Ponatinib for Chronic Myeloid Leukemia (CML) Evaluation 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 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.

Detailed Description
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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). 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. PACE is a multi-center, international, phase 2, uncontrolled, open-label trial of oral ponatinib in patients with Philadelphia chromosome-positive (Ph+) disease. The study enrolled 449 patients. Participants assigned to 1 of 6 cohorts in accordance with disease group and received: Ponatinib 45 mg This multi-center trial is conducted worldwide. The overall time to participate in this study is 96 months after last dose of study drug treatment.

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

Conditions
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Chronic Myeloid Leukemia, Ph+ Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Ponatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ ALL Previously treated with and developed resistance or intolerance to dasatinib or nilotinib OR developed the T3151 mutation after any tyrosine kinase inhibitor (TKI) therapy ≥18 years old Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Minimum life expectancy of ≥3 months Adequate kidney function Adequate liver function Normal pancreatic function Normal QT Fridericia-corrected interval (QTcF) ≤450 ms for males and ≤470 ms for females Negative pregnancy test (if woman of childbearing potential) Agree to use effective form of contraception (as applicable) Ability to comply with study procedures, in the Investigator's opinion Exclusion Criteria: Received prior TKI treatment within 7 days prior to receiving the first dose of ponatinib, or have not recovered from adverse events (except alopecia) due to agents previously administered. Received other therapies as follows: For CML chronic phase (CP) and accelerated phase (AP) participants, received hydroxyurea or anagrelide within 24 hours prior to receiving the first dose of ponatinib; interferon, cytarabine, or immunotherapy within 14 days prior to first dose of ponatinib; or any other cytotoxic chemotherapy, radiotherapy, or investigational therapy within 28 days prior to receiving the first dose of ponatinib. For CML blast phase (BP) participants, received chemotherapy within 14 days prior to the first dose of ponatinib. For Ph+ ALL participants, received corticosteroids within 24 hours before the first dose of ponatinib; or vincristine within 7 days prior to the first dose of ponatinib; or received other chemotherapy within 14 days prior to the first dose of ponatinib. Underwent stem cell transplant <60 days prior to receiving first dose of ponatinib Evidence of on-going graft versus-host disease (GVHD), or GVHD requiring immunosuppressive therapy Taking 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) Previously treated with ponatinib CML CP participants are excluded if they are in Complete cytogenetic response (CCyR) Participants with CML AP, CML BP, or Ph+ ALL are excluded if they are in Major Hematologic Response (MaHR). 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

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: CP-CML R-I<br>CP-CML participants R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). | Drug: Ponatinib<br>* Ponatinib tablets.<br>* Other names: Iclusig;|
| Experimental: Cohort B: CP-CML with T315I Mutation<br>CP-CML participants who had T315I mutation of breakpoint cluster region-Abelson complex (BCR-ABL) were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). | Drug: Ponatinib<br>* Ponatinib tablets.<br>* Other names: Iclusig;|
| Experimental: Cohort C: Accelerated Phase (AP)-CML R-I<br>AP-CML R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). | Drug: Ponatinib<br>* Ponatinib tablets.<br>* Other names: Iclusig;|
| Experimental: Cohort D: AP-CML with T315I Mutation<br>AP-CML participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). | Drug: Ponatinib<br>* Ponatinib tablets.<br>* Other names: Iclusig;|
| Experimental: Cohort E: Blast Phase (BP)-CML/Ph+ ALL R-I<br>BP-CML or Ph+ ALL R-I to dasatinib or nilotinib or Ph+ ALL R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). | Drug: Ponatinib<br>* Ponatinib tablets.<br>* Other names: Iclusig;|
| Experimental: Cohort F: BP-CML or Ph+ ALL with T315I Mutation<br>BP-CML or Ph+ ALL participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). | Drug: Ponatinib<br>* Ponatinib tablets.<br>* Other names: Iclusig;|
| Experimental: Unassigned to Cohorts A-F<br>Participants who were not assigned to any of the cohorts and have no T315I mutation at study entry and were not R-I to dasatinib or nilotinib, administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). | Drug: Ponatinib<br>* Ponatinib tablets.<br>* Other names: Iclusig;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of CP-CML Participants With Major Cytogenetic Response (MCyR) | MCyR is defined as percentage of participants with complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). Cytogenetic response is the percentage of Philadelphia chromosome positive (Ph+) metaphases in bone marrow (BM). Response is further defined as MCyR: CCyR or PCyR, where CCyR: no Ph+ cells; PCyR: 1 to 35% Ph+ cells. | Up to 12 months after initiation of study treatment | 
| Percentage of AP-CML Participants With Major Hematologic Response (MaHR) | MaHR is defined as percentage of participants with complete hematologic response (CHR) or no evidence of leukemia (NEL). Response criteria for CHR is reported as white blood cells (WBC)≤institutional upper limit of normal, absolute neutrophil count (ANC)≥1000/mm^3, platelets≥100,000/mm^3, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement; Response criteria for NEL is reported as WBC≤institutional upper limit of normal, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement, at least 1 of the following: (i) 20,000/mm^3≤platelets<100,000/mm^3; (ii) 500/mm^3≤ANC<1000/mm^3. | Up to 6 months after initiation of study treatment | 
| Percentage of BP-CML/Ph+ ALL Participants With MaHR | MaHR is defined as percentage of participants with CHR or NEL. Response criteria for CHR is reported as WBC≤institutional upper limit of normal, ANC≥1000/mm^3, platelets ≥100,000/mm^3, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement; Response criteria for NEL is reported as WBC≤ institutional upper limit of normal, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement, at least 1 of the following: (i) 20,000/mm^3 ≤platelets<100,000/mm^3; (ii) 500/mm^3≤ANC<1000/mm^3. | Up to 6 months after initiation of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of CP-CML Participants With CHR | Response criteria for CHR is reported as WBC≤institutional upper limit of normal, platelets<450,000/mm^3, no blasts or promyelocytes in peripheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement (including no hepatomegaly or splenomegaly). | Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose) | 
| Percentage of CP-CML Participants With Confirmed MCyR | Confirmed MCyR is defined as 2 assessments of CCyR or PCyR at least 28 days apart. For CP participants entering the trial in PCyR, confirmed MCyR is defined as 2 assessments of CCyR at least 28 days apart. | Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose) | 
| Percentage of CP-CML Participants With Major Molecular Response (MMR) | MMR is defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL ≤0.1% on the international scale (equivalent to a 3-log reduction in transcript). | Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose) | 
| Percentage of AP-CML or BP-CML/Ph+ ALL Participants With MCyR | MCyR is defined as percentage of participants with CCyR or PCyR. Cytogenetic response is the percentage of Ph+ metaphases in BM. Response is further defined as MCyR: CCyR or PCyR, where CCyR: no Ph+ cells; PCyR: 1 to 35% Ph+ cells. | Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose) | 
| Percentage of AP-CML or BP-CML/Ph+ ALL Participants With Confirmed MCyR | Confirmed MCyR is defined as 2 assessments of CCyR or PCyR at least 28 days apart. | Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose) | 
| Percentage of AP-CML or BP-CML/Ph+ ALL Participants With MMR | MMR is defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL ≤0.1% on the international scale (equivalent to a 3-log reduction in transcript). | Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose) | 
| Time to Response | Time to response is defined as the interval from the first dose of study treatment until the criteria for response are first met, censored at the last assessment of response. Median time to response was estimated using the Kaplan-Meier method. | Up to approximately 48 months after first dose | 
| Duration of Response | Duration of Response is defined as the interval between the first assessment at which the criteria for response are met until the criteria for progression are met, censored at the last date at which the criteria for response are met. Duration of response was estimated by the Kaplan-Meier method as the probability of remaining in response. | Up to approximately 48 months after first dose | 
| Progression-free Survival (PFS) | PFS is defined as the interval from the first dose of study treatment until the criteria for progression or death are met, censored at the last response assessment. Progression from CP is reported as death, development of AP or BP, loss of CHR (in the absence of cytogenetic response), confirmed by development in complete blood counts (CBCs) at least 4 weeks apart, loss of MCyR, increasing WBC in participant without CHR defined by doubling of WBC to >20K on 2 occasions at least 4 weeks apart; Progression from AP is reported as death, development of confirmed BP, loss of previous major or minor hematologic response over a 2-week period, no decrease from baseline levels in percentage blasts in peripheral blood or BM on all assessments over a 4-week period; Progression from BP or Ph+ ALL is reported as death, increasing blasts in peripheral blood or BM over a 4 week period. | Every 12 weeks ± 2 weeks from last dose of study drug or the investigator/participant decision to discontinue treatment, whichever occurred later (Up to approximately 96 months after last dose) | 
| Overall Survival (OS) | OS is defined as the interval from the first dose of study treatment until death, censored at the last date at which participant was known to be alive. | From the first dose of study treatment until death (Up to 96 months post last dose) | 
| Number of Participants With Treatment-Emergent Adverse Event (TEAE) and Serious AE (SAE) | An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy. | From first dose up to 30 days after last dose of the study drug (Up to approximately 49 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CML, ALL, PH, ponatinib, Ph+ALL, T315I mutation, Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia