Combination Chemotherapy and Ponatinib Hydrochloride in Treating Patients With Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To evaluate the clinical efficacy (event-free survival) of an intensive short-term
chemotherapy regimen (hyperfractionated cyclophosphamide-vincristine sulfate-Adriamycin
[doxorubicin hydrochloride]-dexamethasone [hyper-CVAD] program) given in combination with the
tyrosine kinase inhibitor ponatinib hydrochloride (ponatinib) for Philadelphia (Ph)-positive
and/or BCR-ABL-positive acute lymphoblastic leukemia (ALL).

II. To evaluate other clinical efficacy endpoints (overall response rate and survival) and
safety of the regimen.

OUTLINE:

ODD COURSES (1, 3, 5, and 7): Patients receive cyclophosphamide intravenously (IV) over 3
hours every 12 hours on days 1-3, doxorubicin hydrochloride IV continuously over 24 hours on
day 4, vincristine sulfate IV over 30 minutes on days 1 and 11, dexamethasone IV over 30
minutes or orally (PO) once daily (QD) on days 1-4 and 11-14, and ponatinib hydrochloride PO
QD on days 1-14 of course 1 and continuously in courses 3, 5, and 7. Patients with CD20
expression may also receive rituximab IV on days 1 and 11 of courses 1 and 3. Treatment
repeats every 3-4 weeks for up to 8 courses in the absence of disease progression or
unacceptable toxicity.

EVEN COURSES (2, 4, 6, and 8): Patients receive methotrexate IV over 24 hours on day 1,
ponatinib hydrochloride PO QD continuously, and cytarabine IV over 3 hours every 12 hours on
days 2 and 3. Patients with CD20 expression may also receive rituximab IV on days 1 and 8 of
courses 2 and 4. Treatment repeats every 3-4 weeks for up to 8 courses in the absence of
disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive vincristine sulfate IV on day 1, prednisone PO daily on
days 1-5, and ponatinib hydrochloride PO QD on days 1-28. Courses repeat every 28 days for 24
months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 6
months for up to 24 months.

Inclusion Criteria:

- Diagnosis of one of the following:

- 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)

- Previously treated Ph-positive ALL, after 1-2 courses of chemotherapy with or
without other tyrosine kinase inhibitors (TKIs)

- If they achieved complete response (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

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

- Total serum bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert's
syndrome

- Alanine aminotransferase (ALT) =< 2 x ULN

- Aspartate aminotransferase (AST) =< 2.5 x ULN

- Serum lipase and amylase =< 1.5 x ULN

- For females of childbearing potential, a negative pregnancy test must be documented
prior to randomization

- Female and male patients who are fertile must agree to use an effective form of
contraception with their sexual partners from randomization through 4 months after the
end of treatment

- 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

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

- History of alcohol abuse

- Uncontrolled hypertriglyceridemia (triglycerides > 450 mg/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 corrected QT (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
cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) within at least 14 days
before the first dose of ponatinib

- Prior history of treatment with 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)

- 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