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

Sponsor
Mayo Clinic (Other)
Overall Status
Completed
CT.gov ID
NCT01806571
Collaborator
National Cancer Institute (NCI) (NIH)
34
Enrollment
2
Locations
1
Arm
56.6
Actual Duration (Months)
17
Patients Per Site
0.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or DiseaseIntervention/TreatmentPhase
Phase 2

Detailed Description

PRIMARY OBJECTIVES:
  1. 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:
  1. Determine the 2-year overall survival (OS) and disease-free survival (DFS) rates.

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

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

  2. 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.

Study Design

Study Type:
Interventional
Actual Enrollment :
34 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Mar 12, 2015
Actual Primary Completion Date :
Jul 31, 2017
Actual Study Completion Date :
Nov 30, 2019

Arms and Interventions

ArmIntervention/Treatment
Experimental: Treatment (nilotinib, daunorubicin hydrochloride, cytarabine)

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
Given IV
Other Names:
  • .beta.-Cytosine arabinoside
  • 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-.beta.-D-Arabinofuranosylcytosine
  • 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-Beta-D-arabinofuranosylcytosine
  • 1.beta.-D-Arabinofuranosylcytosine
  • 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
  • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
  • Alexan
  • Ara-C
  • ARA-cell
  • Arabine
  • Arabinofuranosylcytosine
  • Arabinosylcytosine
  • Aracytidine
  • Aracytin
  • Aracytine
  • Beta-Cytosine Arabinoside
  • CHX-3311
  • Cytarabinum
  • Cytarbel
  • Cytosar
  • Cytosar-U
  • Cytosine Arabinoside
  • Cytosine-.beta.-arabinoside
  • Cytosine-beta-arabinoside
  • Erpalfa
  • Starasid
  • Tarabine PFS
  • U 19920
  • U-19920
  • Udicil
  • WR-28453
  • Drug: Daunorubicin Hydrochloride
    Given IV
    Other Names:
  • Cerubidin
  • Cerubidine
  • Cloridrato de Daunorubicina
  • Daunoblastin
  • Daunoblastina
  • Daunoblastine
  • Daunomycin Hydrochloride
  • Daunomycin, hydrochloride
  • Daunorubicin.HCl
  • Daunorubicini Hydrochloridum
  • FI-6339
  • Ondena
  • RP-13057
  • Rubidomycin Hydrochloride
  • Rubilem
  • Other: Laboratory Biomarker Analysis
    Correlative studies

    Drug: Nilotinib
    Given PO
    Other Names:
  • AMN 107
  • Tasigna
  • Other: Pharmacological Study
    Correlative studies

    Outcome Measures

    Primary Outcome Measures

    1. Proportion of Complete Responses (CR or CRi) During Induction Therapy [Up to 56 days]

      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.

    Secondary Outcome Measures

    1. Disease Free Survival(DFS) Rate [2 years]

      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. In addition, the diseasefree survival rate at 2 years after registration will be reported.

    2. Duration of Complete Response [From the date at which objective status is first noted to be CR or CRi to the earliest date relapse is documented, assessed up to 3 years]

      The distribution of duration of complete response will be estimated using the method of Kaplan-Meier.

    3. Incidence of Adverse Events as Assessed by NCI CTCAE Version 4.0 [Up to 3 years after completion of study treatment]

      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.

    4. Overall Survival(OS) Rate [At 2 years]

      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). In addition, the overall survival rate at 2 years after registration will be reported.

    Other Outcome Measures

    1. Bone Marrow Flt3 Mutation [Baseline]

      Will be summarized and used to help characterize the types of patients accrued to this trial.

    2. Bone Marrow Kit Mutation Status [Up to 3 years]

    3. Bone Marrow Kit Mutation/Expression [Baseline]

      Will be summarized and used to help characterize the types of patients accrued to this trial.

    4. MRD, Assessed by PCR or Flow Cytometry [Up to 3 years]

      MRD status will be correlated with response using Fisher's exact test. In addition, the relationship between MRD status (positive vs. negative) and disease-free survival will be evaluated using landmark analyses.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 69 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Untreated, histological confirmed acute myeloid leukemia (AML) based on World Health Organization (WHO) 2008 criteria with Kit expression (cluster of differentiation [CD]
    1. 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)

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Mayo Clinic in ArizonaScottsdaleArizonaUnited States85259
    2Mayo ClinicRochesterMinnesotaUnited States55905

    Sponsors and Collaborators

    • Mayo Clinic
    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Aref Al-Kali, Mayo Clinic

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Mayo Clinic
    ClinicalTrials.gov Identifier:
    NCT01806571
    Other Study ID Numbers:
    • MC1284
    • NCI-2013-00469
    • 12-006178
    • MC1284
    • P30CA015083
    First Posted:
    Mar 7, 2013
    Last Update Posted:
    Aug 18, 2020
    Last Verified:
    Aug 1, 2020

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleTreatment (Nilotinib, Daunorubicin Hydrochloride, Cytarabine)
    Arm/Group DescriptionINDUCTION 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. Cytarabine: Given IV Daunorubicin Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Nilotinib: Given PO
    Period Title: Overall Study
    STARTED34
    COMPLETED34
    NOT COMPLETED0

    Baseline Characteristics

    Arm/Group TitleTreatment (Nilotinib, Daunorubicin Hydrochloride, Cytarabine)
    Arm/Group DescriptionINDUCTION 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. Cytarabine: Given IV Daunorubicin Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Nilotinib: Given PO
    Overall Participants34
    Age (years) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [years]
    58.6
    Sex: Female, Male (Count of Participants)
    Female
    10
    29.4%
    Male
    24
    70.6%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    1
    2.9%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    0
    0%
    White
    32
    94.1%
    More than one race
    0
    0%
    Unknown or Not Reported
    1
    2.9%

    Outcome Measures

    1. Primary Outcome
    TitleProportion of Complete Responses (CR or CRi) During Induction Therapy
    DescriptionThe 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.
    Time FrameUp to 56 days

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleTreatment (Nilotinib, Daunorubicin Hydrochloride, Cytarabine)
    Arm/Group DescriptionINDUCTION 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. Cytarabine: Given IV Daunorubicin Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Nilotinib: Given PO
    Measure Participants34
    Number [proportion of participants]
    0.618
    1.8%
    2. Secondary Outcome
    TitleDisease Free Survival(DFS) Rate
    DescriptionDisease 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. In addition, the diseasefree survival rate at 2 years after registration will be reported.
    Time Frame2 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleTreatment (Nilotinib, Daunorubicin Hydrochloride, Cytarabine)
    Arm/Group DescriptionINDUCTION 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. Cytarabine: Given IV Daunorubicin Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Nilotinib: Given PO
    Measure Participants34
    Number (95% Confidence Interval) [percentage of patients]
    56.4
    3. Secondary Outcome
    TitleDuration of Complete Response
    DescriptionThe distribution of duration of complete response will be estimated using the method of Kaplan-Meier.
    Time FrameFrom the date at which objective status is first noted to be CR or CRi to the earliest date relapse is documented, assessed up to 3 years

    Outcome Measure Data

    Analysis Population Description
    Patients that acheived a complete response.
    Arm/Group TitleTreatment (Nilotinib, Daunorubicin Hydrochloride, Cytarabine)
    Arm/Group DescriptionINDUCTION 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. Cytarabine: Given IV Daunorubicin Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Nilotinib: Given PO
    Measure Participants21
    Median (95% Confidence Interval) [Months]
    NA
    4. Secondary Outcome
    TitleIncidence of Adverse Events as Assessed by NCI CTCAE Version 4.0
    DescriptionThe 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.
    Time FrameUp to 3 years after completion of study treatment

    Outcome Measure Data

    Analysis Population Description
    All treated patients
    Arm/Group TitleTreatment (Nilotinib, Daunorubicin Hydrochloride, Cytarabine)
    Arm/Group DescriptionINDUCTION 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. Cytarabine: Given IV Daunorubicin Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Nilotinib: Given PO
    Measure Participants34
    Count of Participants [Participants]
    34
    100%
    5. Secondary Outcome
    TitleOverall Survival(OS) Rate
    DescriptionOverall 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). In addition, the overall survival rate at 2 years after registration will be reported.
    Time FrameAt 2 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleTreatment (Nilotinib, Daunorubicin Hydrochloride, Cytarabine)
    Arm/Group DescriptionINDUCTION 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. Cytarabine: Given IV Daunorubicin Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Nilotinib: Given PO
    Measure Participants34
    Number (95% Confidence Interval) [percentage of patients alive]
    70.6
    6. Other Pre-specified Outcome
    TitleBone Marrow Flt3 Mutation
    DescriptionWill be summarized and used to help characterize the types of patients accrued to this trial.
    Time FrameBaseline

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    7. Other Pre-specified Outcome
    TitleBone Marrow Kit Mutation Status
    Description
    Time FrameUp to 3 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    8. Other Pre-specified Outcome
    TitleBone Marrow Kit Mutation/Expression
    DescriptionWill be summarized and used to help characterize the types of patients accrued to this trial.
    Time FrameBaseline

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    9. Other Pre-specified Outcome
    TitleMRD, Assessed by PCR or Flow Cytometry
    DescriptionMRD status will be correlated with response using Fisher's exact test. In addition, the relationship between MRD status (positive vs. negative) and disease-free survival will be evaluated using landmark analyses.
    Time FrameUp to 3 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time Frame2 years
    Adverse Event Reporting Description The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.
    Arm/Group TitleTreatment (Nilotinib, Daunorubicin Hydrochloride, Cytarabine)
    Arm/Group DescriptionINDUCTION 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. Cytarabine: Given IV Daunorubicin Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Nilotinib: Given PO
    All Cause Mortality
    Treatment (Nilotinib, Daunorubicin Hydrochloride, Cytarabine)
    Affected / at Risk (%)# Events
    Total1/34 (2.9%)
    Serious Adverse Events
    Treatment (Nilotinib, Daunorubicin Hydrochloride, Cytarabine)
    Affected / at Risk (%)# Events
    Total31/34 (91.2%)
    Blood and lymphatic system disorders
    Febrile neutropenia18/34 (52.9%) 24
    Cardiac disorders
    Atrial fibrillation1/34 (2.9%) 1
    Atrial flutter1/34 (2.9%) 1
    Heart failure1/34 (2.9%) 1
    Sinus tachycardia1/34 (2.9%) 1
    Ear and labyrinth disorders
    Vertigo1/34 (2.9%) 1
    Gastrointestinal disorders
    Gastrointestinal disorders - Other, specify1/34 (2.9%) 1
    Jejunal hemorrhage1/34 (2.9%) 1
    Nausea1/34 (2.9%) 1
    Pancreatitis1/34 (2.9%) 1
    Rectal fistula1/34 (2.9%) 1
    Vomiting1/34 (2.9%) 1
    Hepatobiliary disorders
    Hepatic failure1/34 (2.9%) 1
    Hepatobiliary disorders - Other, specify1/34 (2.9%) 1
    Infections and infestations
    Anorectal infection2/34 (5.9%) 2
    Appendicitis1/34 (2.9%) 1
    Catheter related infection2/34 (5.9%) 2
    Enterocolitis infectious1/34 (2.9%) 1
    Infections and infestations - Other, specify3/34 (8.8%) 3
    Lung infection4/34 (11.8%) 4
    Sepsis5/34 (14.7%) 6
    Investigations
    Alanine aminotransferase increased7/34 (20.6%) 7
    Alkaline phosphatase increased1/34 (2.9%) 1
    Aspartate aminotransferase increased5/34 (14.7%) 5
    Blood bilirubin increased5/34 (14.7%) 7
    Ejection fraction decreased1/34 (2.9%) 1
    Electrocardiogram QT corrected interval prolonged1/34 (2.9%) 1
    Lipase increased1/34 (2.9%) 1
    Serum amylase increased2/34 (5.9%) 2
    Metabolism and nutrition disorders
    Hyperglycemia3/34 (8.8%) 4
    Hyperkalemia1/34 (2.9%) 1
    Hyperuricemia1/34 (2.9%) 1
    Hypocalcemia2/34 (5.9%) 2
    Hypokalemia2/34 (5.9%) 2
    Hypophosphatemia4/34 (11.8%) 5
    Metabolism and nutrition disorders - Other, specify1/34 (2.9%) 1
    Nervous system disorders
    Peripheral motor neuropathy1/34 (2.9%) 1
    Syncope1/34 (2.9%) 1
    Psychiatric disorders
    Confusion1/34 (2.9%) 1
    Renal and urinary disorders
    Proteinuria1/34 (2.9%) 1
    Reproductive system and breast disorders
    Menorrhagia1/34 (2.9%) 1
    Respiratory, thoracic and mediastinal disorders
    Aspiration1/34 (2.9%) 1
    Hypoxia1/34 (2.9%) 1
    Pneumonitis1/34 (2.9%) 1
    Pulmonary edema1/34 (2.9%) 1
    Respiratory failure3/34 (8.8%) 3
    Sore throat1/34 (2.9%) 1
    Skin and subcutaneous tissue disorders
    Rash maculo-papular2/34 (5.9%) 2
    Vascular disorders
    Hypertension5/34 (14.7%) 7
    Hypotension2/34 (5.9%) 2
    Other (Not Including Serious) Adverse Events
    Treatment (Nilotinib, Daunorubicin Hydrochloride, Cytarabine)
    Affected / at Risk (%)# Events
    Total34/34 (100%)
    Blood and lymphatic system disorders
    Anemia32/34 (94.1%) 72
    Febrile neutropenia5/34 (14.7%) 5
    Cardiac disorders
    Cardiac disorders - Other, specify1/34 (2.9%) 1
    Palpitations1/34 (2.9%) 1
    Sinus tachycardia1/34 (2.9%) 1
    Supraventricular tachycardia1/34 (2.9%) 1
    Eye disorders
    Eye disorders - Other, specify1/34 (2.9%) 1
    Gastrointestinal disorders
    Abdominal pain1/34 (2.9%) 1
    Colitis1/34 (2.9%) 1
    Diarrhea5/34 (14.7%) 7
    Dyspepsia1/34 (2.9%) 1
    Gastrointestinal disorders - Other, specify3/34 (8.8%) 3
    Mucositis oral5/34 (14.7%) 7
    Nausea7/34 (20.6%) 7
    Pancreatitis1/34 (2.9%) 1
    Vomiting4/34 (11.8%) 4
    General disorders
    Edema face1/34 (2.9%) 1
    Edema limbs2/34 (5.9%) 2
    Fatigue5/34 (14.7%) 6
    Fever3/34 (8.8%) 3
    Non-cardiac chest pain1/34 (2.9%) 1
    Infections and infestations
    Catheter related infection1/34 (2.9%) 1
    Lung infection3/34 (8.8%) 4
    Skin infection1/34 (2.9%) 1
    Investigations
    Alanine aminotransferase increased15/34 (44.1%) 29
    Alkaline phosphatase increased2/34 (5.9%) 2
    Aspartate aminotransferase increased15/34 (44.1%) 22
    Blood bilirubin increased20/34 (58.8%) 35
    CD4 lymphocytes decreased10/34 (29.4%) 23
    Creatinine increased1/34 (2.9%) 1
    Ejection fraction decreased1/34 (2.9%) 1
    Electrocardiogram QT corrected interval prolonged22/34 (64.7%) 36
    Lipase increased4/34 (11.8%) 4
    Lymphocyte count decreased15/34 (44.1%) 25
    Neutrophil count decreased34/34 (100%) 78
    Platelet count decreased34/34 (100%) 79
    Serum amylase increased1/34 (2.9%) 1
    Weight loss1/34 (2.9%) 1
    White blood cell decreased34/34 (100%) 77
    Metabolism and nutrition disorders
    Anorexia1/34 (2.9%) 1
    Hyperglycemia3/34 (8.8%) 4
    Hypocalcemia3/34 (8.8%) 3
    Hypokalemia1/34 (2.9%) 1
    Hypophosphatemia8/34 (23.5%) 8
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorder - Other, specify1/34 (2.9%) 1
    Nervous system disorders
    Headache3/34 (8.8%) 5
    Peripheral sensory neuropathy1/34 (2.9%) 1
    Renal and urinary disorders
    Proteinuria1/34 (2.9%) 1
    Reproductive system and breast disorders
    Scrotal pain1/34 (2.9%) 1
    Respiratory, thoracic and mediastinal disorders
    Hypoxia2/34 (5.9%) 2
    Respiratory, thoracic and mediastinal disorders - Other, specify1/34 (2.9%) 1
    Sore throat1/34 (2.9%) 1
    Skin and subcutaneous tissue disorders
    Alopecia13/34 (38.2%) 20
    Purpura1/34 (2.9%) 1
    Rash maculo-papular25/34 (73.5%) 35
    Skin and subcutaneous tissue disorders - Other, specify1/34 (2.9%) 1
    Vascular disorders
    Hypertension2/34 (5.9%) 2

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/TitleAref Al-Kali, M.D.
    OrganizationMayo Clinic
    Phone(507) 538-0591
    Emailalkali.aref@mayo.edu
    Responsible Party:
    Mayo Clinic
    ClinicalTrials.gov Identifier:
    NCT01806571
    Other Study ID Numbers:
    • MC1284
    • NCI-2013-00469
    • 12-006178
    • MC1284
    • P30CA015083
    First Posted:
    Mar 7, 2013
    Last Update Posted:
    Aug 18, 2020
    Last Verified:
    Aug 1, 2020