Ponatinib for Chronic Myeloid Leukemia (CML) Evaluation and Ph+ Acute Lymphoblastic Leukemia (ALL)
Ponatinib for Chronic Myeloid Leukemia (CML) Evaluation and Ph+ Acute Lymphoblastic Leukemia (ALL)
The purpose of this study is to determine the efficacy of ponatinib in patients with chronic
 myeloid leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast phase (BP) or
 with philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who either are
 resistant or intolerant to either dasatinib or nilotinib, or have the
 (T)hreonine-315-(I)soleucine (T315I) mutation.
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. The study enrolled
 449 patients. Participants assigned to 1 of 6 cohorts in accordance with disease group and
 received:

 -  Ponatinib 45 mg

 This multi-center trial is conducted worldwide. The overall time to participate in this study
 is 96 months after last dose of study drug treatment.
Inclusion Criteria:

 -  Participants 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) participants, 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) participants, received chemotherapy within 14 days prior
 to the first dose of ponatinib.

 3. For Ph+ ALL participants, 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 participants are excluded if they are in Complete cytogenetic response (CCyR)

 -  Participants 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