Low-Intensity Chemotherapy and Ponatinib in Treating Participants With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To evaluate the complete molecular response (CMR) rate of ponatinib in combination with
low-intensity chemotherapy in elderly patients with newly diagnosed Philadelphia chromosome
(Ph)-positive and/or BAR-ABL-positive acute lymphoblastic leukemia (ALL).

II. To evaluate the overall response (OR; complete response [CR] + complete response with
hematologic improvement [CRi]) in patients with relapsed/refractory disease.

SECONDARY OBJECTIVES:

I. To evaluate other clinical efficacy endpoints (complete cytogenetic response, complete
molecular response, event-free survival and overall survival) and safety of the combination
regimen.

EXPLORATORY OBJECTIVES:

I. To characterize the frequency of ABL1 kinase domain mutations at diagnosis and to
determine their influence on relapse-free survival in patients with Ph+ ALL treated with
hyper-CVD plus ponatinib.

II. To determine the impact of recurrent genomic alterations and ribonucleic acid (RNA)
expression at diagnosis on relapse free survival (RFS) in patients with Ph+ ALL treated with
hyper-CVD plus ponatinib.

III. To investigate the impact of next-generation sequencing-based minimal residual disease
assessment on relapse-free survival in patients with Ph+ ALL.

OUTLINE:

COURSES 1, 3, 5, 7: Participants receive ponatinib orally (PO) once daily (QD) on days 1-14
of course 1 and days 1-28 of subsequent courses, cyclophosphamide intravenously (IV) twice
daily (BID) over 3 hours on days 1, 2, and 3, rituximab IV over 4-5 hours on days 1 and 11,
receive vincristine IV over 15 minutes on days 1 and 11, pegfilgrastim or filgrastim
subcutaneously (SC) daily on day 4, methotrexate intrathecally via spinal tap on day 2 of
courses 1, 3, and 5, and cytarabine intrathecally on day 7 of courses 1, 3, and 5.

COURSES 2, 4, 6, 8: Participants receive ponatinib PO QD on days 1-28, methotrexate IV over
24 hours on day 1 and intrathecally on day 8 of courses 2, 4, and 8, cytarabine IV BID over
2-3 hours on days 2 and 3 and intrathecally on day 5 of courses 2, 4, and 6, pegfilgrastim or
filgrastim SC daily on day 4, and rituximab IV over 4-6 hours on days 1 and 8.

MAINTENANCE THERAPY: After course 8, if disease has gotten worse, participants receive
vincristine IV over 15 minutes on day 1, prednisone PO on days 1-5, and ponatinib PO QD on
days 1-28. Courses repeat every 28 days for up to 2 years in the absence of disease
progression or unacceptable toxicity.

POST-MAINTENANCE THERAPY: Participants receive ponatinib PO QD on days 1-28. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 30 days.

Inclusion Criteria:

- Patients >= 60 years of age with previously untreated Ph-positive ALL [either t(9;22)
and/or BCR-ABL positive] (includes patients initiated on first course of hyper-CVAD
before cytogenetics known).

- Patients >= 60 years of age with previously treated Ph-positive ALL, after 1-2 courses
of chemotherapy with or without other tyrosine kinase inhibitors (TKIs). If they
achieved CR, they are assessable only for event-free and overall survival, or If they
failed to achieve CR, they are assessable for CR, event-free, and overall survival.

- Patients >= 18 years of age with relapsed/refractory Ph-positive ALL.

- Performance status =< 2 (Eastern Cooperative Oncology Group [ECOG] scale).

- Total serum bilirubin =< 2 x upper limit of normal (ULN), unless due to Gilbert's
syndrome.

- Alanine aminotransferase (ALT) =< 3 x ULN.

- Aspartate aminotransferase (AST) =< 3 x ULN.

- Serum lipase and amylase =< 1.5 x ULN.

- Creatinine =< 2.0 mg/dl

- Female patients who: Are postmenopausal for at least 1 year before the screening
visit, OR Are surgically sterile, OR If they are of childbearing potential, agree to
practice 2 effective methods of contraception, at the same time, from the time of
signing the informed consent through 4 months after the last dose of study drug, or
agree to completely abstain from heterosexual intercourse.

- Male patients, even if surgically sterilized (i.e., status post-vasectomy), who: Agree
to practice effective barrier contraception during the entire study treatment period
and through 4 months after the last dose of study drug, or Agree to completely abstain
from heterosexual intercourse.

- Adequate cardiac function as assessed clinically by history and physical examination.

- Signed informed consent.

Exclusion Criteria:

- Active serious infection not controlled by oral or intravenous antibiotics.

- Active hepatitis B. Patients with chronic hepatitis B who are on appropriate viral
suppressive therapy may be allowed after discussion with the principal investigator
(PI).

- History of acute pancreatitis within 1 year of study or history of chronic
pancreatitis.

- History of alcohol abuse.

- Uncontrolled hypertriglyceridemia (triglycerides > 450mg/dL).

- Active secondary malignancy other than skin cancer (e.g., basal cell carcinoma or
squamous cell carcinoma) that in the investigator's opinion will shorten survival to
less than 1 year.

- Active grade III-V cardiac failure as defined by the New York Heart Association
criteria.

- Clinically significant, uncontrolled, or active cardiovascular disease, specifically
including, but not restricted to: Any history of myocardial infarction (MI), stroke,
or revascularization; Unstable angina or transient ischemic attack prior to
enrollment; Congestive heart failure prior to enrollment, or left ventricular ejection
fraction (LVEF) less than lower limit of normal per local institutional standards
prior to enrollment; Diagnosed or suspected congenital long QT syndrome; Any history
of clinically significant atrial or ventricular arrhythmias (such as atrial
fibrillation, ventricular tachycardia, ventricular fibrillation, or Torsades de
pointes) as determined by the treating physician; Prolonged QTc interval on pre-entry
electrocardiogram (> 470 msec) unless corrected after electrolyte replacement. Any
history of venous thromboembolism including deep venous thrombosis or pulmonary
embolism; Uncontrolled hypertension (diastolic blood pressure > 90 mmHg; systolic >
140 mmHg). Patients with hypertension should be under treatment on study entry to
effect blood pressure control.

- Patients currently taking drugs that are generally accepted to have a risk of causing
Torsades de Pointes (unless these can be changed to acceptable alternatives).

- Taking any medications or herbal supplements that are known to be strong inhibitors of
CYP3A4 within at least 14 days before the first dose of ponatinib.

- Treatment with any investigational antileukemic agents or chemotherapy agents in the
last 7 days before study entry, unless full recovery from side effects has occurred or
patient has rapidly progressive disease judged to be life-threatening by the
investigator.

- Pregnant and lactating women will not be eligible; women of childbearing potential
should have a negative pregnancy test prior to entering on the study and be willing to
practice methods of contraception. Women do not have childbearing potential if they
have had a hysterectomy or are postmenopausal without menses for 12 months. In
addition, men enrolled on this study should understand the risks to any sexual partner
of childbearing potential and should practice an effective method of birth control.

- History of significant bleeding disorder unrelated to cancer, including: Diagnosed
congenital bleeding disorders (e.g., von Willebrand's disease); and diagnosed acquired
bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies).

- Patients with documented significant pleural or pericardial effusions unless they are
thought to be secondary to their leukemia.