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

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.

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