Ponatinib Hydrochloride as Second Line Therapy in Treating Patients With Chronic Myeloid Leukemia in Chronic Phase Resistant or Intolerant to Imatinib Mesylate, Dasatinib, or Nilotinib

PRIMARY OBJECTIVES:

I. To estimate the proportion of patients with tyrosine kinase inhibitor (TKI)-resistant or
intolerant, chronic phase chronic myeloid leukemia (CML) (chronic phase [CP]-CML) attaining
major cytogenetic response (MCyR) at 6 months of treatment with second line ponatinib
(ponatinib hydrochloride) therapy.

II. To estimate the time to toxicity related to ponatinib for patients with TKI-intolerant or
TKI-resistant CP-CML.

SECONDARY OBJECTIVES:

I. To estimate the proportion of patients achieving a MCyR, complete cytogenetic response
(CCyR), major molecular response (MMR) and complete molecular response (CMR) at 3, 6, 12, 18
and 24 months of treatment with ponatinib after one TKI failure (by resistance or
intolerance).

II. To estimate the time to CCyR, MMR, MCyR and CMR for patients treated with ponatinib as
second line therapy for CP-CML.

III. To evaluate the durations of hematologic, cytogenetic and molecular response to
ponatinib after one TKI failure.

IV. To define the time to progression and overall survival for patients with CML in chronic
phase treated with ponatinib after one TKI failure.

V. To evaluate the toxicity profile of ponatinib in patients with CML in chronic phase after
one TKI failure.

VI. To evaluate the probability of developing v-abl Abelson murine leukemia viral oncogene
homolog 1 (ABL) mutations for patients with CML in chronic phase treated with ponatinib after
one TKI failure.

VII. To analyze differences in response rates and in prognosis according to pre-treatment
mutations and patient characteristics.

VIII. To investigate mechanisms of resistance in patients who develop resistance to ponatinib
used as second line therapy for CP-CML.

IX. To evaluate symptom burden in patients with CP-CML receiving ponatinib.

TERTIARY OBJECTIVES:

I. To investigate the presence of micro-ribonucleic acid (miRNA) that may be predictive of
outcome.

OUTLINE:

Patients receive ponatinib hydrochloride orally (PO) once daily (QD). Treatment continues for
up to 5 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 30 days.

Inclusion Criteria:

- Diagnosis of Philadelphia chromosome (Ph)-positive (by cytogenetics or fluorescent in
situ hybridization [FISH]) or breakpoint cluster region (BCR)-ABL-positive (by
polymerase chain reaction [PCR]) CML in chronic phase

- Patients should have demonstrated to have failure to therapy to one Food and Drug
Administration (FDA)-approved TKI (currently imatinib [imatinib mesylate], dasatinib,
and nilotinib are approved as frontline therapy), defined as per European LeukemiaNet
(ELN) recommendations: 1) less than complete hematologic response (CHR) at or beyond 3
months; 2) no cytogenetic response at or beyond 6 months; 3) less than PCyR (Ph+ >
35%) at or beyond 12 months; 4) less than CCyR at or beyond 18 months; 5) loss of
response or development of mutations or other clonal chromosomal abnormalities at any
time during TKI treatment; 6) intolerance to imatinib, dasatinib or nilotinib defined
as grade 3 or 4 toxicity, or persistent grade 2 toxicity despite optimal management
including dose adjustment, or in a patient where dose reductions are considered to be
not in the patients best interest to obtain or maintain an adequate response;
intolerant patients should not have achieved or have lost major cytogenetic response
at the time of enrollment

- Eastern Cooperative Oncology Group (ECOG) performance of 0-2

- Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless due to Gilbert syndrome,
in which case it should be =< 3.0 x ULN)

- Serum glutamate pyruvate transaminase (SGPT) =< 2.5 x ULN

- Creatinine =< 1.5 x ULN

- Patients must sign an informed consent indicating they are aware of the
investigational nature of this study, in keeping with the policies of the hospital

- Reliable telephone access to receive calls from an interactive voice response system
(IVR) (only applicable to patients who will participate in optional symptom burden
assessment)

- Women of pregnancy potential must practice an effective method of birth control during
the course of the study, in a manner such that risk of failure is minimized: 1) prior
to study enrollment, women of childbearing potential (WOCBP) must be advised of the
importance of avoiding pregnancy during trial participation & the potential risk
factors for an unintentional pregnancy; 2) postmenopausal women must be amenorrheic
for at least 12 months to be considered of non-childbearing potential; 3) in addition,
men enrolled on this study should understand the risks to any sexual partner of
childbearing potential & should practice an effective method of birth control; 4)
women & men must continue birth control for the duration of the trial & at least 3
months after the last dose of study drug; 5) all WOCBP MUST have a negative pregnancy
test prior to first receiving investigational product

- Patients should have discontinued therapy with imatinib, dasatinib or nilotinib or
other anti-leukemia therapy (except hydroxyurea), at least 48 hours prior to start of
study therapy and recovered from any toxicity due to these therapies to at least grade
1; the use of hydroxyurea is allowed immediately prior to study entry

Exclusion Criteria:

- Prior therapy with other BCR-ABL-targeted TKIs except imatinib, dasatinib or nilotinib
(e.g., bosutinib)

- New York Heart Association (NYHA) cardiac class 3-4 heart disease

- Patients meeting the following criteria are not eligible: history of unstable angina,
myocardial infarction, transient ischemic attack (TIA), stroke, peripheral arterial
occlusive disease, venous thromboembolism or pulmonary embolism; any history of
clinically significant ventricular arrhythmias (such as ventricular tachycardia,
ventricular fibrillation, or torsades de pointes); prolonged corrected QT (QTc)
interval on pre-entry electrocardiogram (> 470 msec) on both the Fridericia and
Bazett's correction; congestive heart failure (NYHA class III or IV) within 3 months
prior to first dose of ponatinib

- Patients with active, uncontrolled psychiatric disorders including: psychosis, major
depression, and bipolar disorders

- Patients with uncontrolled hypertension (defined as sustained systolic blood pressure
> 160 mmHg or diastolic > 100 mmHg)

- Pregnant or breast-feeding women are excluded

- Patients with history of pancreatitis

- Patients in accelerated or blast phase, or patients who have ever been documented to
be in blast phase CML, are excluded; the definitions of excluded CML phases are as
follows:

- Blastic phase:

- Presence of 30% blasts or more in the peripheral blood or bone marrow

- Accelerated phase CML:

- Peripheral or marrow blasts 15% or more

- Peripheral or marrow basophils 20% or more

- Thrombocytopenia < 100 x 10(9)/L unrelated to therapy

- Documented extramedullary blastic disease outside liver or spleen

- Clonal evolution defined as the presence of additional chromosomal abnormalities
other than the Ph chromosome has been historically been included as a criterion
for accelerated phase; however, patients with clonal evolution as the only
criterion of accelerated phase have a significantly better prognosis; thus,
patients with clonal evolution and no other criteria for accelerated phase will
be eligible for this study, but analyzed separately

- Patients who have received more than one FDA-approved TKI for CML, or any
investigational, non-FDA approved TKI