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

Information source: Mayo Clinic
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

Intervention: Cytarabine (Drug); Daunorubicin Hydrochloride (Drug); Laboratory Biomarker Analysis (Other); Nilotinib (Drug); Pharmacological Study (Other)

Phase: Phase 2

Status: Recruiting

Sponsored by: Mayo Clinic

Official(s) and/or principal investigator(s):
Aref Al-Kali, Principal Investigator, Affiliation: Mayo Clinic


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 or by stopping them from dividing. 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.

Clinical Details

Official title: 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

Study design: Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Proportion of complete responses (CR or CRi) during induction therapy

Secondary outcome:

DFS rate

Disease-free survival time (DFS)

Duration of complete response

Incidence of adverse events as assessed by NCI CTCAE version 4.0

OS rate

Overall survival (OS)

Detailed description: 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 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.


Minimum age: 18 Years. Maximum age: 69 Years. Gender(s): Both.


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)

- 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 3A4 (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 of

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


- 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


- 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)

Locations and Contacts

Mayo Clinic, Rochester, Minnesota 55905, United States; Recruiting
Clinical Trials Referral Office, Phone: 855-776-0015
Aref Al-Kali, Principal Investigator
Additional Information

Starting date: July 2013
Last updated: May 15, 2015

Page last updated: August 23, 2015

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