A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients with Refractory Chronic
Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia

1. Patients must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ ALL (defined in Sections 12.3 and 12.4).
a. All patients must have screening bone marrow (BM) cytogenetics with conventional banding performed within 42 days prior to beginning treatment
b. Examination of at least 20 metaphases is required. If less than 20 metaphases are examined, the BM aspirate should be repeated.
Patients must either meet criterion 2 or 3:
2. Be previously treated with and resistant, or intolerant, to either dasatinib or nilotinib:
2.1 Resistance is defined for CML CP patients (CP at the time of initiation of dasatinib or nilotinib therapy) as follows. Patients must meet at least 1 criterion.
a. Three months after the initiation of therapy: No cytogenetic response (>95% Ph+) or failure to achieve CHR.
b. Six months after the initiation of therapy: Less than a minor cytogenetic response (>65% Ph+).
c. Twelve months after the initiation of therapy: Less than a PCyR (>35% Ph+).
d. At any time after the initiation of therapy, the development of new BCR-ABL kinase domain mutations in the absence of CCyR.
e. At any time after the initiation of therapy, the development of new clonal evolution in the absence of CCyR.
f. At any time after the initiation of therapy, the loss of any cytogenetic response [from complete (0%), partial (1% to 35%), minor (36% to 65%), or minimal (66% to 95%) to a
response at least 1 grade worse], confirmed in at least 2 consecutive analyses separated by at least 4 weeks.
g. At any time after the initiation of therapy, progression of disease (to AP or BP).
2.2 Resistance is defined for CML AP patients (AP at the time of initiation of dasatinib or nilotinib therapy) as follows. Patients must meet at least 1 criterion.
a. Three months after the initiation of therapy: failure to achieve a MaHR.
b. At any time after the initiation of therapy, the loss of a MaHR, confirmed in at least 2 consecutive analyses separated by at least 4 weeks.
c. At any time after the initiation of therapy, the development of new BCR-ABL kinase domain mutations in the absence of a MaHR.
2.3 Resistance is defined for CML BP patients (BP at the time of initiation of dasatinib or nilotinib therapy) and Ph+ ALL patients as follows. Patients must meet at least 1 criterion.
a. One month after the initiation of therapy: failure to achieve a MaHR.
b. At any time after the initiation of therapy, the loss of a MaHR, confirmed in at least 2 consecutive analyses separated by at least 1 week.
c. At any time after the initiation of therapy, the development of new BCR-ABL kinase domain mutations in the absence of a MaHR.
2.4 Intolerance to dasatinib or nilotinib is defined as: a. Non-hematologic intolerance: Patients with grade 3 or 4 toxicity while on therapy, or with persistent grade 2 toxicity, unresponsive to optimal management, including dose adjustments (unless dose reduction is not considered in the best interest of the patient if response is already suboptimal) in the absence of a CCyR for CP patients or MaHR for AP, BP or Ph+ ALL patients.
b. Hematologic intolerance: Patients with grade 3 or 4 toxicity (absolute neutrophil count [ANC] or platelets) while on therapy that is recurrent after dose reduction to the lowest doses recommended by manufacturer (80 mg daily [QD] for dasatinib; 400 mg QD for nilotinib) in the absence of a CCyR for CP patients or MaHR for AP, BP or Ph+ ALL patients.
NOTE: Although, the above criteria define failure after dasatinib or nilotinib (mostly according to Baccarani et al., 2009), patients who have gone on to later line therapy are eligible having failed dasatinib or nilotinib.
OR
3. Develop the T315I mutation after any TKI therapy.
3.1 Patients with T315I mutation after any TKI need not have been treated
with dasatinib or nilotinib.
3.2 Patients with T315I in CP must have less than a CCyR (>0% Ph+).
3.3 Patients with T315I in AP, BP, or Ph+ ALL must have less than a MaHR.
3.4 Patients with any history of T315I mutation will be eligible for study participation. However, only those patients who carry a T315I mutation that is detected by direct sequencing in a pre-treatment blood sample using the study*s central laboratory will be analyzed in the T315I subset.
Details are provided in Section 12.5 of the protocol.
Patients must meet all of the remaining criteria to be eligible for the study:
4. Must be *18 years old.
5. Provide written informed consent.
6. Eastern Cooperative Oncology Group (ECOG) performance status *2.
7. Minimum life expectancy of 3 months or more.
8. Adequate renal function defined as serum creatinine < 1.5 × upper limit of normal (ULN) for institution.
9. Adequate hepatic function defined as:
a. Total bilirubin < 1.5 × ULN,
b. Alanine aminotransferase (ALT [SGPT]) and aspartate aminotransferase (AST [SGOT]) < 2.5 × ULN for institution (<5 × ULN if liver involvement with leukemia),
c. Prothrombin time (PT) < 1.5 × ULN.
10. Normal pancreatic status defined as:
a. Lipase *1.5 × ULN for institution,
b. Amylase *1.5 × ULN for institution.
11. Normal QTcF interval on screening electrocardiogram (ECG) evaluation, defined as QTcF of *450 ms in males or *470 ms in females.
12. For females of childbearing potential, a negative pregnancy test must be documented prior to enrollment.
13. Female and male patients who are of childbearing potential must agree to use an effective form of contraception with their sexual partners throughout participation in this study.
14. Ability to comply with study procedures, in the Investigator*s opinion.

Patients are not eligible for participation in the study if they meet any of the following
exclusion criteria:
1. Received TKI therapy within 7 days prior to receiving the first dose of onatinib, or have not recovered (> grade 1 by NCI CTCAE, v. 4.0) from AEs except alopecia) due to agents previously administered.
2. Received other therapies as follows:
a. For CP and AP patients, received hydroxyurea or anagrelide within 24 hours prior to receiving the first dose of ponatinib, interferon, cytarabine, or immunotherapy within 14 days, or any other cytotoxic chemotherapy, radiotherapy, or investigational therapy within 28 days prior to receiving the first dose of ponatinib.
b. For BP patients, received chemotherapy within 14 days prior to the first dose of ponatinib. Otherwise 2a applies.
c. 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. Otherwise, 2a applies.
d. All patients are excluded if they have not recovered (> grade 1 by NCI CTCAE, v. 4.0) from AEs (except alopecia) due to agents previously administered.
3. Underwent autologous or allogeneic stem cell transplant < 60 days prior to receiving the first dose of ponatinib; any evidence of on-going graft versus-host disease (GVHD), or GVHD requiring immunosuppressive therapy.
4. Take medications that are known to be associated with Torsades de Pointes. These prohibited medications are listed in Attachment B.
5. Require concurrent treatment with immunosuppressive agents, other than corticosteroids prescribed for a short course of therapy.
6. Have previously been treated with ponatinib.
7. Patients with CML CP are excluded if they are in CCyR.
8. Patients with CML AP, CML BP, or Ph+ ALL are excluded if they are in MaHR.
9. Have active central nervous system (CNS) disease as evidenced by cytology or pathology. In the absence of clinical CNS disease, lumbar puncture is not required. History itself of CNS involvement is not exclusionary if CNS has been cleared with a documented negative lumbar puncture.
10. Have significant or active cardiovascular disease, specifically including, but not restricted to:
a. Myocardial infarction within 3 months prior to first dose of ponatinib,
b. History of clinically significant atrial arrhythmia or any ventricular arrhythmia,
c. Unstable angina within 3 months prior to first dose of ponatinib,
d. Congestive heart failure within 3 months prior to first dose of ponatinib.
11. Have a significant bleeding disorder unrelated to CML or Ph+ ALL.
12. Have a history of pancreatitis or alcohol abuse.
13. Have uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL).
14. Have malabsorption syndrome or other gastrointestinal illness that could affect absorption of orally administered ponatinib.
15. Have been diagnosed with another primary malignancy within the past 3 years (except for non-melanoma skin cancer or cervical cancer in situ, or controlled prostate cancer, which are allowed within 3 years).
16. Are pregnant or lactating. Women of childbearing potential must agree to effective contraception from the time of signing informed consent through the Follow-up Visit, approximately 30 days after last dose of ponatinib.
17. Underwent major surgery (with the exception of minor surgical procedures, such as catheter placement or BM biopsy) within 14 days prior to first dose of ponatinib.
18. Have ongoing or active infection (including known history of human immunodeficiency virus [HIV], hepatitis B virus [HBV], or hepatitis C virus [HCV]). Testing for these viruses is not required in the absence of history.
19. Suffer from any condition or illness that, in the opinion of the Investigator or the medical monitor, would compromise patient safety or interfere with the evaluation of the safety of the study drug.