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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---

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 ---