A Study Comparing Ponatinib and Nilotinib in Participants With Chronic Myeloid Leukemia

Study Overview
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Brief Summary
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The purpose of this study is to compare the efficacy and safety of 2 starting doses of ponatinib compared to nilotinib in participants with imatinib-resistant chronic myeloid leukemia (CML) in chronic phase (CP).

Detailed Description
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This is a multi-center, randomized study to demonstrate the efficacy and safety of 2 starting doses of ponatinib as a treatment for CP-CML compared to nilotinib. Eligible participants must have chronic phase chronic myeloid leukemia (CP-CML), be resistant to first-line imatinib treatment and have received no other tyrosine kinase inhibitors (TKIs).

Official Title
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A Randomized, Open-label Study of Ponatinib Versus Nilotinib in Patients With Chronic Myeloid Leukemia in Chronic Phase Following Resistance to Imatinib

Conditions
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Chronic Phase Chronic Myeloid Leukemia

Intervention / Treatment
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* Drug: Ponatinib 30 mg QD
* Drug: Ponatinib 15 mg QD
* Drug: Nilotinib 400 mg BID


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have CP-CML and are resistant to first-line imatinib treatment. Be male or female ≥18 years old. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Have adequate renal function as defined by the following criterion: • Serum creatinine ≤1.5 × upper limit of normal (ULN) for institution. Have adequate hepatic function as defined by all of the following criteria: Total serum bilirubin ≤1.5 × ULN, unless due to Gilbert's syndrome Alanine aminotransferase (ALT) ≤2.5 × ULN or ≤5 × ULN if leukemic infiltration of the liver is present Aspartate aminotransferase (AST) ≤2.5 × ULN or ≤5 × ULN if leukemic infiltration of the liver is present. Have normal pancreatic status as defined by the following criterion: Serum lipase and amylase ≤1.5 × ULN. Exclusion Criteria: Have previously been treated with any approved or investigational TKIs other than imatinib or treated with imatinib within 14 days prior to receiving study drug. Have previously been treated with any anti-CML therapy other than hydroxyurea, including interferon, cytarabine, immunotherapy, or any cytotoxic chemotherapy, radiotherapy, or investigational therapy. Underwent autologous or allogeneic stem cell transplant. Are in CCyR or MMR. Have clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: Any history of myocardial infarction (MI), unstable angina, cerebrovascular accident, or transient ischemic attack (TIA) Any history of peripheral vascular infarction, including visceral infarction Any history of a revascularization procedure, including vascular surgery or the placement of a stent History of venous thromboembolism, including deep venous thrombosis, superficial venous thrombosis, or pulmonary embolism, within 6 months prior to enrollment Congestive heart failure (New York Heart Association [NYHA] class III or IV) within 6 months prior to enrollment or left ventricular ejection fraction (LVEF) less than 45% or less than the institutional lower limit of normal (whichever is higher) within 6 months prior to enrollment.

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: Ponatinib 30 mg<br>Ponatinib 30 mg, tablets, orally, once daily (QD) until achievement of major molecular response (MMR) up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to 42 months. | Drug: Ponatinib 30 mg QD<br>* Ponatinib 30 mg, taken orally once daily.<br>* Other names: AP24534;|
| Experimental: Cohort B: Ponatinib 15 mg<br>Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to 45 months. | Drug: Ponatinib 15 mg QD<br>* Ponatinib 15 mg, taken orally once daily.<br>* Other names: AP24534;|
| Active Comparator: Cohort C: Nilotinib 400 mg<br>Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months. | Drug: Nilotinib 400 mg BID<br>* Nilotinib 400 mg, taken orally twice daily.<br>* Other names: AMN107;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Major Molecular Response (MMR) | MMR is defined as the percentage of participants achieving a ratio of ≤0.1% Breakpoint Cluster Region-Abelson (BCR ABL) to ABL transcripts on the international scale (≤0.1% BCR-ABL/ABL[IS]) at any time within 12 months after randomization. | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Major Cytogenetic Response (MCyR) | MCyR was the percentage of participants achieving Complete cytogenetic response (CCyR: defined as 0% Philadelphia chromosome-positive [Ph+] metaphases by cytogenetic analysis of bone marrow) or Partial Cytogenetic Response (PCyR: defined as >0% to 35% Ph+ metaphases by cytogenetic analysis of bone marrow) at any time within 12 months after randomization. | Up to 12 months | 
| Percentage of Participants With Complete Cytogenetic Response (CCyR) | CCyR rate was defined as the percentage of participants achieving CCyR up to 12 months after randomization. CCyR is defined as 0% Philadelphia chromosome-positive [Ph+] metaphases by cytogenetic analysis of bone marrow. | Up to 12 months | 
| Percentage of Participants With Molecular Response (MR) | Molecular response rate is defined as percentage of participants achieving MR2: Molecular response with 2-log reduction (defined as ≤1% BCR-ABL[IS]), MMR: Major molecular responder, MR4 (defined as ≤0.01% BCR-ABL[IS]), and MR4.5 (defined as ≤0.0032% BCR-ABL[IS]) after randomization. | From Month 3 to every 3 months up to 48 months | 
| Percentage of Participants With MR1 | MR1 was defined as the percentage of participants achieving a ratio of ≤10% BCR ABL to ABL transcripts on the international scale at 3 months. | Month 3 | 
| Percentage of Participants With Treatment Emergent Arterial Occlusive Events (TE-AOEs), Treatment Emergent Venous Thromboembolic Events (TE-VTE), Adverse Events (AEs), and Serious AEs (SAEs) | TE-AOE: arterial occlusive event with an initial onset date on or after first dose date and no later than 30 days after last dose date of study treatment or events starting after initial consent that worsen in severity on or after first dose date. TE-VTE: vascular occlusive event with an initial onset date on or after first dose date and no later than 30 days after last dose date of study treatment or events starting after initial consent that worsen in severity on or after first dose date. AE: any untoward medical occurrence in participant administered pharmaceutical product; untoward medical occurrence does not necessarily have causal relationship with this treatment. SAE: any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is congenital anomaly/birth defect/is medically important event. | From first dose up to 30 days post last dose (Up to approximately 46 months) | 
| Time to Response | Time to MMR defined as the interval between the randomization date and the first date at which the criteria for response was met. MMR was defined as <=0.1% BCR-ABL. | Up to approximately 60 months | 
| Duration of Response | Duration of response defined as the interval between the first assessment at which the criteria for response was met until the earliest date at which loss of response occurs, or the criteria for progression was met. | Up to approximately 60 months | 
| Progression-free Survival (PFS) | Progression-free survival (PFS) defined as the interval between the first dose date of study treatment and the first date at which the criteria for progression was met (progression to AP- or BP CML), or death due to any cause, censored at the last response assessment. | Up to end of study (approximately 60 months) | 
| Overall Survival | Overall survival (OS) defined as the interval between the first dose date of study treatment and date of death due to any cause, censored at the last contact date to be alive. | Up to end of study (approximately 60 months) | 
| Percentage of Participants Who Achieved/Maintained Complete Hematologic Response (CHR) | CHR rate is defined as the percentage of participants achieving CHR at any time after initiation of study treatment. CHR is defined as achieving all of the following measurements: White blood cells (WBC) ≤ institutional upper limit of normal (ULN); Platelets <450 x 10^9/L; 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). | 3 months after the first dose of study treatment | 
| Percentage of Participants With Treatment Emergent AEs Leading to Treatment Discontinuation, Dose Reduction and Dose Interruption | An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. | From first dose up to end of treatment (Up to approximately 45 months) | 
| Percentage of Participants With Progression to Accelerated Phase (AP) or Blast Phase (BP)-CML | Progression to AP is defined as: >=15% and <30% blasts in peripheral blood or bone marrow or >=20% basophils in peripheral blood or bone marrow or >=30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*10^9 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP-CML is defined as: >=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly. | Up to end of study (Up to approximately 60 months) | 

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