An Open Label, 3-arm, Randomised Phase II Study to Compare the Safety and Efficacy of Ponatinib in Combination With Either Chemotherapy or Blinatumomab With Imatinib Plus Chemotherapy as Front-line Therapy for Patients Aged 55 Years and Over With Philadelphia Chromosome Positive (Ph+ or BCR-ABL+) Acute Lymphoblastic Leukemia (ALL)

NCT04688983

Conditions

1. Acute Lymphoblastic Leukemia, Adult

Interventions

1. Drug: Ponatinib
2. Drug: Blinatumomab
3. Drug: Imatinib

MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid

HPO:Leukemia Lymphoid leukemia

In particular, a BCR-ABL mutation known as T315I has been recognized to cause resistance to all approved 1st and 2nd generation TKI. --- T315I ---

More recently, a highly potent 3rd generation TKI called ponatinib has been developed and is the only approved TKI shown to be active against the T315I and all other resistance mutations. --- T315I ---

Imatinib has revolutionized the treatment of chronic myeloid leukemia (CML) and is the current standard of care in the treatment of patients with newly diagnosed CML. However, about 30% of patients still show drug resistance or disease progression. Currently, the most widely studied mechanism of TKI resistance in CML patients is mutations in the ABL kinase region. So far, more than 100 kinase domain mutations have been found in disease progression and imatinib resistance. It is estimated that more than 25% of CML patients will change TKI at least once in their lifetime due to drug resistance or intolerance. The 2020 edition of the "Guidelines for the Diagnosis and Treatment of Chronic Myelogenous Leukemia in China" proposes that patients with F317L/V/I/C, V299L and T315A mutations are more likely to obtain clinical efficacy by switching to the second-generation TKI nilotinib; patients with Y253H, E255K/V and F359C/V/I mutations are more likely to obtain clinical efficacy by switching to the second-generation TKI dasatinib; patients with T315I mutations are resistant to both nilotinib and dasatinib. Flumatinib has been shown to be a more potent inhibitor of BCR-ABL1 tyrosine kinase than imatinib. In vitro studies, it has shown that flumatinib inhibits wild-type and common BCR-ABL mutations(Q252H, V299L, F317L/I, M351T, H396P, etc.) more potently, and the anti-mutation spectrum of flumatinib is similar to nilotinib. Therefore, this study is designed to provide clearer guidance for patients with specific BCR-ABL kinase point mutations during CML treatment.

NCT04681820

Conditions

1. CML-CP; Mutation;TKI

Interventions

1. Drug: Flumatinib
2. Drug: Nilotinib

MeSH:Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myelo Leukemia, Myeloid, Chronic-Phase

HPO:Chronic myelogenous leukemia

The 2020 edition of the "Guidelines for the Diagnosis and Treatment of Chronic Myelogenous Leukemia in China" proposes that patients with F317L/V/I/C, V299L and T315A mutations are more likely to obtain clinical efficacy by switching to the second-generation TKI nilotinib; patients with Y253H, E255K/V and F359C/V/I mutations are more likely to obtain clinical efficacy by switching to the second-generation TKI dasatinib; patients with T315I mutations are resistant to both nilotinib and dasatinib. --- F317L --- --- V299L --- --- T315A --- --- Y253H --- --- E255K --- --- F359C --- --- T315I ---

The study is a Phase II, single-arm, open-label, single-dose clinical trial, and its primary objective is to evaluate the efficacy and safety of CNCT19 Cell Injection in the treatment of CD19 positive Relapsed or Refractory acute lymphoblastic leukemia.

NCT04684147

Conditions

1. Relapsed or Refractory Acute Lymphoblastic Leukemia

Interventions

1. Biological: single dose of CNCT19

MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid

HPO:Leukemia Lymphoid leukemia

5. Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are intolerant to or have failed 2 generation of tyrosine kinase inhibitor therapy (TKI); no TKI salvage treatments if the patient has a T315I mutation. --- T315I ---

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

Conditions

1. Myeloid Leukemia, Chronic, Chronic Phase

Interventions

1. Drug: Ponatinib 45 mg
2. Drug: Ponatinib 30 mg
3. 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 ---

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

Conditions

1. B Acute Lymphoblastic Leukemia
2. B Lymphoblastic Lymphoma
3. Recurrent Adult Acute Lymphoblastic Leukemia
4. Recurrent B Lymphoblastic Lymphoma
5. Recurrent T Lymphoblastic Leukemia/Lymphoma
6. Refractory B Lymphoblastic Lymphoma
7. Refractory T Lymphoblastic Lymphoma
8. T Acute Lymphoblastic Leukemia
9. T Lymphoblastic Lymphoma

Interventions

1. Drug: Asparaginase
2. Drug: Cyclophosphamide
3. Drug: Doxorubicin Hydrochloride
4. Drug: Etoposide
5. Drug: Imatinib Mesylate
6. Other: Laboratory Biomarker Analysis
7. Drug: Prednisone
8. Biological: Rituximab
9. 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 ---

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

Conditions

1. Blasts Under 15 Percent of Bone Marrow Nucleated Cells
2. Blasts Under 15 Percent of Peripheral Blood White Cells
3. Blasts Under 30 Percent of Bone Marrow Nucleated Cells
4. Blasts Under 30 Percent of Peripheral Blood White Cells
5. Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive

Interventions

1. Drug: Bosutinib
2. 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 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 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 ---

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

Conditions

1. Chronic Myeloid Leukemia

Interventions

1. 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 ---

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

NCT01254188

Conditions

1. Chronic Myeloid Leukemia

Interventions

1. 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 ---

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

NCT01275196

Conditions

1. Chronic Myeloid Leukemia

Interventions

1. Drug: Nilotinib
2. Drug: Imatinib

MeSH:Leukemia Leukemia, Myeloid 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 ---

In this study, the efficacy and safety of two nilotinib doses, 300 mg twice daily and 400 mg twice daily, were 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 was included in this study design to allow patients who did not show sufficient response to their assigned treatments the opportunity to receive imatinib 400 mg BID (option available until protocol amendment 7) or nilotinib 400 mg BID, using an abbreviated safety and efficacy assessment schedule.

NCT00471497

Conditions

1. Myelogenous Leukemia, Chronic

Interventions

1. Drug: nilotinib
2. 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 Key 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 ---

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

Conditions

1. Chronic Myelogenous Leukemia, Ph1-Positive
2. Acute Myeloid Leukemia
3. Myelodysplastic Syndrome

Interventions

1. Drug: BP1001 (varying dose)
2. Drug: BP1001 (fixed dose)
3. 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 ---

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

Conditions

1. Chronic Myelogenous Leukemia

Interventions

1. 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 ---

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

Conditions

1. Accelerated Phase Chronic Myelogenous Leukemia (CML)
2. Blast Phase Chronic Myelogenous Leukemia (CML)
3. Chronic Phase Phase Chronic Myelogenous Leukemia (CML)
4. Philadelphia Chromosome Positive (Ph+) Phase Chronic Myelogenous Leukemia (CML)

Interventions

1. Drug: Axitinib
2. Drug: Bosutinib
3. 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 ---

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

Conditions

1. Chronic Myeloid Leukemia
2. Leukemia, Lymphoblastic, Acute, Philadelphia-Positive

Interventions

1. 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 ---

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

Conditions

1. Chronic Myeloid Leukemia

Interventions

1. 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 ---

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

Conditions

1. Chronic Myeloid Leukemia

Interventions

1. 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 ---

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

Conditions

1. Chronic Myelogenous Leukaemia

Interventions

1. Drug: Bosulif

MeSH:Leukemia, Myeloid Leukemia, Myeloge 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 ---

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

Conditions

1. Chronic Myelogenous Leukemia

Interventions

1. 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 ---

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

Conditions

1. Chronic Myeloid Leukemia

Interventions

1. 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 ---

"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

Conditions

1. Chronic Myelogenous Leukemia in Chronic Phase

Interventions

1. 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 ---

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

Conditions

1. Chronic Myeloid Leukemia

Interventions

1. 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 ---

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

Conditions

1. Chronic Myelogenous Leukemia

Interventions

1. Drug: nilotinib
2. 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 ---

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

Conditions

1. Leukemia

Interventions

1. Drug: nilotinib
2. Genetic: cytogenetic analysis
3. Genetic: mutation analysis
4. Genetic: polymerase chain reaction
5. 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 ---

This phase III trial compares the effect of usual treatment of chemotherapy and steroids and a tyrosine kinase inhibitor (TKI) to the same treatment plus blinatumomab. Blinatumomab is a Bi-specific T-Cell Engager ('BiTE') that may interfere with the ability of cancer cells to grow and spread. The information gained from this study may help researchers determine if combination therapy with steroids, TKIs, and blinatumomab work better than the standard of care.

NCT04530565

Conditions

1. B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1

Interventions

1. Biological: Blinatumomab
2. Drug: Cyclophosphamide
3. Drug: Cytarabine
4. Drug: Dasatinib
5. Drug: Dexamethasone
6. Drug: Doxorubicin Hydrochloride
7. Drug: Mesna
8. Drug: Methotrexate
9. Drug: Ponatinib Hydrochloride
10. Drug: Prednisone
11. Drug: Vincristine Sulfate

MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid

HPO:Leukemia Lymphoid leukemia

To be eligible for this trial, patients must be class 2B or better - Investigators must confirm which TKI patient is to receive - NOTE: Patients with known T315I mutation status should receive ponatinib treatment - NOTE: In situations due to insurance coverage issues and the pre-selected TKI is not immediately available, patients can receive dasatinib or imatinib during Step 1. --- T315I ---

- NOTE: Patients with known T315I mutation status should receive ponatinib treatment - For patients under age 70, intended chemotherapy regimen must have been determined prior to randomization - STEP 3: REGISTRATION (RE-INDUCTION) - ELIGIBILITY CRITERIA - INCLUSION - Institution has received centralized MRD results confirming positive status - Patients who presented with acute organ dysfunction must have their total bilirubin and AST (SGOT)/ALT (SGPT) reduce to < 2 X institutional ULN - Patients who presented with acute organ dysfunction must have an estimated creatinine clearance > 45 mg/min (based on Cockcroft-Gault equation) - Investigators must confirm which TKI patient is to receive - NOTE: Patients with known T315I mutation status should receive ponatinib treatment - For patients under age 70 and previously assigned to Arm C, intended chemotherapy regimen must have been determined Exclusion Criteria: - PREREGISTRATION (STEP 0) ELIGIBILITY CRITERIA - EXCLUSION - Patient must not have received chemotherapy for B-ALL. --- T315I ---

- NOTE: Patients with known T315I mutation status should receive ponatinib treatment - For patients under age 70, intended chemotherapy regimen must have been determined prior to randomization - STEP 3: REGISTRATION (RE-INDUCTION) - ELIGIBILITY CRITERIA - INCLUSION - Institution has received centralized MRD results confirming positive status - Patients who presented with acute organ dysfunction must have their total bilirubin and AST (SGOT)/ALT (SGPT) reduce to < 2 X institutional ULN - Patients who presented with acute organ dysfunction must have an estimated creatinine clearance > 45 mg/min (based on Cockcroft-Gault equation) - Investigators must confirm which TKI patient is to receive - NOTE: Patients with known T315I mutation status should receive ponatinib treatment - For patients under age 70 and previously assigned to Arm C, intended chemotherapy regimen must have been determined Exclusion Criteria: - PREREGISTRATION (STEP 0) ELIGIBILITY CRITERIA - EXCLUSION - Patient must not have received chemotherapy for B-ALL. --- T315I --- --- T315I ---

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

Conditions

1. Leukemia

Interventions

1. Drug: Dasatinib
2. 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 ---

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

Conditions

1. Leukemia

Interventions

1. Drug: Dasatinib
2. 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 ---

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

Conditions

1. Chronic Myeloid Leukemia

Interventions

1. 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 ---

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

Conditions

1. Acute Myeloid Lukemia

Interventions

1. 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 ---

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

Conditions

1. Chronic Myeloid Leukemia

Interventions

1. 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 ---

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

Conditions

1. Chronic Myeloid Leukemia

Interventions

1. 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 ---

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

Conditions

1. B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); BCR-ABL1
2. Recurrent Adult Acute Lymphoblastic Leukemia
3. Recurrent Childhood Acute Lymphoblastic Leukemia
4. Refractory Adult Acute Lymphoblastic Leukemia
5. Refractory Childhood Acute Lymphoblastic Leukemia

Interventions

1. Drug: Dasatinib
2. Other: Laboratory Biomarker Analysis
3. Biological: Nivolumab
4. 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 ---

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

Conditions

1. Leukemia

Interventions

1. 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 ---

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

NCT01342679

Conditions

1. Chronic Myeloid Leukemia

Interventions

1. 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 ---

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

Conditions

1. Chronic Myeloid Leukemia
2. Ph+ Acute Lymphoblastic Leukemia

Interventions

1. 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 ---

The purpose of the study is to determine the recommended phase 2 dose (RP2D) of ponatinib (tablet and age-appropriate formulation [AAF]) in combination with chemotherapy in Phase 1 and the efficacy of ponatinib in combination with chemotherapy as measured by the rate of complete remission (CR) at the end of the reinduction block at the RP2D.

NCT04501614

Conditions

1. Pediatric Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia (Ph+ALL)
2. Ph+ Mixed Phenotype Acute Leukemia (MPAL)

Interventions

1. Drug: Ponatinib
2. Drug: Ponatinib AAF
3. Drug: Chemotherapy Agents

MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Philadelphia Chromosome

HPO:Leukemia Lymphoid leukemia

A Pivotal Phase 1/2, Single-Arm, Open-label Study to Evaluate the Safety and Efficacy of Ponatinib With Chemotherapy in Pediatric Patients With Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Who Have Relapsed or Are Resistant or Intolerant to a Prior Tyrosine Kinase Inhibitor-Containing Therapy, or Who Have the T315I Mutation. --- T315I ---

Ponatinib With Chemotherapy in Pediatric Participants With Relapsed, Resistant, or Intolerant Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) or Have the T315I Mutation The purpose of the study is to determine the recommended phase 2 dose (RP2D) of ponatinib (tablet and age-appropriate formulation [AAF]) in combination with chemotherapy in Phase 1 and the efficacy of ponatinib in combination with chemotherapy as measured by the rate of complete remission (CR) at the end of the reinduction block at the RP2D. --- T315I ---

Inclusion Criteria: 1. Have a diagnosis of acute lymphoblastic leukemia (ALL) or mixed phenotype acute leukemia (MPAL) with definite evidence of breakpoint cluster region- Abelson 1 (BCR-ABL1) fusion (Ph) or Ph-like ALL (USA-only) with targetable kinase-activating lesions and either (i) or (ii) as follows: (i) For non-US sites: participants who have relapsed or are resistant or intolerant to at least one prior therapy that contained a BCR-ABL-targeted tyrosine kinase inhibitor (TKI); or for US sites: participants who have relapsed or are resistant or intolerant to at least one prior therapy that contained a second-generation BCR-ABL1-targeted TKI (ie, dasatinib, nilotinib, and bosutinib); or (ii) have a T315I mutation. --- T315I ---

2. Participants with BCR-ABL1 T315I mutation, irrespective of relapse, resistance/intolerance, or transplant status and irrespective of any prior TKI use. 3. Participants with Ph-like ALL (US only) with TKI-targetable lesions involving any of the following kinase genes: ABL1, ABL2, cerebrospinal fluid (CSF1R), and platelet-derived growth factor receptor, beta polypeptide (PDGFRB). --- T315I ---

Ponatinib is being tested to treat pediatric population who have Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who have relapsed or are resistant or intolerant to a prior tyrosine kinase inhibitor (TKI)-containing therapy, or who have the T315I mutation. --- T315I ---

This protocol will allow ponatinib with refractory Chronic Myeloid Leukemia or Ph+ Acute Lymphoblastic Leukemia

NCT04233346

Conditions

1. Chronic Myeloid Leukemia
2. Acute Lymphoblastic Leukemia

Interventions

1. Drug: Ponatinib

MeSH:Leukemia Leukemia, Myeloid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Myelogenous, Chronic, BCR-ABL Positive

HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

A Phase II Multi-center, Randomized, Open-label Study of Ponatinib in Chinese Patients With Chronic Myeloid Leukemia Who Have Failed Prior TKIs or With T315I Mutation, or Ph+ALL Who Have Failed Prior TKIs or With T315I Mutation. --- T315I ---

A Phase II Multi-center, Randomized, Open-label Study of Ponatinib in Chinese Patients With Chronic Myeloid Leukemia Who Have Failed Prior TKIs or With T315I Mutation, or Ph+ALL Who Have Failed Prior TKIs or With T315I Mutation. --- T315I --- --- T315I ---

The Study for CML Who Failed Prior TKIs or With T315I Mutation or Ph+ ALL Who Failed Prior TKIs or With T315I Mutation This protocol will allow ponatinib with refractory Chronic Myeloid Leukemia or Ph+ Acute Lymphoblastic Leukemia MCyR(Major Cytogenetic Response) of CP-CML patients. --- T315I ---

The Study for CML Who Failed Prior TKIs or With T315I Mutation or Ph+ ALL Who Failed Prior TKIs or With T315I Mutation This protocol will allow ponatinib with refractory Chronic Myeloid Leukemia or Ph+ Acute Lymphoblastic Leukemia MCyR(Major Cytogenetic Response) of CP-CML patients. --- T315I --- --- T315I ---

To confirm the efficacy of Ponatinib in Chinese patients with CML who have failed Dasatinib or Nilotinib or with T315I mutation, or Ph+ ALL who have failed prior TKIs or with T315I mutation as evidenced by cytogenetic responses. --- T315I ---

To confirm the efficacy of Ponatinib in Chinese patients with CML who have failed Dasatinib or Nilotinib or with T315I mutation, or Ph+ ALL who have failed prior TKIs or with T315I mutation as evidenced by cytogenetic responses. --- T315I --- --- T315I ---

To confirm the efficacy of Ponatinib in Chinese patients with CML who have failed Dasatinib or Nilotinib or with T315I mutation, or Ph+ ALL who have failed prior TKIs or with T315I mutation as evidenced by hematology responses. --- T315I ---

To confirm the efficacy of Ponatinib in Chinese patients with CML who have failed Dasatinib or Nilotinib or with T315I mutation, or Ph+ ALL who have failed prior TKIs or with T315I mutation as evidenced by hematology responses. --- T315I --- --- T315I ---

Inclusion Criteria: For CP-CML patients： 1. Patients with CP-CML Patients must either meet criterion 2 or 3: 2. Be previously treated with and resistant or intolerant to either Dasatinib or Nilotinib: 3. Develop the T315I mutation after any TKI therapy; 4. Must be ≥18 years old. 5. Provide written informed consent. --- T315I ---

Chronic Myeloid Leukemia Acute Lymphoblastic Leukemia Leukemia Leukemia, Myeloid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Myelogenous, Chronic, BCR-ABL Positive The purpose of this study is to determine the safety and efficacy of ponatinib in patients with chronic myeloid leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast phase (BP) or with Ph positive (Ph+) acute lymphoblastic leukemia (ALL) who either are resistant or intolerant to either dasatinib or nilotinib, or have the T315I mutation. --- T315I ---

This is a single arm, open-label, non-randomized, dose-escalation, phase I study to determine the safety and efficacy of CNCT19 in adult patients with relapsed or refractory acute lymphoblastic leukemia.

NCT04230473

Conditions

1. Relapsed or Refractory Acute Lymphob
2. Relapsed or Refractory Acute Lymphoblastic Leukemia

Interventions

1. Biological: single dose of CNCT19

MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid

HPO:Leukemia Lymphoid leukemia

5. Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are intolerant to or have failed 1 generation and/or 2 generation of tyrosine kinase inhibitor therapy (TKI); no TKI salvage treatments if the patient has a T315I mutation. --- T315I ---

In a multinational, multicenter, single-arm, open-label and Phase III Radotinib clinical study, chronic phase Ph+ chronic myeloid leukemia patients with failure or intolerance to previous TKIs therapy including Imatinib will be recruited. In this phase 3 study, 173 subjects are expected to be enrolled in a single arm with the administration of Radotinib 400mg twice daily, which includes 10% of dropout rate.

NCT03459534

Conditions

1. Chronic Myeloid Leukemia, Chronic Phase
2. CML, Chronic Phase
3. CML, Refractory
4. CML - Philadelphia Chromosome

Interventions

1. Drug: Radotinib HCl

MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase Philadelphia Chromosome

HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

- Medical history of clinically confirmed myocardial infarction - Medical history of unstable angina (within last 12 months) - Other clinically significant cardiac disease 4. Patients with T315I point mutations 5. Patients with central nervous system involvement as cytopathologically confirmed 6. Severe or uncontrolled chronic disease 7. Significant medical history of congenital or acquired bleeding disorders that are not related to leukemia 8. Patients who previously received radiotherapy to at least 25% of the bodies with high portion of bone marrow 9. Patients who received the major surgery within 4 weeks before the initiation of the IP administration or who failed to recover from the surgery that was performed before then. --- T315I ---

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

Conditions

1. Leukemia

Interventions

1. Drug: danusertib
2. Other: laboratory biomarker analysis
3. 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 ---

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

Conditions

1. B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1
2. Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
3. Blasts More Than 5 Percent of Bone Marrow Nucleated Cells
4. CD22 Positive
5. Philadelphia Chromosome Positive, BCR-ABL1 Positive Chronic Myelogenous Leukemia
6. Recurrent Chronic Myel
7. Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive
8. Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive

Interventions

1. Drug: Bosutinib
2. Biological: Inotuzumab Ozogamicin
3. 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 ---

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

Conditions

1. Philadelphia Chromsome Positive Acute Lymphoblastic Leukemia

Interventions

1. 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 ---

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

Conditions

1. Chronic Phase Chronic Myeloid Leukemia
2. Accelerated Phase Chronic Myeloid Leukemia
3. Blastic Phase Chronic Myeloid Leukemia
4. Philadelphia Positive Acute Lymphoblastic Leukemia
5. Resistant to Tyrosine Kinase Inhibitor Therapy

Interventions

1. Drug: Nilotinib
2. 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 ---

This program provides access to asciminib for patients with CML in chronic phase, with or without documented T315I mutation, without comparable or satisfactory alternative therapy to treat the disease

NCT04360005

Conditions

1. Chronic Myeloid Leukemia

Interventions

1. Drug: Asciminib

MeSH:Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive

HPO:Chronic myelogenous leukemia Myeloid leukemia

Managed Access Program (MAP) to Provide Access to Asciminib for Patients With CML in Chronic Phase, With or Without Documented T315I Mutation, Without Comparable or Satisfactory Alternative Therapy to Treat the Disease. --- T315I ---

Managed Access Program (MAP)* to Provide Access to Asciminibfor Patients With CML in Chronic Phase This program provides access to asciminib for patients with CML in chronic phase, with or without documented T315I mutation, without comparable or satisfactory alternative therapy to treat the disease Inclusion Criteria: Patients eligible for inclusion in this treatment plan have to meet all of the following criteria: Written patient informed consent must be obtained prior to start of treatment, including all necessary consents (or their legal representatives, where applicable). --- T315I ---

- Male or female patients ≥ 18 years of age - Patients with CML in chronic phase with or without T315I mutation, who were previously treated with all commercially available tyrosine kinase inhibitors (TKIs) for the specific market and are relapsed, refractory to or intolerant of TKIs as determined by the treating physician or for whom the treatment with one or more available TKIs is contraindicated based on approved label - Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 - Patient is deemed by the treating physician to have the initiative and means to be compliant with treatment and follow-up requested - Adequate end organ function, within 14 days before the first dose of asciminib treatment, as defined by: - Total bilirubin ≤ 1.5 x ULN except for patients with Gilbert's syndrome who may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN - Aspartate transaminase (AST) ≤ 3.0 x ULN - Alanine transaminase (ALT) ≤ 3.0 x ULN - Serum lipase ≤ 1.5 x ULN. --- T315I ---

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and efficacy of ponatinib in children aged 1 to < 18 years with advanced leukemias, lymphomas, and solid tumors.

NCT03934372

Conditions

1. Acute Myeloid Leukemia
2. Accelerated Phase Chronic Myeloid Leukemia
3. Blast Phase Chronic Myeloid Leukemia
4. Chronic Phase Chronic Myeloid Leukemia
5. Acute Lymphoblastic Leukemia
6. Acute Lymphocytic Leukemia
7. Leukemia
8. Lymphoma
9. Solid Tumors

Interventions

1. Drug: Ponatinib

MeSH:Leukemia Leukemia, Myeloid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Myelogenous, Chronic, BCR-ABL Positive Blast Crisis Leukemia, Myeloid, Chronic-Phase Leukemia, Myeloid, Accelerated Phase

HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

- Phase 2 (CP-CML): Participants who are resistant to or intolerant of at least 1 prior BCR-ABL-targeted TKI therapy or have the T315I kinase domain mutation. --- T315I ---

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

NCT03874858

Conditions

1. Chronic Myeloid Leukemia

Interventions

1. Drug: Nilotinib

MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive

HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

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

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

Conditions

1. Myelogenous Leukemia, Chronic

Interventions

1. Drug: flumatinib
2. 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 ---

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

Conditions

1. Philadelphia Chromosome Positive Chronic Myelogenous Leukemia

Interventions

1. 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 ---

The purpose of this study is to see if a condensed version of the chemotherapy regimen busulfan, melphalan, fludarabine (bu/mel/flu) and the drug antithymocyte globulin (ATG-also referred to as rATG or thymoglobulin) can have the same or fewer number of severe side effects in people with various blood cancers 30 days after they receive an allogeneic hematopoietic cell transplantation.

NCT04098393

Conditions

1. Hematologic Malignancies

Interventions

1. Drug: Busulfan 3.2 mg/kg/day
2. Drug: Fludarabine
3. Drug: Melphalan
4. Drug: Antithymocyte globulin (ATG)
5. Drug: Busulfan 0.8 mg/kg
6. Procedure: Allogeneic hematopoietic cell transplantation (Allo-HCT)

MeSH:Hematologic Neoplasms

HPO:Hematological neoplasm Leukemia

- CML with BCR-ABL mutation consistent with poor response to TKIs (e.g., T315I mutation) - CML in accelerated phase or blast crisis with <10% blasts after therapy, or in second chronic phase. --- T315I ---

This is a phase IIIb, multi-centre, single-arm, open-label, prospective study investigating the efficacy and safety of nilotinib as the first-line treatment for the adult patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in China. Nilotinib 300 mg BID will be provided in this study. The assessment for the primary efficacy endpoint will be performed at 18 months and the rate of patients obtaining MR4.5 will be measured at this time point. Secondary endpoints include the complete hematologic response(CHR) and the rates of major molecular reactions (MMR) by 3, 6, 9,12,18 and 24 months; event free survival (EFS); overall survival (OS).

NCT03942094

Conditions

1. Chronic Myeloid Leukemia, Chronic Phase
2. Nilotinib

Interventions

1. Drug: Nilotinib

MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive

HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Inclusion Criteria: - Male and female patients - Newly diagnosed CP-CML within 6 months prior to study entry, positive Philadelphia chromosome or positive BCR-ABL (M-bcr transcript) - Age ≥ 18 years old (no upper age limit given) - CML-CP defined by primordial cells in peripheral blood or bone marrow <20%, basophils in peripheral blood <20%, platelets ≥100 x 109/L(≥100,000/mm3), except for hepatosplenomegaly - Patient for whom treatment with Imatinib within 2 weeks is expected No other CML treatment except for hydroxyurea and/or anagrelide and/or IFN ECOG score 0 to 2 - Organ function defined by total serum bilirubin levels < 1.5 × the upper limit of the normal range (ULN), SGOT and SGPT < 2.5 UNL, creatinine < 1.5 × ULN, amylase and lipase ≤ 1.5 × ULN and alkaline phosphatase ≤ 2.5 × ULN not directly related to the CML - Laboratory values defined by potassium ≥ LLN, magnesium ≥ LLN, phosphate ≥ LLN, total calcium (correction for serum albumin) ≥ LLN - No planned allogeneic stem cell transplantation - Signed informed consent Exclusion Criteria: - Patients confirmed to have a T315I mutation - TKIs are not allowed to be treated prior to entering the study, unless the patient has an emergency pending the start of the study, and any dose of commercial imatinib may be used to the patient, but no more than 2 weeks - Treatment with IFN for more than 3 mouths - Impaired cardiac function including any of the following: 1. Complete left bundle branch block 2. Right bundle branch block plus left anterior hemiblock,bifascicular block 3. Use of a ventricular-paced pacemaker 4. Congenital long QT syndrome 5. Clinically significant ventricular or atrial tachyarrhythmias 6. Clinically significant resting bradycardia (<50 beats per minute) 7. QTcF >450 msec on screening ECG.If QTcF >450 msec and electrolytes are not within normal ranges before nilotinib dosing, electrolytes should be corrected and then the patient rescreened for QTcF criterion 8. Myocardial infarction within 12 months prior to starting nilotinib 9. Other clinical significant heart disease (e.g. --- T315I ---

uncontrolled diabetes, active or uncontrolled infections) - Congenital or acquired bleeding tendency - Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy - Received other study medications within 30 days (defined as drugs that cannot be used based on approved indications) - Patients unwilling or unable to comply with the protocol - Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention - Concomitant medications known to be strong inducers or inhibitors of the CYP450 Isoenzyme CYP3A4 (for example, erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, and midazolam) - Impaired gastrointestinal function or disease that may alter the absorption of study drug (e.g.ulcerative disease,uncontrolled nausea,vomiting and diarrhea,malabsorption syndrome,small bowel resection or gastric by-pass surgery) - History of acute pancreatitis within 12 months or chronic pancreatitis - History of acute or chronic diseases of Liver, pancreas or kidney - Concomitant medications with potential QT prolongation - Patients who are pregnant or breast feeding or women of reproductive potential not employing an effective method of birth control.Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to administration of nilotinib.Post menopausal women must be amenorrheic for at least 12 months in order to be considered of non-childbearing potential.Female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug Inclusion Criteria: - Male and female patients - Newly diagnosed CP-CML within 6 months prior to study entry, positive Philadelphia chromosome or positive BCR-ABL (M-bcr transcript) - Age ≥ 18 years old (no upper age limit given) - CML-CP defined by primordial cells in peripheral blood or bone marrow <20%, basophils in peripheral blood <20%, platelets ≥100 x 109/L(≥100,000/mm3), except for hepatosplenomegaly - Patient for whom treatment with Imatinib within 2 weeks is expected No other CML treatment except for hydroxyurea and/or anagrelide and/or IFN ECOG score 0 to 2 - Organ function defined by total serum bilirubin levels < 1.5 × the upper limit of the normal range (ULN), SGOT and SGPT < 2.5 UNL, creatinine < 1.5 × ULN, amylase and lipase ≤ 1.5 × ULN and alkaline phosphatase ≤ 2.5 × ULN not directly related to the CML - Laboratory values defined by potassium ≥ LLN, magnesium ≥ LLN, phosphate ≥ LLN, total calcium (correction for serum albumin) ≥ LLN - No planned allogeneic stem cell transplantation - Signed informed consent Exclusion Criteria: - Patients confirmed to have a T315I mutation - TKIs are not allowed to be treated prior to entering the study, unless the patient has an emergency pending the start of the study, and any dose of commercial imatinib may be used to the patient, but no more than 2 weeks - Treatment with IFN for more than 3 mouths - Impaired cardiac function including any of the following: 1. Complete left bundle branch block 2. Right bundle branch block plus left anterior hemiblock,bifascicular block 3. Use of a ventricular-paced pacemaker 4. Congenital long QT syndrome 5. Clinically significant ventricular or atrial tachyarrhythmias 6. Clinically significant resting bradycardia (<50 beats per minute) 7. QTcF >450 msec on screening ECG.If QTcF >450 msec and electrolytes are not within normal ranges before nilotinib dosing, electrolytes should be corrected and then the patient rescreened for QTcF criterion 8. Myocardial infarction within 12 months prior to starting nilotinib 9. Other clinical significant heart disease (e.g. --- T315I ---

This is a Phase 1-2, multicenter, international, single-arm, open-label study designed to identify a recommended dose of bosutinib administered orally once daily in pediatric patients with newly diagnosed chronic phase Ph+ CML (ND CML) and pediatric patients with Ph+CML who have received at least one prior TKI therapy (R/I CML), to preliminary estimate the safety and tolerability and efficacy, and to evaluate the PK of bosutinib in this patient population.

NCT04258943

Conditions

1. Philadelphia Chromosome Positive CML
2. Accelerated Phase Chronic Myelogenous Leukemia
3. Blastic Phase Chronic Myelogenous Leukemia
4. Chronic Phase Chronic Myelogenous Leukemia

Interventions

1. Drug: Bosutinib

MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase Blast Crisis Leukemia, Myeloid, Accelerated Phase Philadelphia Chromosome

HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

4. Documented prior history of T315I or V299L BCR-ABL1 mutations (Note: BCR-ABL1 mutation testing will be performed at screening for a baseline assessment, but results are not used to determine eligibility. --- T315I ---

3. Documented prior history of T315I or V299L BCR-ABL1 mutations (Note: BCR-ABL1 mutation testing will be performed at screening for a baseline assessment, but results are not used to determine eligibility. --- T315I ---

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

Conditions

1. Chronic Myeloid Leukemia

Interventions

1. 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 ---

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

Conditions

1. Previously Treated PH + CML

Interventions

1. 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 ---

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

Conditions

1. Chronic Myeloid Leukemia

Interventions

1. Drug: Nilotinib, Imatinib

MeSH:Leukemia, Myelogenous, Chronic, BCR-ABL Positive

HPO:Chronic myelogenous leukemia

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

A multi-center, open-label, randomized, phase Ib study to evaluate the pharmacokinetics (PK) of HQP1351 and to determine the recommended phase 2 dose (RP2D) of HQP1351 in subjects with CML CP and AP, who have experienced resistance or intolerance to at least two tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, dasatinib, bosutinib or ponatinib.

NCT04260022

Conditions

1. Leukemia, Myeloid, Chronic
2. Myeloid Leukemia
3. Chronic Myeloid Leukemia

Interventions

1. Drug: Ascentage Pharma HQP1351 bioavailable inhibitor

MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive

HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

Inclusion Criteria: - Patients must have CML in chronic phase (CP) or accelerated phase (AP) of any phenotype, with or without T315I mutation - Be previously treated with and developed resistance or intolerance to at least two TKIs (such as imatinib, dasatinib, nilotinib, bosutinib or ponatinib) 1. --- T315I ---

- Known allergy to any components in the study drug - Pregnant or lactating - Patients who have any conditions or illness that, according to the opinions of the investigator or the medical monitor, would comprise patient safety or interfere with the evaluation of safety and efficacy to the study drug Inclusion Criteria: - Patients must have CML in chronic phase (CP) or accelerated phase (AP) of any phenotype, with or without T315I mutation - Be previously treated with and developed resistance or intolerance to at least two TKIs (such as imatinib, dasatinib, nilotinib, bosutinib or ponatinib) 1. --- T315I ---

The randomization will be stratified to 3 groups: T315I mutated CML-CP and CML-AP, T315I un-mutated CML-CP, and T315I unmutated CML-AP to ensure that the subgroups are represented across all dose cohorts. --- T315I ---

The randomization will be stratified to 3 groups: T315I mutated CML-CP and CML-AP, T315I un-mutated CML-CP, and T315I unmutated CML-AP to ensure that the subgroups are represented across all dose cohorts. --- T315I --- --- T315I ---

The randomization will be stratified to 3 groups: T315I mutated CML-CP and CML-AP, T315I un-mutated CML-CP, and T315I unmutated CML-AP to ensure that the subgroups are represented across all dose cohorts. --- T315I --- --- T315I --- --- T315I ---

: The purpose of this study is to test whether blinatumomab in combination with TKI therapy (such as dasatinib) is an effective treatment for people with Ph+ ALL. Researchers want to improve the response to standard-of-care treatment of corticosteroids + TKI therapy by adding the study drug, blinatumomab.

NCT04329325

Conditions

1. Acute Lymphoblastic Leukemia
2. Philadelphia Chromosome-Positive

Interventions

1. Biological: Blinatumomab
2. Drug: dasatinib
3. Drug: dexamethasone
4. Drug: methotrexate

MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Philadelphia Chromosome

HPO:Leukemia Lymphoid leukemia

- Presence of known ABL kinase mutations conferring resistance to dasatinib at time of study entry, including T315I mutation. --- T315I ---

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

Conditions

1. Chronic Graft Versus Host Disease

Interventions

1. 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 ---

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

Conditions

1. Chronic Myeloid Leukemia

Interventions

1. 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 ---

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

Conditions

1. Leukemia

Interventions

1. Drug: Dasatinib
2. Drug: Imatinib

MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive

HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia

In this study, ABL was used as the control gene.. 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 ---

In this study, ABL was used as the control gene.. 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 ---

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

Conditions

1. Chronic Myelogenous Leukemia
2. Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia

Interventions

1. Drug: ABL001
2. Drug: ABL001 + Nilotinib
3. Drug: ABL001
4. Drug: ABL001+imatinib
5. 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 ---

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

Conditions

1. Myeloid Leukemia, Chronic

Interventions

1. Drug: Nilotinib 300 mg.

MeSH:Leukemia, Myelogenous, 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 ---

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

Conditions

1. Chronic Myeloid Leukemia

Interventions

1. 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 ---

Recent advances in acute myeloid leukemia (AML) have been characterized by a better understanding of disease biology. As such, FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) have been recognized as conferring a poor prognosis. The FLT3-ITD molecular mutation is observed in about one-quarter of patients diagnosed with AML. Patients presenting with this abnormality are referred for early allogeneic stem-cell transplantation (allo-SCT). However, some data suggest that FLT3-ITD remains associated with a poor prognosis even after allo-SCT because of higher risk of relapse and strategies for preventing relapse in the post-transplant setting are required (Hu et al, Expert Rev Hematol, 2014). For example, in a large cohort of patients (Brunet et al, JCO, 2012), the incidence of relapse for FLT3-ITD AML patients after allo-SCT was 30% at 2-years, significantly higher compared to FLT3-ITD negative patients (p=0.006). Ponatinib (Iclusig®) is an orally available, tyrosine kinase inhibitor with a unique binding mechanism allowing inhibition of BCR-ABL kinases, including those with the T315I point mutation. Ponatinib also has in vitro inhibitory activity against a discrete set of kinases implicated in the pathogenesis of other hematologic malignancies, including FLT3, KIT, fibroblast growth factor receptor 1 (FGFR1), and platelet derived growth factor receptor α (PDGFRα). In vitro activity of ponatinib in AML has been already demonstrated (Gozgit et al, Mol Cancer Ther, 2011; Smith et al, Blood 2013). If some trials are on-going to test ponatinib alone or in combination with chemotherapy in FLT3-ITD AML (Clinical.trials.gov), no study is dedicated to the use of ponatinib in the post-transplant setting in order to prevent relapse in these patients. The main goal of this study will be to determine the maximal tolerated dose (MDT) of ponatinib after allo-SCT in FLT3-ITD AML patients, then to investigate the efficacy of ponatinib in a larger cohort of patients

NCT03690115

Conditions

1. Leukemia, Myeloid, Acute

Interventions

1. Drug: Ponatinib 30 MG

MeSH:Leukemia, Myeloid Leukemia, Myeloid, Acute

HPO:Acute megakaryocytic leukemia Acute myeloid leukemia Myeloid leukemia

Ponatinib (Iclusig®) is an orally available, tyrosine kinase inhibitor with a unique binding mechanism allowing inhibition of BCR-ABL kinases, including those with the T315I point mutation. --- T315I ---

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

Conditions

1. Ph+ Acute Lymphoblastic Leukemia (Ph+ALL)
2. Ph- Acute Lymphoblastic Leukemia (Ph-ALL)
3. Chronic Myeloid Leukemia Accelerated Phase (CML-AP, Ph+)
4. Chronic Myeloid Leukemia Blast Crisis (CML-BC, Ph+)

Interventions

1. Drug: ETC-1907206
2. 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 ---

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

NCT04160546

Conditions

1. Chronic Myeloid Leukemia, Chronic Phase

Interventions

1. Drug: Ponatinib 15 MG
2. Drug: Acetylsalicylic acid 100 MG

MeSH:Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive

HPO:Chronic myelogenous leukemia Myeloid leukemia

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

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

Conditions

1. Chronic Phase Chronic Myeloid Leukemia

Interventions

1. 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 ---

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

Conditions

1. Leukemia, Chronic Myeloid

Interventions

1. Drug: Nilotinib

MeSH:Leukemia Leukemia, Myelogenous, Chronic, BCR-ABL Positive

HPO:Chronic myelogenous leukemia Leukemia

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

Primary 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

Conditions

1. Philadelphia Positive (Ph+) Chronic Myeloid Leukemia

Interventions

1. 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 ---