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

This study is currently recruiting participants.
Verified March 2014 by Mayo Clinic
Sponsor:
Information provided by (Responsible Party):
Aref Al-Kali, Mayo Clinic
ClinicalTrials.gov Identifier:
NCT01806571
First received: February 25, 2013
Last updated: March 30, 2014
Last verified: March 2014
  Purpose

This phase II trial studies how well giving daunorubicin hydrochloride, cytarabine, and nilotinib together works 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 cell, 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 together with cytarabine and nilotinib may kill more cancer cells


Condition Intervention Phase
Adult Acute Basophilic Leukemia
Adult Acute Eosinophilic Leukemia
Adult Acute Megakaryoblastic Leukemia (M7)
Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
Adult Acute Monoblastic Leukemia (M5a)
Adult Acute Monocytic Leukemia (M5b)
Adult Acute Myeloblastic Leukemia With Maturation (M2)
Adult Acute Myeloblastic Leukemia Without Maturation (M1)
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Adult Acute Myelomonocytic Leukemia (M4)
Adult Erythroleukemia (M6a)
Adult Pure Erythroid Leukemia (M6b)
Untreated Adult Acute Myeloid Leukemia
Drug: daunorubicin hydrochloride
Drug: cytarabine
Drug: nilotinib
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Proportion of complete responses (CR or CRi) during induction therapy [ Time Frame: Up to 28 days ] [ Designated as safety issue: No ]
    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 (Duffy D 1987).


Secondary Outcome Measures:
  • Overall survival (OS) [ Time Frame: From registration to death due to any cause, assessed up to 3 years ] [ Designated as safety issue: No ]
    The distribution of survival time will be estimated using the method of Kaplan-Meier (Kaplan E 1958).

  • OS rate [ Time Frame: At 2 years ] [ Designated as safety issue: No ]
  • Disease-free survival time (DFS) [ Time Frame: From registration to relapse or death due to any cause, assessed up to 3 years ] [ Designated as safety issue: No ]
    The distribution of DFS will be estimated using the method of Kaplan- Meier.

  • DFS rate [ Time Frame: At 2 years ] [ Designated as safety issue: No ]
  • Duration of complete response [ Time Frame: 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 ] [ Designated as safety issue: No ]
    The distribution of duration of complete response will be estimated using the method of Kaplan-Meier.

  • Number of Participants with Adverse Events as a Measure of Safety and Tolerability assessed by NCI CTCAE version 4.0 out to 3 years [ Time Frame: Up to 3 years after completion of study treatment ] [ Designated as safety issue: Yes ]
    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.


Estimated Enrollment: 43
Study Start Date: July 2013
Estimated Study Completion Date: June 2017
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 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: daunorubicin hydrochloride
Given IV
Other Names:
  • Cerubidin
  • Cerubidine
  • daunomycin hydrochloride
  • daunorubicin
  • RP-13057
Drug: cytarabine
Given IV
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
Drug: nilotinib
Given PO
Other Names:
  • AMN 107
  • Tasigna
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

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 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Untreated, histological confirmed acute myeloid leukemia (AML) based on World Heath 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 =< 2 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 then 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 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
Please refer to this study by its ClinicalTrials.gov identifier: NCT01806571

Locations
United States, Arizona
Mayo Clinic in Arizona Not yet recruiting
Scottsdale, Arizona, United States, 85259
Contact: Mayo Clinic Clinical Trials Referral Office    507-538-7623      
Principal Investigator: Raoul Tibes, M.D., Ph.D.         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Mayo Clinic Clinical Trials Referral Office    507-538-7623    alkali.aref@mayo.edu   
Principal Investigator: Aref Al-Kali, M.D.         
Sponsors and Collaborators
Mayo Clinic
Investigators
Study Chair: Aref Al-Kali, M.D. Mayo Clinic
  More Information

No publications provided

Responsible Party: Aref Al-Kali, Principal Investigator, Mayo Clinic
ClinicalTrials.gov Identifier: NCT01806571     History of Changes
Other Study ID Numbers: MC1284, NCI-2013-00469
Study First Received: February 25, 2013
Last Updated: March 30, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia, Myeloid, Acute
Congenital Abnormalities
Leukemia
Leukemia, Basophilic, Acute
Leukemia, Eosinophilic, Acute
Leukemia, Erythroblastic, Acute
Leukemia, Megakaryoblastic, Acute
Leukemia, Monocytic, Acute
Leukemia, Myeloid
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Hypereosinophilic Syndrome
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Myelodysplastic-Myeloproliferative Diseases
Eosinophilia
Leukocyte Disorders
Cytarabine
Daunorubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on April 15, 2014