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

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 pluspromyelocytes in bone marrow; (iii) <20% basophils in peripheral blood; (iv) ≥100 × 10^9/L platelets (≥100,000/mm^3); (v) No evidence of extramedullary diseaseexcept 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 forcytogenetic response utilizing conventional cytogenetic techniques; (b)Conventional chromosome banding must be performed; AND (c) A minimum of 20metaphases 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'ssyndrome; (b) Alanine aminotransferase (ALT) ≤2.5 × ULN; AND (c) Aspartateaminotransferase (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, orradiation 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 chronicpancreatitis

8. History of alcohol abuse

9. Have uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL)

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

11. Myocardial infarction, within 6 months prior to randomization

12. Unstable angina within 6 months prior to randomization

13. Congestive heart failure within 6 months prior to randomization

14. History of clinically significant (as determined by the treating physician)atrial arrhythmia or any ventricular arrhythmia

15. Any history of ventricular arrhythmia

16. Cerebrovascular accident or transient ischemic attack within 6 months prior torandomization

17. Any history of peripheral arterial occlusive disease requiring revascularization

18. Any history of venous thromboembolism including deep venous thrombosis orpulmonary embolism

19. Uncontrolled hypertension (diastolic blood pressure >90 mm Hg; systolic >140 mm Hg).Patients with hypertension should be under treatment on study entry to effect bloodpressure control

20. Taking medications that are known to be associated with Torsades de Pointes

21. Ongoing or active infection. The requirement for intravenous (IV) antibiotics isconsidered active infection

22. Known history of human immunodeficiency virus (HIV). Testing is not required in theabsence of history

23. Pregnant or breastfeeding

24. Malabsorption syndrome or other gastrointestinal illness that could affect oralabsorption of study drugs

25. Diagnosed with or received anticancer therapy for another primary malignancy within 3years prior to entry (except for non-melanoma skin cancer or cervical cancer in situ)

26. Any condition or illness that, in the opinion of the Investigator, would compromisepatient safety or interfere with the evaluation of the drug