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

Study Overview
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Brief Summary
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This phase II trial studies how well daunorubicin hydrochloride, cytarabine, and nilotinib work in treating patients newly diagnosed with acute myeloid leukemia. Drugs used in chemotherapy, such as daunorubicin hydrochloride and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Nilotinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving daunorubicin hydrochloride with cytarabine and nilotinib may kill more cancer cells.

Detailed Description
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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.

Official Title
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A Phase II Study of Combination Daunorubicin and Cytarabine (Ara-c) and Nilotinib (Tasigna) (DATA) in Patients Newly Diagnosed With Acute Myeloid Leukemia and KIT Overexpression

Conditions
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Untreated Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Cytarabine
* Drug: Daunorubicin Hydrochloride
* Other: Laboratory Biomarker Analysis
* Drug: Nilotinib
* Other: Pharmacological Study


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (nilotinib, daunorubicin hydrochloride, cytarabine)<br>INDUCTION THERAPY: Patients receive daunorubicin hydrochloride IV over 10 minutes on days 1-3, cytarabine IV continuously on days 1-7, and nilotinib PO BID on days 4-14. Patients achieving CR or 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. | Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Drug: Daunorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubilem;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Nilotinib<br>* Given PO<br>* Other names: Tasigna;Other: Pharmacological Study<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Complete Responses (CR or CRi) During Induction Therapy | The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner. | Up to 56 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival(DFS) Rate | Disease free survival time is defined for all evaluable patients who have achieved a CR or CRi as the time from registration to relapse or death due to any cause. The distribution of disease-free survival will be estimated using the method of Kaplan-Meier. | 35 months | 
| Duration of Complete Response | The distribution of duration of complete response will be estimated using the method of Kaplan-Meier. | 2 years | 
| Incidence of Adverse Events as Assessed by NCI CTCAE Version 4.0 | The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. This data will be reported in the Adverse Events section of the results. | 35 months | 
| Overall Survival(OS) Rate | Overall survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier(Kaplan E 1958). | 39 Months |