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

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

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).

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).

Inclusion Criteria:

1. Have CP-CML and are resistant to first-line imatinib treatment.

2. Be male or female ≥18 years old.

3. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

4. Have adequate renal function as defined by the following criterion:

   • Serum creatinine ≤1.5 × upper limit of normal (ULN) for institution.

5. 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.

6. Have normal pancreatic status as defined by the following criterion:

   • Serum lipase and amylase ≤1.5 × ULN.

Exclusion Criteria:

1. 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.

2. Have previously been treated with any anti-CML therapy other than hydroxyurea, including interferon, cytarabine, immunotherapy, or any cytotoxic chemotherapy, radiotherapy, or investigational therapy.

3. Underwent autologous or allogeneic stem cell transplant.

4. Are in CCyR or MMR.

5. 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.