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

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

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.

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.

Inclusion Criteria:

1. Cytogenetic and/or molecular confirmed diagnosis of Ph+ and/or BCR-ABL1+ CML

2. Age ≥ 18 years

3. Chronic phase CML

4. Prior treatment with imatinib, any dose

5. 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

6. For females of childbearing potential, a negative pregnancy test must be documented prior to enrolment

7. An effective form of contraception with their sexual partners from enrolment through 4 months after the end of treatment

8. Signed written informed consent according to ICH/EU/GCP and national local laws prior to any study procedures

9. Willingness and ability to comply with scheduled visits and study procedures.

Exclusion Criteria:

1. Accelerated or blastic phase CML
2. Patients previously treated with nilotinib or dasatinib
3. Patients with the T315I mutation
4. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis or of alcohol abuse
5. 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)
6. Compelled to take medications that are known to be associated with Torsades de Pointes and/or with significant QTc prolongation
7. Pregnant or breastfeeding
8. Any condition or illness that, in the opinion of the Investigator, would compromise patient safety or interfere with the evaluation of the drug
9. Lack of informed consent