Activity and Risk Profile of Ponatinib in Chronic Phase Patients With Chronic Myeloid Leukemia Resistant to Imatinib

Study Overview
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Brief Summary
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This study aims at evaluating the efficacy of treatment with ponatinib in patients with chronic myeloid leukemia who are in a chronic phase and who previously received treatment with imatinib but resulted to be resistant to it.

Detailed Description
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Phase 2, single-arm, multicentre, open label. No interim analysis is planned, but a monitoring committee will evaluate the data every 6 months. Ponatinib is given orally 30 mg daily, with dose adjustment to 15 mg daily once a BCR-ABL1 level smaller or equal to 0.1% (MMR) has been achieved and confirmed in the next test, 4 weeks apart. A return to prior, 30 mg, dose is due in case of return of BCR-ABL1 transcripts level to > 1%. Dose adjustments for toxicity are detailed in the protocol. Treatment time will be 52 weeks, during which study drug will be provided free-of-charge by ARIAD Pharmaceuticals, upon approval of the protocol. Treatment is discontinued at any time in case of failure or treatment-related SAEs. After one year of treatment, upon request of the local investigator and upon confirmation of the Treatment Advisory Committee (TAC, see section 23), ARIAD Pharmaceutics, Inc. will continue to provide ponatinib for the study patients who will benefit from treatment continuation, for at least 2 years, until the drug will be approved with that indication.

Official Title
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Optimizing Ponatinib USe (OPUS). A GIMEMA Phase 2 Study of the Activity and Risk Profile of Ponatinib, 30 mg Once Daily, in Chronic Myeloid Leukemia (CML) Chronic Phase (CP) Patients Resistant to Imatinib

Conditions
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Chronic Myeloid Leukemia, Chronic Phase, Adults

Intervention / Treatment
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* Drug: Ponatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cytogenetic and/or molecular confirmed diagnosis of Ph+ and/or BCR-ABL1+ CML Age ≥ 18 years Chronic phase CML Prior treatment with imatinib, any dose Resistance to imatinib, as defined by any one of the ELN 2013 failure criteria, as follows: no complete hematologic response (CHR) at 3 months no cytogenetic response (CyR) (Ph+ > 95%) at 3 months Less than partial CyR (PCyR, Ph+ > 35%) at 6 months BCR-ABL1 > 10% at 6 months Non complete CyR (CCyR) (Ph+ > 0%) at 12 months BCR-ABL1 > 1% at 12 months Loss of CHR, at any time Loss of CCyR, at any time Confirmed loss of major molecular response (MMR) (BCR-ABL1 bigger or equal to 0.1% in two consecutive tests, of which one bigger or equal to 1%), at any time Any new BCR-ABL1 mutation, at any time For females of childbearing potential, a negative pregnancy test must be documented prior to enrolment An effective form of contraception with their sexual partners from enrolment through 4 months after the end of treatment Signed written informed consent according to ICH/EU/GCP and national local laws prior to any study procedures Willingness and ability to comply with scheduled visits and study procedures. Exclusion Criteria: Accelerated or blastic phase CML Patients previously treated with nilotinib or dasatinib Patients with the T315I mutation History of acute pancreatitis within 1 year of study or history of chronic pancreatitis or of alcohol abuse Patients with history of acute myocardial infarction (AMI), unstable angina or coronary heart disease (CHD), congestive heart failure, cerebrovascular events (CVE) (stroke or transitory ischemic attack), or peripheral artery occlusive disease (PAOD) Compelled to take medications that are known to be associated with Torsades de Pointes and/or with significant QTc prolongation Pregnant or breastfeeding Any condition or illness that, in the opinion of the Investigator, would compromise patient safety or interfere with the evaluation of the drug Lack of informed consent

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ponatinib<br> | Drug: Ponatinib<br>* Ponatinib is given orally 30 mg daily, with dose adjustment to 15 mg daily once a BCR-ABL1 level minor or equal to 0.1% (MMR) has been achieved and confirmed in the next test, 4 weeks apart. A return to prior, 30 mg, dose is due in case of return of BCR-ABL1 transcripts level to > 1%. Dose adjustments for toxicity are detailed in the protocol.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with major cytogenetic response | Cytogenetic response (CyR) is defined based on the percentage of Ph pos metaphases, as evaluated by chromosome banding analysis (CBA) of at least 20 marrow cell metaphases: Major Cytogenetic Response if Ph pos metaphases < 35% Complete (CCyR) if Ph pos metaphases 0 or FISH BCR-ABL1 nuclei minor or equal to 1% Partial (PCyR) if Ph pos metaphases 1-34% Minor (mCyR) if Ph pos metaphases 35-65% Minimal or none (min/none CyR) if Ph pos metaphases > 65% If marrow cell metaphases cannot be obtained or analysed, interphase fluorescence-in-situ-hybridization (FISH) can be used, but only to distinguish a CCyR (minor or equal to 1% positive nuclei out of at least 200 nuclei) from a non CCyR. FISH data cannot be used to classify a response as minimal, minor, or partial. | After 52 weeks of ponatinib treatment start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Cardiovascular Adverse Events (AEs) |  | After three years from ponatinib treatment start | 
| Number of blood hypertension AEs |  | After three years from ponatinib treatment start | 
| Number of pancreatitis AEs |  | After three years from ponatinib treatment start | 
| Number of patients achieving Complete Cytogenetic Response (CCyR) |  | After 52 weeks of ponatinib treatment start | 
| Number of patients achieving major molecular response |  | After 52 weeks of ponatinib treatment start | 
| Number of patients with failure-free survival |  | At 36 months from ponatinib treatment start | 
| Number of patients with progression-free survival |  | At 36 months from ponatinib treatment start | 
| Number of patients in overal survival |  | At 36 months from ponatinib treatment start | 
| Number of patients in event-free survival |  | At 36 months from ponatinib treatment start | 
| Quality of Life patterns over time with the EORTC QLQ-C30 and the EORTC QLQ-CML24 questionnaires |  | At baseline and at at weeks 4, 12, 24, 36 and 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adults, Chronic myeloid leukemia, Chronic phase, Ponatinib, Imatinib resistant