A Study of Ponatinib in Japanese Participants With Chronic Myeloid Leukemia (CML) and Ph+ Acute Lymphoblastic Leukemia (ALL)

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and efficacy of ponatinib in Japanese patients with chronic myeloid leukemia (CML) who have experienced failure of dasatinib or nilotinib or with Ph+ acute lymphoblastic leukemia (ALL) following failure of prior tyrosine kinase inhibitors (TKIs).

Detailed Description
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This multi-center, phase 1/2, open-label study will consist of two phases. The first will be a dose escalation phase employing a modified 3+3 design with two dose cohorts (30mg and 45mg). After 6 patients complete the first cycle in a cohort, safety events will be evaluated before opening the next dose cohort. Patients will continue on treatment as long as it is tolerated and disease progression has not occurred. Phase 2 will occur at the recommended dose determined in phase 1 in an additional 25 patients. Another 3 patients will be dosed at 15mg for collection of pharmacokinetic data. These patients may also escalate to the recommended dose and be assessed for efficacy and safety as phase 2 patients. Efficacy measures include molecular, cytogenetic, and hematologic response rates at various time points; time to response; duration of response; and survival follow-up. Safety measures include routine physical and laboratory evaluations, adverse event monitoring, and ECGs. Other measures include mutation testing and molecular genetic assessment. Accrual is expected to take approximately 12 months, and patients will be followed for survival for up to 60 months from the last dose of study drug; therefore, the estimated duration of the trial is 72 months.

Official Title
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A Phase 1/2 Multi-center, Open-label Study of Ponatinib in Japanese Patients With Chronic Myeloid Leukemia (CML) Who Have Failed Dasatinib or Nilotinib or Ph+ Acute Lymphoblastic Leukemia (ALL) Who Have Failed Prior Tyrosine Kinase Inhibitors (TKIs)

Conditions
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Chronic Myeloid Leukemia (CML), Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

Intervention / Treatment
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* Drug: ponatinib - Phase 1
* Drug: ponatinib - Phase 2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ ALL, as follows: All patients must have screening bone marrow (BM) cytogenetics with conventional banding performed within 42 days prior to beginning treatment. Examination of at least 20 metaphases is required in patients in CP. If less than 20 metaphases are examined, the BM aspirate must be repeated. Adequate BM aspirate with differential cell counts is required in patients with AP, BP, or Ph+ ALL. If an adequate aspirate is not obtained, the aspirate must be repeated. Be previously treated with and resistant, or intolerant, as defined in the protocol, to either dasatinib or nilotinib for CML or at least one TKI for Ph+ ALL, regardless of whether dasatinib or nilotinib or the prior TKI were used to treat newly diagnosed or resistant patients. Must be ≥ 18 years old. Provide written informed consent. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Minimum life expectancy of 3 months or more. Adequate renal function defined as serum creatinine < 1.5 × upper limit of normal (ULN) for institution. Adequate hepatic function defined as: Total bilirubin < 1.5 × ULN Alanine aminotransferase (ALT [SGPT]) and aspartate aminotransferase (AST [SGOT]) < 2.5 × ULN for institution (< 5 × ULN if liver involvement with leukemia) Prothrombin time < 1.5 × ULN Normal pancreatic status defined as: Lipase ≤ 1.5 × ULN for institution Amylase ≤ 1.5 × ULN for institution Normal QT interval corrected (Fridericia) (QTcF) interval on screening ECG evaluation, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females. For females of childbearing potential, a negative pregnancy test must be documented prior to enrolment. Female and male patients who are of childbearing potential must agree to use an effective form of contraception with their sexual partners throughout participation in this study. Ability to comply with study procedures, in the Investigator's opinion. Exclusion Criteria: Patients are not eligible for participation in the study if they meet any of the following exclusion criteria: Received TKI therapy within 7 days prior to receiving the first dose of ponatinib, or have not recovered (> grade 1 by National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 [NCI CTCAE v.4.0]) from adverse events (AEs) (except alopecia) due to agents previously administered. Received other therapies as follows: For CP and AP patients, received interferon, cytarabine, or immunotherapy within 14 days, or any other cytotoxic chemotherapy, radiotherapy, or investigational therapy within 28 days prior to receiving the first dose of ponatinib. For BP patients, received chemotherapy within 7 days prior to the first dose of ponatinib. Otherwise, 2a applies. For Ph+ ALL patients, received corticosteroids within 24 hours before the first dose of ponatinib and other chemotherapy within 7 days prior to the first dose of ponatinib. Otherwise, 2a applies. All patients are excluded if they have not recovered (> grade 1 by NCI CTCAE v.4.0) from AEs (except alopecia) due to agents previously administered. Underwent autologous or allogeneic stem cell transplant < 60 days prior to receiving the first dose of ponatinib; any evidence of ongoing graft versus-host disease (GVHD) or GVHD requiring immunosuppressive therapy. Take medications that are known to be associated with Torsades de Pointes. Require concurrent treatment with immunosuppressive agents, other than corticosteroids prescribed for a short course of therapy. Have previously been treated with ponatinib. Patients with CP-CML are excluded if they are in CCyR. Patients with CP-CML are excluded if a baseline BM aspirate adequate for conventional cytogenetic analysis with 20 metaphases examined is not available. Patients with AP-CML, BP-CML, or Ph+ ALL are excluded if they are in MaHR. Patients with AP-CML, BP-CML, or Ph+ ALL are excluded if a baseline BM aspirate adequate for cell count and differential report is not available. Patients with a fibrotic marrow or dry tap that does not yield adequate cell counts for diagnosis are not evaluable for classification, and endpoints are not eligible. Have active central nervous system (CNS) disease as evidenced by cytology or pathology. In the absence of clinical CNS disease, lumbar puncture is not required. History itself of CNS involvement is not exclusionary if CNS has been cleared with a documented negative lumbar puncture. Have significant or active cardiovascular disease, specifically including, but not restricted to: Myocardial infarction within 3 months prior to first dose of ponatinib History of clinically significant atrial arrhythmia or any ventricular arrhythmia Unstable angina within 3 months prior to first dose of ponatinib Congestive heart failure within 3 months prior to first dose of ponatinib 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 orally administered ponatinib. Have been diagnosed with another primary malignancy within the past 3 years (except for non-melanoma skin cancer or cervical cancer in situ, or controlled prostate cancer, which are allowed within 3 years). Are pregnant or lactating. Women of childbearing potential must agree to an effective contraception from the time of signing the informed consent through the Follow-up Visit, approximately 30 days after last dose of ponatinib. Underwent major surgery (with the exception of minor surgical procedures, such as catheter placement or BM biopsy) within 14 days prior to first dose of ponatinib. Have ongoing or active infection (including known history of human immunodeficiency virus [HIV], hepatitis B virus [HBV], or hepatitis C virus [HCV]). Testing for these viruses is not required in the absence of history. Suffer from any condition or illness that, in the opinion of the Investigator or the Medical Monitor, would compromise patients safety or interfere with the evaluation of the safety of the study drug.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 dose escalation<br>Phase 1 | Drug: ponatinib - Phase 1<br>* 30 mg dose of ponatinib taken orally once daily for at least the first 6 patients. If no dose-limiting toxicities are observed, the next patients will receive 45 mg dose of ponatinib taken orally once daily. Once the recommended dose is confirmed, all patients may receive the recommended dose, at the investigators' discretion.<br>* Other names: AP24534;|
| Experimental: Phase 2 expansion<br>Phase 2 | Drug: ponatinib - Phase 2<br>* Recommended dose of ponatinib as determined in the dose escalation phase. In addition, 3 patients will receive 15 mg dose once daily for 8 days for PK testing. These PK patients may be allowed to receive the recommended dose after PK testing is complete, at the investigators' discretion.<br>* Other names: AP24534;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) as a Measure of Safety Profile to Determine Recommended Dose of Ponatinib | DLT was evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 and was defined as any of the following events: 1. Grade greater than or equal to (>=) 3 non-hematologic, with the exception of medically controllable toxicities (example; nausea, vomiting, fatigue, electrolyte disturbances, hypersensitivity reactions) lasting <=3 days, but excluding alopecia; 2. Missed doses: >25% of planned ponatinib doses over 28 days due to AEs in the first cycle; 3. Febrile neutropenia (the occurrence of an ANC <500/microliter concurrently with a temperature elevation of >101 degree Fahrenheit), when neutropenia is not related to underlying acute leukemia, as defined hematologic toxicity: Dose-limiting hematologic toxicity is the occurrence of a Grade 4 cytopenia >28 days, not related to underlying disease according to the investigator. Bone marrow examination must demonstrate <5% cellularity. | Cycle 1 (Cycle length= 28 days) | 
| Phase 2, CP-CML Participants: Percentage of Participants With Major Cytogenetic Response (MCyR) | MCyR was defined as percentage of participants who achieved a complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR) after the initiation of study treatment. Cytogenic response was the percentage of Philadelphia chromosome positive (Ph+) metaphases in bone marrow. CCyR: no Ph+ cells. PCyR: 1% to 35% Ph+ cells. Participants entering the study already in PCyR had to achieve a CCyR in order to be considered a success for the confirmed MCyR rate. | Baseline up to 60 months | 
| Phase 2, BP-CML and Ph+ALL: Percentage of Participants With Major Hematologic Response (MaHR) | MaHR was defined as percentage of participants with complete hematologic response (CHR) or no evidence of leukemia (NEL). MaHR response was confirmed by a peripheral blood complete blood count (CBC) and differential no earlier than 28 days after the response was observed. Response criteria for CHR was reported as white blood cells (WBC)<=institutional upper limit of normal (ULN), absolute neutrophil count (ANC)>=1000/mm^3, platelets>=100,000/mm^3, no blasts or promyelocytes in peripheral blood, BM blasts <=5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement; Response criteria for NEL reported as WBC<=institutional ULN, no blasts or promyelocytes in peripheral blood, BM blasts <=5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement, at least 1 of the following: (i) 20,000/mm^3<=platelets<100,000/mm^3; (ii) 500/mm^3<=ANC<1000/mm^3. | Baseline up to 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CP-CML Participants: Percentage of Participants With CHR | Hematologic response was defined as CHR for CP-CML participants. Participants who entered the trial in CHR and continued to meet the criteria for CHR on study were analyzed as responders. Response criteria for CHR was reported as WBC <=institutional ULN, platelets <450,000 per cubic millimeter (/mm^3), no blasts or promyelocytes in peripheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement (including no hepatomegaly or splenomegaly). | Baseline up to 60 months | 
| CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Confirmed MCyR | Confirmed MCyR was defined as 2 assessments of CCyR or PCyR at least 28 days apart. Participants entering the trial in PCyR must achieve two consecutive assessments of CCyR no fewer than 28 days apart in order to be considered as meeting the criteria for confirmed MCyR. Participants entering the trial in less than PCyR must achieve two consecutive assessments of PCyR or CCyR no fewer than 28 days apart in order to be considered as meeting the criteria for confirmed MCyR. CCyR: no Ph+ cells. PCyR: 1% to 35% Ph+ cells. | Baseline up to 60 months | 
| CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Major Molecular Response (MMR) | MMR was defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL <=0.1% on the International scale (equivalent to a 3-log reduction in transcript). Participants were non-responders in any of the following situations: BCR-ABL or ABL levels not detectable at baseline, no valid baseline or post-baseline assessment, and baseline assessment for e1a2 variant only. | Baseline up to 60 months | 
| CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Time to response was defined as the interval from the first dose of study treatment until the criteria for response were first met, censored at the last assessment of response. Median time to response was estimated by Kaplan-Meier method. | From the first dose of study treatment until the criteria for response were first met (up to 60 months) | 
| CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | DOR: interval between first assessment at which criteria for response was met, until criteria for progression was met, censored at last date at which criteria for response was met. DOR was estimated using the Kaplan-Meier method. Progression criteria for CP was: death, development of AP/BP, or loss of CHR (in absence of cytogenic response), or loss of MCyR, or increasing WBC in participant without CHR (doubling of WBCs to >20,000 on 2 occasions at least 4 weeks apart, after first week of therapy), as confirmed by development in complete blood cells (CBCs) at least 4 weeks apart; AP was: death, development of confirmed BP, loss of previous major/minor hematologic response over-2 week period, or no decrease from baseline levels in percentage blasts in peripheral blood/BM on all assessments over a 4-week period; and BP/Ph+ALL was: death/increasing blasts in peripheral blood or BM over a 4-week period. As planned, DOR is reported for all participants by entry mutation (T315I and Other). | From the first assessment at which criteria for response was met until the criteria for progression was first met (up to 60 months) | 
| CP-CML and Advanced Phase Participants: Median Progression-free Survival (PFS) | PFS: interval from the first dose of study treatment until the criteria for progression or death were met, censored at the last response assessment. PFS was estimated using the Kaplan-Meier method. Progression criteria for CP was: death, development of AP/BP, or loss of CHR (in absence of cytogenic response), or loss of MCyR, or increasing WBC in participant without CHR (doubling of WBCs to >20,000 on 2 occasions at least 4 weeks apart, after first week of therapy), as confirmed by development in CBCs at least 4 weeks apart; AP was: death, development of confirmed BP, loss of previous major/minor hematologic response over-2 week period, or no decrease from baseline levels in percentage blasts in peripheral blood/BM on all assessments over a 4-week period; BP/Ph+ALL was: death or increasing blasts in peripheral blood or BM over a 4-week period. As planned, PFS is reported for all participants by entry mutation (T315I and Other). | From the first assessment at which criteria for response was met until the criteria for progression or death was met (up to 60 months) | 
| CP-CML and Advanced Phase Participants: Overall Survival (OS) | OS was defined as the interval from the first dose of study treatment until death, censored at the last date at which participant was known to be alive. Overall survival was estimated using the Kaplan-Meier method. As planned, OS is reported for all participants by entry mutation (T315I and Other). | From the first dose of study treatment until death (up to 60 months) | 
| Cmax: Maximum Observed Plasma Concentration for Ponatinib |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days) | 
| Tmax: Time to Reach the Cmax for Ponatinib |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days) | 
| AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose for Ponatinib |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days) | 
| T1/2: Terminal Phase Elimination Half-life for Ponatinib |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, Leukemia, Myeloid, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Neoplasms by Histologic Type, Neoplasms, Lymphoproliferative Disorders, Lymphatic Diseases, Immunoproliferative Disorders, Immune System Diseases, Myeloproliferative Disorders, Bone Marrow Diseases, Hematologic Diseases