Daunorubicin Hydrochloride, Cytarabine, and Nilotinib in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine the complete response rates of combination nilotinib, cytarabine, and
daunorubicin (daunorubicin hydrochloride) in patients newly diagnosed with acute myeloid
leukemia (AML) and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (Kit)
overexpression.

SECONDARY OBJECTIVES:

I. Determine the 2-year overall survival (OS) and disease-free survival (DFS) rates.

II. Determine the complete response duration in patients treated with this regimen.

III. Assess the safety and toxicity of this regimen based on National Cancer Institute (NCI)
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

TERTIARY OBJECTIVES:

I. Assess the prognostic and predictive factors (Kit mutation/expression level, fms-related
tyrosine kinase 3 [Flt3] mutation) for patients treated with this regimen.

II. Assess the patterns of molecular response and relapse for Kit. III. Assess the effect on
minimal residual disease (MRD) by polymerase chain reaction (PCR) or flow cytometry.

OUTLINE:

INDUCTION THERAPY: Patients receive daunorubicin hydrochloride intravenously (IV) over 10
minutes on days 1-3, cytarabine IV continuously on days 1-7, and nilotinib orally (PO) twice
daily (BID) on days 4-14. Patients achieving complete remission (CR) or complete remission
with incomplete blood count recovery (CRi) proceed to consolidation therapy. Patients not
achieving a significant decrease in bone marrow recovery or CR/CRi upon bone marrow recovery
receive another course of induction therapy.

CONSOLIDATION THERAPY: Patients receive cytarabine IV every 12 hours on days 1, 3, and 5, and
nilotinib PO BID on days 4-14. Treatment repeats every 28 days for 4 courses in the absence
of disease progression or unacceptable toxicity. Patients achieving CR or CRi proceed to
maintenance therapy.

MAINTENANCE THERAPY: Patients receive nilotinib PO BID on days 1-84. Treatment repeats every
84 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 3
years.

Inclusion Criteria:

- Untreated, histological confirmed acute myeloid leukemia (AML) based on World Health
Organization (WHO) 2008 criteria with Kit expression (cluster of differentiation [CD]
117) of myeloblasts >= 20% by flow cytometry from bone marrow aspirate at diagnosis

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

- Magnesium within normal limits (WNL)

- Potassium WNL

- Phosphorus WNL

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

- Serum 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 that case direct bilirubin should be
=< 2 x ULN)

- Alkaline phosphatase =< 3 x ULN

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

- Creatinine =<1.5 x ULN

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

- Provide informed written consent

- Willing to return to consenting Mayo Clinic (Mayo Clinic's campus in Rochester, Mayo
Clinic's campus in Arizona, or Mayo Clinic's campus in Florida) institution for
follow-up during the active monitoring phase of the study

- Willing to provide bone marrow aspirate 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

- 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

- Previous treatment with chemotherapy or any other tyrosine kinase inhibitor for a
hematological disorder; Exceptions: patients with prior diagnosis of myelodysplastic
syndrome (MDS) and/or treatment with hypomethylating agent (azacytidine or decitabine)
are not excluded, prior hydroxyurea 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

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

- Corrected QT (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

- Myocardial infarction =< 12 months prior to starting study

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

- History of or presence of clinically significant ventricular, atrial
tachyarrhythmias or ejection fraction cutoff

- Left ventricle ejection fraction < 45%

- History of, congestive heart failure requiring use of ongoing maintenance therapy
for life-threatening ventricular arrhythmias

- Patients currently receiving treatment with strong cytochrome P450 family 3, subfamily
A, polypeptide 4 (CYP3A4) inhibitors and treatment that cannot be either discontinued
or switched to a different medication prior to starting study drug; patients receiving
any medications or substances that are strong or moderate inhibitors of CYP3A4

- Use of the following strong or moderate inhibitors is prohibited < 7 days prior
to registration

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

- Boceprevir (Victrelis)

- Clarithromycin (Biaxin, Biaxin XL)

- Conivaptan (Vaprisol)

- Grapefruit juice

- Indinavir (Crixivan)

- Itraconazole (Sporanox)

- Ketoconazole (Nizoral)

- Lopinavir/ritonavir (Kaletra)

- Mibefradil

- Nefazodone (Serzone)

- Nelfinavir (Viracept)

- Posaconazole (Noxafil)

- Ritonavir (Novir, Kaletra)

- Saquinivir (Fortovase, Invirase)

- Telaprevir (Incivek)

- Telithromycin (Ketek)

- Voriconazole (Vfend)

- Moderate inhibitors of CYP3A4/5 > 2-fold in the plasma AUC values or 50-80%
decrease in clearance

- Amprenavir (Agenerase)

- Aprepitant (Emend)

- Atazanavir (Reyataz)

- Ciprofloxacin (Cipro)

- Darunavir (Prezista)

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

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

- Fluconazole (Diflucan)

- Fosamprenavir (Lexiva)

- Imatinib (Gleevec)

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

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

- Strong inducers of CYP3A4/5 > 80% decrease in AUC

- Avasimibe

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

- Phenytoin (Dilantin, Phenytek)

- Rifampin (Rifadin)

- St. John's wort

- Moderate inducers of CYP3A4/5 50-80% decrease in AUC

- Bosentan (Tracleer)

- Efavirenz (Sustiva)

- Etravirine (Intelence)

- Modafinil (Provigil)

- Nafcillin

- Nevirapine (Viramune)

- Phenobarbital (Luminal)

- Rifabutin (Mycobutin)

- Troglitazone

- 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 of the study or who have not recovered
from prior surgery

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

- Diagnosis of AML-M3 (or acute promyelocytic leukemia)