Ponatinib for Chronic Myeloid Leukemia (CML) Evaluation and Ph+ Acute Lymphoblastic Leukemia (ALL)

The preliminary analysis of the phase 1 clinical trial revealed evidence of clinical
antitumor activity in patients with resistance to approved second-generation tyrosine kinase
inhibitors (TKI), dasatinib and nilotinib, including patients with the T315I mutation of the
BCR-ABL gene (BCR-ABL). This Phase 1 study, taken together with the strong preclinical data
that characterize ponatinib, provides the rationale for moving to a pivotal phase 2 trial of
this agent in a population of patients with chronic myeloid leukemia (CML) and Ph+ Acute
Lymphoblastic Leukemia (ALL) who are resistant or intolerant to prior TKI therapy and in
those patients with the T315I mutation.

PACE is a multi-center, international, phase 2, uncontrolled, open-label trial of oral
ponatinib in patients with Philadelphia chromosome-positive (Ph+) disease.

Inclusion Criteria:

- Patients must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ ALL

- Previously treated with and developed resistance or intolerance to dasatinib or
nilotinib OR developed the T3151 mutation after any tyrosine kinase inhibitor (TKI)
therapy

- ≥18 years old

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

- Minimum life expectancy of ≥3 months

- Adequate kidney function

- Adequate liver function

- Normal pancreatic function

- Normal QT Fridericia-corrected interval (QTcF) ≤450 ms for males and ≤470 ms for
females

- Negative pregnancy test (if woman of childbearing potential)

- Agree to use effective form of contraception (as applicable)

- Ability to comply with study procedures, in the Investigator's opinion

Exclusion Criteria:

- Received prior TKI treatment within 7 days prior to receiving the first dose of
ponatinib, or have not recovered from adverse events (except alopecia) due to agents
previously administered.

- Received other therapies as follows:

1. For CML chronic phase (CP) and accelerated phase (AP) patients, received
hydroxyurea or anagrelide within 24 hours prior to receiving the first dose of
ponatinib; interferon, cytarabine, or immunotherapy within 14 days prior to first
dose of ponatinib; or any other cytotoxic chemotherapy, radiotherapy, or
investigational therapy within 28 days prior to receiving the first dose of
ponatinib.

2. For CML blast phase (BP) patients, received chemotherapy within 14 days prior to
the first dose of ponatinib.

3. For Ph+ ALL patients, received corticosteroids within 24 hours before the first
dose of ponatinib; or vincristine within 7 days prior to the first dose of
ponatinib; or received other chemotherapy within 14 days prior to the first dose
of ponatinib.

- Underwent stem cell transplant <60 days prior to receiving first dose of ponatinib

- Evidence of on-going graft versus-host disease (GVHD), or GVHD requiring
immunosuppressive therapy

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

- Require concurrent treatment with immunosuppressive agents (other than corticosteroids
prescribed for a short course of therapy)

- Previously treated with ponatinib

- CML CP patients are excluded if they are in Complete cytogenetic response (CCyR)

- Patients with CML AP, CML BP, or Ph+ ALL are excluded if they are in Major Hematologic
Response (MaHR).

- Have active Central Nervous System (CNS) disease

- Have significant or active cardiovascular disease

- Have a significant bleeding disorder unrelated to CML or Ph+ALL

- Have a history of pancreatitis or alcohol abuse

- Have uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL)

- Have malabsorption syndrome or other gastrointestinal illness that could affect
absorption of ponatinib

- Diagnosed with another primary malignancy in the past 3 years

- Pregnant or lactating

- Underwent major surgery within 14 days prior to first dose of ponatinib

- Have ongoing or active infection

- Suffer from any other condition or illness that would compromise safety or interfere
with evaluation of the drug