Ponatinib in Newly Diagnosed Chronic Myeloid Leukemia (CML) (EPIC)

• MMR rate [ Time Frame: 5 years after first dose ] [ Designated as safety issue: No ]
  To compare the efficacy of ponatinib with imatinib, as measured by MMR rate, at 5 years
• <10% BCR-ABL^IS rate [ Time Frame: 3 months after first dose ] [ Designated as safety issue: No ]
  To compare the proportion of patients achieving a ratio of <10% BCR-ABL to ABL transcript levels at 3 months, as measured by the international scale (<10% BCR-ABL^IS), in patients administered ponatinib versus those administered imatinib
• Complete cytogenetic response (CCyR) rate [ Time Frame: 12 months after first dose ] [ Designated as safety issue: No ]
  To compare, according to treatment with ponatinib versus imatinib, the CCyR rate at 12 months
• Progression-free survival [ Time Frame: Up to 8 years after the last patient's first dose ] [ Designated as safety issue: No ]
  To compare, according to treatment with ponatinib versus imatinib, progression-free survival
• Overall survival [ Time Frame: Up to 8 years after the last patient's first dose ] [ Designated as safety issue: No ]
  To compare, according to treatment with ponatinib versus imatinib, overall survival

• <10% BCR-ABL^IS rate [ Time Frame: 3 months after dose ] [ Designated as safety issue: No ]
  To compare the proportion of patients achieving a ratio of <10% BCR-ABL to ABL transcript levels at 3 months, as measured by the international scale (<10% BCR-ABL^IS), in patients administered ponatinib versus those administered imatinib
• MMR rate [ Time Frame: 18 months after first dose ] [ Designated as safety issue: No ]
  To compare, according to treatment with ponatinib versus imatinib, MMR rate at 18 months
• Durable MMR rate [ Time Frame: 24 months after first dose ] [ Designated as safety issue: No ]
  To compare, according to treatment with ponatinib versus imatinib, the durable MMR rate at 24 months
• Complete cytogenetic response (CCyR) rate [ Time Frame: 12 months after first dose ] [ Designated as safety issue: No ]
  To compare, according to treatment with ponatinib versus imatinib, the CCyR rate at 12 months
• Progression-free survival [ Time Frame: Up to 8 years after the last patient's first dose ] [ Designated as safety issue: No ]
  To compare, according to treatment with ponatinib versus imatinib, progression-free survival
• Overall survival [ Time Frame: Up to 8 years after the last patient's first dose ] [ Designated as safety issue: No ]
  To compare, according to treatment with ponatinib versus imatinib, overall survival

The purpose of this study is to compare the efficacy of ponatinib and imatinib in patients with newly diagnosed chronic myeloid leukemia (CML) in the chronic phase.

This multicenter, international, phase 3 trial will test the hypothesis that ponatinib is an effective treatment for newly diagnosed CP-CML patients when compared with standard imatinib.

Patients will be randomized in a 1:1 fashion, stratified by Sokal risk score at diagnosis (low, intermediate, high), to receive once daily oral administration of either ponatinib or imatinib. Efficacy measures include molecular, cytogenetic, and hematologic response rates at various timepoints; time to, duration of, and durability of responses; and survival follow-up. Safety measures include clinical laboratory testing, adverse event monitoring, vital signs, physical exams, ECGs, and ECHOs. Other measures include two patient-reported health outcomes questionnaires (FACT-Leu and EQ-5D-5L), determination of mutation status, and, for ponatinib only, measurement of steady-state plasma concentration. Accrual is expected to take approximately 2 years, and patients will be followed for survival for up to 8 years after the last patient's first dose; therefore, patient participation may last up to 10 years.

• Drug: ponatinib
  45 mg tablet, taken orally once daily
• Drug: imatinib (Gleevec/ Glivec)
  400 mg tablet, taken orally once daily

• Experimental: ponatinib
  Intervention: Drug: ponatinib
• Active Comparator: imatinib
  Intervention: Drug: imatinib (Gleevec/ Glivec)

Inclusion Criteria:

1. CP CML within 6 months of diagnosis

   • CP-CML will be defined by (i) <15% blasts in bone marrow; (ii) <30% blasts plus promyelocytes in bone marrow; (iii) <20% basophils in peripheral blood; (iv) ≥100 × 10^9/L platelets (≥100,000/mm^3); (v) No evidence of extramedullary disease except hepatosplenomegaly; AND (vi) No prior diagnosis of AP-CML or BP-CML

2. Cytogenetic assessment must demonstrate the BCR-ABL fusion by presence of the t(9;22) Philadelphia chromosome

   • (a)Variant translocations are only allowed provided they are assessable for cytogenetic response utilizing conventional cytogenetic techniques; (b) Conventional chromosome banding must be performed; AND (c) A minimum of 20 metaphases must be assessable at entry
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2

4. Adequate hepatic function as defined by the following criteria:

   (a) Total serum bilirubin ≤1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome; (b) Alanine aminotransferase (ALT) ≤2.5 × ULN; AND (c) Aspartate aminotransferase (AST) ≤2.5 × ULN

5. Adequate renal function as defined as defined by serum creatinine <1.5 x ULN
6. Adequate pancreatic function as defined by serum lipase and amylase ≤1.5 × ULN

Exclusion Criteria:

1. Received prior imatinib therapy
2. Received prior dasatinib therapy
3. Received prior nilotinib therapy
4. Received, for CML, any other systemic anticancer therapy, experimental therapy, or radiation therapy with the exception of anagrelide or hydroxyurea
5. Major surgery within 28 days prior to initiating therapy
6. History of bleeding disorder unrelated to CML
7. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis
8. History of alcohol abuse
9. Have uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL)

10. Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:

    1. Myocardial infarction, within 6 months prior to randomization
    2. Unstable angina within 6 months prior to randomization
    3. Congestive heart failure within 6 months prior to randomization
    4. History of clinically significant (as determined by the treating physician) atrial arrhythmia or any ventricular arrhythmia
    5. Any history of ventricular arrhythmia
    6. Cerebrovascular accident or transient ischemic attack within 6 months prior to randomization
    7. Any history of peripheral arterial occlusive disease requiring revascularization
    8. Any history of venous thromboembolism including deep venous thrombosis or pulmonary embolism
11. Uncontrolled hypertension (diastolic blood pressure >90 mm Hg; systolic >140 mm Hg). Patients with hypertension should be under treatment on study entry to effect blood pressure control
12. Taking medications that are known to be associated with Torsades de Pointes
13. Ongoing or active infection. The requirement for intravenous (IV) antibiotics is considered active infection
14. Known history of human immunodeficiency virus (HIV). Testing is not required in the absence of history
15. Pregnant or breastfeeding
16. Malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drugs
17. Diagnosed with or received anticancer therapy for another primary malignancy within 3 years prior to entry (except for non-melanoma skin cancer or cervical cancer in situ)
18. Any condition or illness that, in the opinion of the Investigator, would compromise patient safety or interfere with the evaluation of the drug