Nilotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia or Blastic Phase Chronic Myelogenous Leukemia

PRIMARY OBJECTIVES:

I. To determine the clinical efficacy (2-year disease-free survival rate) of nilotinib and
combination chemotherapy in adult patients newly diagnosed with Philadelphia chromosome
positive B-cell acute lymphoblastic leukemia or blast crisis of chronic myeloid leukemia.

SECONDARY OBJECTIVES:

I. Determine the 2-year overall survival rate. II. Determine the complete response (CR)
rates (hematological, cytogenetic, and molecular) in patients treated with this regimen.

III. Determine the CR duration in patients treated with this regimen. IV. Assess the safety
and toxicity of this regimen by National Cancer Institute (NCI) Common Terminology Criteria
for Adverse Events (CTCAE) version 4.0.

TERTIARY OBJECTIVES:

I. Assess the prognostic and predictive factors for patients treated with this regimen.

II. Assess the cerebrospinal fluid (CSF) penetration for Nilotinib (CSF Nilotinib levels) in
humans.

III. Assess the Abelson (ABL) kinase domain mutations frequency at diagnosis, during
therapy, and at relapse.

OUTLINE:

INDUCTION AND CONSOLIDATION SCHEDULE A (COURSES 1, 3, 5, 7): Patients receive
cyclophosphamide intravenously (IV) twice daily (BID) over 2 hours on days 1-3, mesna IV
continuously on days 1-3, doxorubicin hydrochloride IV push on day 4, vincristine sulfate IV
on days 4 and 11, dexamethasone IV or orally (PO) on days 1-4 and 11-14, methotrexate
intrathecally (IT) on day 2, cytarabine IT on day 8, and nilotinib PO BID on days 1-14.
Patients with CD20-positive disease also receive rituximab IV on days 1 and 11.

INDUCTION AND CONSOLIDATION SCHEDULE B (COURSES 2, 4, 6, 8): Patients receive methotrexate
IV continuously over 24 hours on day 1, cytarabine IV over 2 hours on days 2-3, leucovorin
calcium IV every 6 hours on days 2-3, methotrexate IT on day 2, cytarabine IT on day 8, and
nilotinib PO BID on days 1-14. Patients with CD20-positive disease also receive rituximab IV
on days 1 and 11.

MAINTENANCE (COURSES 9-32): Patients receive nilotinib PO BID on days 1-28 (days 1-14 for
minimal residual disease [MRD]-positive patients), vincristine sulfate IV on day 1, and
prednisone PO on days 1 to 5. Patients also receive rituximab IV on day 1 of each course if
CD20-positive, every sixth course if MRD-negative, or every third course if MRD-positive.

INTENSIFICATION: Patients receive treatment as in Schedule A in courses 14 and 21 of
maintenance therapy and treatment as in Schedule B in courses 15 and 22 of maintenance
therapy.

DELAYED MAINTENANCE (COURSES 33-36): Patients receive nilotinib PO BID on days 1 to 84.
Treatment repeats every 84 days for up to 4 courses.

Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6-12 months for 4 years.

Inclusion Criteria:

- Untreated, histological confirmed Philadelphia positive B-cell acute lymphoblastic
leukemia or chronic myeloid leukemia blast-phase lymphoid lineage (bilineal,
biphenotypic or undifferentiated) per World Health Organization (WHO) criteria; NOTE:
Dexamethasone (or corticosteroids) use is allowed if needed before starting
chemotherapy; prior imatinib or dasatinib therapy for CML chronic phase (CP) or
accelerated phase (AP) is allowed

- Molecular or cytogenetic documentation of BCR-ABL fusion gene via any of the
following: reverse transcriptase-polymerase chain reaction (RT-PCR), G-banding, or
fluorescence in situ hybridization (FISH) testing from peripheral blood and/or bone
marrow sampling

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2

- Magnesium/potassium/phosphorus within normal limits (WNL)

- Serum amylase =< 1.5 x upper limit of normal (ULN)

- Lipase =< 1.5 x ULN

- Total bilirubin < 1.5 x ULN (does not apply to patients with isolated
hyperbilirubinemia [e.g., Gilbert's disease], in this situation the direct bilirubin
=< 2 x ULN)

- Alkaline phosphatase =< 3 x ULN

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =<
3 x ULN

- Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x
ULN

- Creatinine =< 1.5 x ULN

- Negative serum pregnancy test done =< 7 days prior to registration, for women of
childbearing potential only

- Provide informed written consent

- Willing to return to Mayo Clinic Rochester or Mayo Clinic Arizona for follow-up
during the active monitoring phase of the study

- Willing to provide CSF and blood samples for correlative research purposes

Exclusion Criteria:

- Any of the following because this study involves investigational agent(s) whose
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
unknown:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception throughout the study and for 3 months after completion of study
treatment

- Co-morbid systemic illnesses or other severe concurrent disease which, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study or interfere significantly with the proper assessment of safety and
toxicity of the prescribed regimens

- Immunocompromised patients (other than that related to the use of corticosteroids)
including patients known to be human immunodeficiency virus (HIV) positive (even if
on highly active antiretroviral therapy [HAART])

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, or psychiatric illness/social situations that would limit compliance with
study requirements

- Receiving any other investigational agent which would be considered as a treatment
for the primary neoplasm

- Other active malignancy =< 3 years prior to registration; EXCEPTIONS: Non-melanotic
skin cancer or carcinoma-in-situ of the cervix

- History of myocardial infarction =< 12 months, or congestive heart failure requiring
use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

- Previous treatment with chemotherapy or any other tyrosine kinase inhibitor (prior
imatinib or dasatinib for CML-CP/-AP is allowed)

- Impaired cardiac function including any one of the following:

- Inability to monitor the QT interval on electrocardiogram (ECG)

- Congenital long QT syndrome or a known family history of long QT syndrome

- Cardiac ejection fraction (EF) < 45%

- Clinically significant resting brachycardia (< 50 beats per minute)

- Corrected QT interval (QTc) > 450 msec on baseline ECG; if QTc > 450 msec and
electrolytes are not within normal ranges, electrolytes should be corrected and
then the patient re-screened for QTc

- Other clinically significant uncontrolled heart disease (e.g. unstable angina,
congestive heart failure or uncontrolled hypertension)

- History of or presence of clinically significant ventricular or atrial
tachyarrhythmias

- Patients receiving any medications or substances that are strong or moderate
inhibitors of cytochrome P450 3A4 (CYP3A4); use of the following strong or moderate
inhibitors are prohibited =< 7 days prior to registration:

- Strong Inhibitors of CYP3A4; > 5-fold increase in the plasma area under the
curve (AUC) values or more than 80% decrease in clearance

- Indinavir (Crixivan®)

- Nelfinavir (Viracept®)

- Atazanavir (Reyataz®)

- Ritonavir (Norvir®)

- Clarithromycin (Biaxin®, Biaxin XL®)

- Itraconazole (Sporanox®)

- Ketoconazole (Nizoral®)

- Nefazodone (Serzone®)

- Saquinavir (Fortovase®, Invirase®)

- Telithromycin (Ketek®)

- Moderate Inhibitors of CYP3A4; > 2-fold increase in the plasma AUC values or
50-80% decrease in clearance

- Aprepitant (Emend®)

- Erythromycin (Erythrocin®, E.E.S. ®, Ery-Tab®, Eryc®, EryPed®, PCE®)

- Fluconazole (Diflucan®)

- Grapefruit juice

- Verapamil (Calan®, Calan SR®, Covera-HS®, Isoptin SR®, Verelan®, Verelan
PM®)

- Diltiazem (Cardizem®, Cardizem CD®, Cardizem LA®, Cardizem SR®, Cartia XT™,
Dilacor XR®, Diltia XT®, Taztia XT™, Tiazac®)

- Patients receiving any medications or substances that are inducers of CYP3A4; use of
the following inducers are prohibited =< 7 days prior to registration

* Inducers of CYP3A4

- Efavirenz (Sustiva®)

- Nevirapine (Viramune®)

- Carbamazepine (Carbatrol®, Epitol®, Equetro™, Tegretol®, Tegretol-XR®)

- Modafinil (Provigil®)

- Phenobarbital (Luminal®)

- Phenytoin (Dilantin®, Phenytek®)

- Pioglitazone (Actos®)

- Rifabutin (Mycobutin®)

- Rifampin (Rifadin®)

- St. John's wort

- Patients currently receiving treatment with any medications that have the potential
to prolong the QT interval and the treatment cannot be either discontinued or
switched to a different medication prior to starting study drug

- Impaired gastrointestinal (GI) function or GI disease that may significantly alter
the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea,
vomiting, diarrhea, malabsorption syndrome, small bowel resection or gastric bypass
surgery)

- Acute or chronic pancreatic disease

- Known cytopathologically confirmed central nervous system (CNS) infiltration

- Acute or chronic liver disease or severe renal disease considered unrelated to the
cancer

- History of significant congenital or acquired bleeding disorder unrelated to cancer

- Major surgery =< 4 weeks prior to registration or not recovered from prior surgery

- Treatment with other investigational agents =< 14 days of registration