FKTN TPMT SLC2A1 PARN NRAS VPS13A GBA SSR4 LEPR BLM ACVRL1 KRT14 ANKRD11 SH2B3 DNMT3B RAD54B IFNG RPS19 RPL35A HLA-DPA1 GUCY1A1 SDHB CXCR4 GPI ECHS1 AKR1D1 ACD MPL RUNX1 MAN2B1 ACSL4 HBG1 MVK PROS1 STAT1 FN1 JAK2 AMACR PFKM GP1BB KCNE5 GATA1 BRCA1 ZBTB24 RFWD3 PIK3R1 HBA1 NDUFS2 TGFB3 RPS28 COL4A2 COL7A1 JAK2 MPI SMPD1 RPS17 ABCA1 ICOS NUMA1 DKC1 LIG4 NBAS ITGB3 ND5 SDHD PEX3 SMAD4 BCL6 MYC STAT5B GBA LMAN1 PMM2 JAK2 NTHL1 FLNA STIM1 HOXA11 VHL MRPS7 EPHB4 MMUT TGFB1 BRCA2 F13A1 SCN5A SLC17A5 ORAI1 GFI1B NABP1 PUS1 SLC19A2 NSUN2 PHKG2 CYP2C9 NBN KRAS TXNRD2 STAT3 PEX1 SRC PRF1 EOGT PHGDH HLCS FERMT3 LAMB3 ATM COL7A1 MYH9 THPO NDUFA10 TERT TF MECOM PIGT NPM1 NDUFS1 ITGA2 KCNJ11 KIT SLC4A4 LPIN2 CASR TPP2 COL4A5 CD3G NDUFAF3 ABCG8 CASP10 CYB5R3 RBM10 SLC46A1 UBE2T TACO1 COL7A1 RNASEH2B NDUFA9 GSS SMAD4 F10 PSTPIP1 BCR CD79B RPL18 RPS26 IKBKG FAH COX20 GATA6 FANCE RIN2 ARF1 HBA1 KIF11 RFX5 NPHP1 CHD7 OCLN TPI1 MPIG6B GNAS CLPB PSAP FOXRED1 CARD9 PHGDH SLC35A1 CARD11 RRAS NOD2 APOB SDHC HTRA2 SLC19A2 BAG3 RIN2 LYST RPL5 GP9 TCF3 FECH CACNA1S HLA-B CIITA HAMP CDAN1 PROC CBL ADAR GTF2E2 PLG RPS17 PARN COL3A1 RFXANK BMPR1A STX11 TET2 GALC ADA2 HNF1A SH3GL1 TTI2 IL23R PMS1 FGG RFXAP COL4A1 FLNA PRF1 COG1 MTAP FANCA MSH6 AMN NDUFA13 COL5A2 SERPINC1 PRLR CD151 MYH7 TONSL GTF2H5 PIK3CA FANCM KCNE1 GGCX VHL ABCA1 CAPN3 PIEZO1 ARHGAP31 RBM8A PSEN1 CTLA4 RPS15A HELLS GFI1B EPCAM NF1 HPRT1 TRIP13 MPLKIP RAG1 MYLK RASGRP1 MLLT10 MTHFR PDHA1 F5 TNFRSF11A IL10RA PCNT HLA-B CTRC SMARCD2 PLOD3 SPTA1 PTPN22 SLC17A5 KCNJ11 F12 TFR2 TREX1 BTNL2 SLX4 TNFRSF13B OPA1 NEXN CYBA GATA1 ADAR DKC1 ARPC1B FGB VPS45 ALG12 SCO1 CR2 VWF SMAD3 GATA1 RPS15A APOE FANCI LYST TET2 STT3B ATOH7 ABCC9 HBG2 MMP1 RPSA HBB PDX1 JAK2 COL17A1 LYST HBB RNASEH2A PIK3CA C2 CIITA SFXN4 RET PEX16 HBB-LCR CYP7B1 BRD4 GNAS GSS A4GALT F13A1 TTC7A FLNA FARSB GATA1 KRT14 HNF4A MLH3 CLCN7 CLPB GDNF TAF1A GBA CBLIF ALG2 GATA2 ARL6IP6 G6PD TERT IL2RG KLF1 RNASEH2C SRP54 ABCC8 SLC20A2 CYP2A6 IGHM FOXN1 SLC2A1 TAZ TMPO NOTCH3 CYP4V2 SCARB2 CD70 SPINK1 MUC1 FAM111A RAB27A NOTCH1 DPM1 RAG2 LAMC2 PEX12 NT5C3A RNU4ATAC IRAK1 DAXX MST1 RAF1 NHEJ1 TNFSF12 GNAS TRMU KCNQ1 ALAS2 PDE4D CBL TCF4 NHP2 SLC39A13 CCM2 APC DLL4 TERT DNAJC21 UNC93B1 CTSK HBB RYR1 AKT1 FLNA MVK G6PC3 ANK1 TEK NHP2 ETV6 CFH RIT1 UNC119 HBB RAG1 STEAP3 PPCS CDCA7 IGH CCND1 DCLRE1C VPS33B PGK1 F8 LMNA TRNQ PAX4 COL7A1 MDM2 COX8A PTF1A WAS ABL1 KDM6A FANCE ICOS SDHD LIG4 KIF23 HLA-DRB1 FANCF TET2 TSC1 SLC4A1 NDUFS2 STT3B ADA2 TGFBR2 GFI1 CFTR FOXN1 FANCD2 FKBP14 ATP11C VHL GLA CDC42 TERT ARMC5 SLC25A11 MAP1B BIRC3 STXBP1 ASAH1 RFWD3 NAXD GLA TNFRSF13B FANCL YARS2 F7 THRA GBA AKT1 RPL27 PLOD1 FIBP FLT1 COMT MVK GBA KIT MTFMT CFB WAS NFKB2 AK2 TMTC3 TGFBR2 UMPS CDC42 SLC4A1 TRNS1 FADD PARN DDOST CHEK2 COX1 LIPA ANGPTL6 GCNT2 GATA2 ACTN4 ABCB7 ZBTB16 FUCA1 BMPR1A ND4 CAPN5 KCNN4 PTEN TREX1 SLC2A1 GLB1 RPS27 RPS26 PTPN22 HYOU1 HPGD C1QA TGFB1 CBS SLX4 RAG2 PICALM TERC MMUT KCNN4 HMOX1 ENG BUB3 RYR1 FANCA DYNC2LI1 ELANE PET100 TERC CCR1 MAD2L2 MPDU1 ERCC2 KRAS FOXP3 CD3E CD19 KIT HLA-DRB1 GCLC COX14 CSRP3 ACAD9 FLT3 CRIPT CEP57 TREX1 CD3D WIPF1 SLC25A13 PEX12 TERC BCL11B TRNN NDUFV1 BLNK PTPN11 IL7R PDGFRB RHOH F5 CTLA4 RARA GPC1 F13B HLA-B NUMA1 KRAS TNFAIP3 JAK3 EPAS1 NDP GALT ITK PRKCD ABCD4 IDH1 RUNX1 FOXE3 ATRX CLCN7 GATA1 NPM1 COL1A2 PEX26 TAZ ANKRD26 LAMTOR2 ELN EPB41 TCN2 SLC12A3 PRDX1 WFS1 NRAS CISD2 GLRX5 LRRC8A COA8 SH2B3 OSTM1 CEBPA KLF1 FIP1L1 CPOX TRNT1 CALR SPTB TBL1XR1 TERT IL2RG MDH2 MMADHC ICOS FBXL4 MARS1 TNNC1 RASA2 GREM1 VCL ACP2 MMP1 NDUFAF2 ATP7B TP53 HBB TGFBR1 CLCN7 SCN11A SOS1 HIRA DPM2 TFAM CCBE1 APP ELANE NUP214 KMT2D SEC63 ADAMTS13 BUB1B NBN FANCF CARD11 CD36 PLVAP FAS PTH1R PDGFB CLCN7 ADAMTS2 WAS PCCB HLA-DPB1 ARHGAP26 DLST PGM3 POLE ADA PANK2 GDF2 RFXANK CYP26C1 UROD SIK3 SEC23B RPL31 TP63 HBG1 DNMT3B NLRC4 BMPR2 COQ2 PFKM BTK NBEAL2 EPOR ITGB4 TBX2 NDUFS4 RASA1 MAT2A CASP10 ATRX PRKCSH F9 SOS2 PIK3R1 RRAS2 COL3A1 CHST14 HAX1 GNAQ PRDM5 SDHB PRKAR1A ITGA2B SLC7A7 CYTB KCNQ1 CDH23 SAA1 ATP6V1A RASGRP2 LBR KCNJ11 CD79A ATRX ANK1 ATM RNASEH2B PRSS1 ETHE1 TNXB SPTA1 RTEL1 IRX5 GDF2 PMS2 GBA HBB HBB TSC2 GP1BB ATR ADA2 CASR SGCG PNP ETHE1 NPHP4 TP53 PSMB8 RAD51C LARS2 CYP11B2 TCN2 KIT AGA SMARCAL1 MYD88 APOE TRAC NPM1 IKZF1 PHKA2 GNAQ GLB1 HPS3 NDUFA2 KRT5 GATA2 TMPRSS6 PLEKHM1 BAP1 TP53 TNXB PGM1 GATA2 LMNA IKBKG ALDOB TGFBR1 CTLA4 IL12B MAX PRDM16 MYD88 ZNF341 ABCC6 IDH1 NDUFS8 TERT GATA1 BCL10 SPP1 CYBB CUBN PTEN NBEAL2 CCND1 NOP10 GP1BA SDHB MSH2 PLEC ABCB6 GLB1 UNC13D TRNW CCM2 JAK2 MMAB RET SDHA IGHM FZD4 ANK1 CFH LBR TAL2 NF2 HOXA11 ANO6 MYH6 NIPBL HBA2 CISD2 TET2 DOCK8 MPL CYCS CREBBP ATP6V1E1 IFIH1 GP1BA THBD SPATA5 SRD5A3 NDUFS7 EPG5 TBXAS1 ATP7A IL2RG MYORG IDH2 FLT3 TGFB2 NR1H4 MLX HLCS CD40LG ERCC6L2 GATA1 TTC37 DNM2 CFI IVD UBE2T BRAF NEU1 DOCK6 RBPJ SERPIND1 RNF43 HSD3B7 VPS33A CTRC TSR2 TRNL1 PNPO PLEC TP53 TINF2 MCFD2 ALG6 CR2 DSE CASK PDCD10 CD3D GBA ACTN1 TINF2 ZBTB20 TACO1 RPS20 RPL35A ACTN2 IL7R TCIRG1 BMPR1A CFI BMPR1A LAT ACVR1 CHST14 ADA MTRR TBX1 PEX11B B2M ND1 EPO MAP2K2 NFIX SAMHD1 INS HBB COL1A2 AIP CLCNKB COL4A1 RPS10 MTHFD1 COX2 FASTKD2 AASS BRCA1 UROS PIK3CD CORIN SBDS CD81 RHAG NCF2 CP TNFRSF1B RMRP RECQL4 B4GALT1 COG8 NPHP4 RHAG BCL11B SLC30A10 SPINK5 SMPD1 REN RPL35 CBS UBE2A LMX1B NDUFB8 FTCD FGG SPTA1 LDB3 MEFV SLC11A2 CA2 PSEN2 ALAD RAG1 RPL26 DCLRE1C F5 FGA STAT3 TAZ CYB5A SEC24C TSC1 RAF1 ELANE ACTC1 C1R APOA1 NF1 AGK ATRX ADAMTS3 TET2 UMPS SLCO2A1 RTEL1 TMEM67 FANCC HBA1 ZNF469 TNFSF11 SDHA RPS14 HAVCR2 MSH2 WRAP53 PEPD ACAT1 SPTA1 ACVRL1 PIGA RS1 COL5A2 DOCK2 KRIT1 NDUFA12 SNX10 APC GP6 GATAD1 FGB FHL2 NDUFV2 BCOR MTRR ALAS2 ERCC4 PIEZO1 SBDS VPS13A NFKB1 SDHD IFT140 GBA PTPN11 TREM2 MMACHC NPC1 FZD4 PEX5 SH2B3 MAP2K1 ERCC4 STIM1 FIG4 LAMA4 ITGB4 GLI1 PSMB4 HPS1 DNASE1 HBA2 ALDOA MTTP TET2 LRP5 CALR SRSF2 RPS7 NDUFAF6 PEX10 NPHP1 RPL15 FMO3 MMUT RAC2 F11 KIF1B RAB27A SLC2A10 RREB1 SLC2A1 SLC19A3 CST3 MPL SLC35A1 FANCC CD46 PGM3 F9 SLC4A1 SLFN14 LRP5 NFKBIL1 CYP4F22 G6PC RPS7 F11 MCM4 ABCC2 HLA-DRB1 AMMECR1 SERAC1 ABHD5 TICAM1 SARS2 SBDS TERT GP1BB EFL1 COX4I2 STING1 KRAS CA2 FARS2 ABCC6 DKC1 CYBC1 USP18 MAX WAS SP110 PALB2 UBR1 PUS1 C1R PRTN3 MSH2 RECQL4 SALL4 IL2RB MEFV RAC2 PIGL MPL ATP7B RPL27 USP8 LCAT CCND1 C3 XYLT1 TERT ENG CD59 CD109 CEL TBXA2R DPAGT1 SRP72 MPO TRNF LPIN2 CD247 VKORC1 COL3A1 DNAJC19 PTEN SMPD1 AK2 FLI1 STK11 BEST1 RPL11 CALR ITCH CRYAB PTPN22 COPA TUBB1 CFHR1 PRKAR1A CTCF RPS29 ATRX SCO2 DGKE MYSM1 USP8 SLC29A3 KIF1B CD3E ZMPSTE24 MTR PML ARFGEF2 TRNT1 VHL SRP54 SRP54 SMAD3 SLC27A4 AKR1D1 SMARCAL1 SC5D ATP7A SPTA1 SLC39A13 TYROBP ABCC6 COL3A1 TDP2 C1GALT1C1 GSN FANCL SDHB PEX14 ATRX HSPA9 ABCC8 BCL2 TERC SF3B1 TTN CYSLTR2 SMARCB1 F7 SERPINE1 USB1 SLC22A4 HBB GATA1 PSMB9 RFXAP COL4A1 ACD CP TMEM127 GYPC ABCB7 IGH CD28 FANCI FAM111A LMBRD1 HBG2 FYB1 TMEM127 RHAG ALDOB TNFRSF13C TBC1D24 CD27 UBAC2 ACAD8 RFT1 NLRP3 PNP USB1 TSC2 PTPN11 GNA11 ADA HSD3B7 RAG2 RMRP PRSS1 FDX2 VKORC1 CLCN7 NGLY1 TF NCF1 JAK2 SCN9A SEC61A1 F2 ERMARD TGFB2 STEAP3 LMBRD1 RB1 MYH11 TARS1 CLDN1 RET FGA TNFSF11 BRIP1 PNPO APP ITGB2 COL1A1 P2RY12 AMMECR1 RPS10 KRAS SDHAF2 TRAF3 PDGFRB HBB GATA2 ITGB4 SAMD9L TNNI3 GNAS MYBPC3 IGH SDHA TPM1 FANCD2 SDHA XIAP TCIRG1 NHLRC2 LIG4 PRKAR1A COL7A1 BRCA2 KCNJ1 DLL4 RMRP SDHC HBA2 NUP214 EPB42 C1S TRNW THPO RPL11 IL2RA KIT PRKAR1A BCS1L MYPN SAMD9 PACS2 TRNH KRT14 PLAT TCF3 RPS19 GPR35 HPS4 TBX1 PRKCD KCNJ5 SGCD ACTA2 SCARB2 NLRP3 APOE TCIRG1 RAG2 FLI1 DNMT3A FAN1 PKLR FAS FERMT1 CYP7B1 PROC HADH ADAM17 VPS13B PRKACG LPP BLOC1S3 TBK1 ATP6V0A2 COLGALT1 CTC1 TAL1 RNF168 LIPT1 IFNGR1 BCL10 COL1A1 XRCC4 GALT PLA2G4A KLF11 SF3B1 WDR19 GNAQ IGLL1 SURF1 TALDO1 FGG AGXT PDCD10 MPL MMADHC HK1 GP1BA ENG PRSS1 PDGFRA PDE11A CTPS1 BAP1 ATP7A TLR3 PEX13 AMMECR1 GGCX FGA XK APPL1 CPT2 PEX6 XPR1 TNFRSF1B YARS2 DCLRE1C EVC2 HABP2 COL5A1 AHCY XRCC4 MYH7 APP IL12A WT1 FASLG IKZF1 STOX1 RPS29 BUB1 PRKACA KRT5 ENG SDHD FGFR2 PSMB8 STS IL12A-AS1 WFS1 MLH1 SMAD4 TINF2 COX10 DOLK ASXL1 PEX2 LYRM7 ATP6V0A2 DHFR RPL15 HBA1 LCK RANBP2 TGFBR2 NDE1 DNMT3A RFT1 LZTR1 NEDD4L WAS STN1 PTEN SEMA4A EPB42 NBN UFD1 MYSM1 APP SMAD4 RNASEH2A LRBA C4A ARHGEF1 DNAJC21 ITGA2B HMGCL RAG1 HELLPAR TNNT2 NFKB2 FBN1 NOP10 JMJD1C RAF1 FGB CD46 HMCN1 PALB2 RAG2 FAT4 DGUOK FCGR2A ITGA2B HPRT1 POT1 TBCE POMP ABL1 FUT8 DES FAS NCF1 PROC RAD51 EWSR1 MMAA INHBA CAT FGA PIGL PEX19 SEMA3E FGB EPB41 IFNG LBR EVC LAMTOR2 VWF LRP5 CCND1 MET RPL5 ITGB3 CST3 CYB5A HBA2 LEP LAMA3 KRT5 IRF2BP2 TCF4 TCIRG1 STAT4 CTNNB1 KRT1 CORO1A STK11 SPATA5 NRAS FGG SF3B1 ACP5 CD19 RPL26 CSF3R DLD AK1 DTNBP1 ADAMTS2 NEBL NLRP12 RPS24 RNF113A HMGCL JAK2 BLM LBR HBB TNFRSF1A EPAS1 KIF15 PCCA SH2B3 ABCD3 BRAF TINF2 AGGF1 RAG1 UROS F8 IREB2 SALL4 CPA1 KIT ALPL BMPR1A DNAJC21 CYBB FANCB LAMA3 RPS28 PLN PDGFB CYP11B1 CACNA1D MSH6 RUNX1 DOLK CD247 HBG2 PADI4 WRAP53 PANK2 ATP6AP1 SMAD3 ERCC3 HRG CTLA4 ETV6 CFTR STK4 F2 ND6 PET100 EP300 CHIC2 NLRC4 XYLT2 HBG1 COX15 DSG2 SCN10A DOCK8 DNAJC19 PRF1 SC5D PIGM PMM2 SPINK1 LIPA HAVCR2 IL10 KLRC4 NOS3 SAMD9L ALAS2 KIF1B SLC30A10 F9 MTOR HBB ENPP1 POLG LAMC2 NLRP3 HPS5 FH LAMB3 SLC37A4 MCFD2 HBD KLHDC8B CEBPE HBA1 JAK2 SHPK ISCU DNM1L ELANE IDH2 MAGT1 GNA14 CAD IL7R ACAD9 ESCO2 HPS6 LRP5 NSMCE2 COL14A1 RHBDF2 MPL MMACHC IFIH1 JAK2 SLC40A1 NCF2 RPL18 LIG4 SURF1 FANCG ITGB3 SLC35C1 MYC CD79A SBDS BRIP1 BCR KRIT1 PDGFRA BLNK ANKRD1 ALG8 CD4 MSH6 APP TALDO1 BUB1B CTLA4 CD81 GCK RAD54L NOTCH1 STIM1 DBH NCF4 SMAD4 STAT1 TTC37 TMEM165 RPS14 BCR CD244 PRF1 MSN C4A TNFRSF13B CALR PTPN22 SPINK1 CD28 ATP7A CIITA F13A1 ABHD5 LARS1 TET2 GFI1 CFHR3 PROS1 MFAP5 PKLR BMS1 SLC25A15 TNFRSF13C SLC4A1 F10 MGAT2 SKIV2L CXCR4 CLN3 RTEL1 SLC46A1 CD55 TLR4 GFI1 TINF2 NPC2 RBM8A PLEC NDUFAF5 COG4 SDHB AP3D1 ELMO2 IL10 ITGB3 DDX41 SAR1B RAG1 RBM20 LMAN1 COA8 TFRC CASP10 EXTL3 STAT4 PLEC ARVCF SH2D1A ERF COX3 ZAP70 C15ORF41 RNU4ATAC RNASEH2C TYMP COL5A1 GPX1 TREX1 NDUFA4 FH GCLC COG6 COG4 SLC7A7 CYBA NLRP1 CBL RFX5 MS4A1 CFHR1 JAGN1 PLAU PUF60 COL1A2 AIRE BPGM TRNS2 BLOC1S6 FANCG SAMHD1 LIG4 TNFRSF4 CFHR3 NLRP3 IRAK4 PRKG1 PRSS2 DIAPH1 SLC4A1 HBA2 BLK SNX10 KIT RRM2B AAGAB ITGA2B RARA CD40 NEUROD1 PHF21A MLH1 FANCB FKBP14 EXTL3 GP1BB XIAP CTNNB1 SPTB PIK3R1 NAGS DMD TTC7A JAK2 APC PMS2 PRSS2 PLEC PLOD1 GP1BA MRAS FAS STXBP2 HBB NBN PTPRC KRT14 VPS33A GP1BA MAD2L2 FECH AP3B1 CDKN2A TBXAS1 ERBB3 A2ML1 WIPF1
Protein Mutations 3
C282Y H63D T315I