Decitabine, Cytarabine, and Daunorubicin Hydrochloride in Treating Patients With Acute Myeloid Leukemia

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01627041
First received: June 21, 2012
Last updated: September 16, 2014
Last verified: June 2014
  Purpose

This randomized phase II trial studies how well decitabine works when given together with daunorubicin hydrochloride and cytarabine in treating patients with acute myeloid leukemia. Drugs used in chemotherapy, such as decitabine, 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. Decitabine may help daunorubicin hydrochloride and cytarabine kill more cancer cells by making them more sensitive to the drugs. It is not yet known whether low-dose decitabine is more effective than high-dose decitabine when giving together with daunorubicin hydrochloride and cytarabine in treating acute myeloid leukemia.


Condition Intervention Phase
Adult Acute Basophilic Leukemia
Adult Acute Eosinophilic Leukemia
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 Myelomonocytic Leukemia (M4)
Secondary Acute Myeloid Leukemia
Untreated Adult Acute Myeloid Leukemia
Drug: daunorubicin hydrochloride
Drug: cytarabine
Drug: decitabine
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Phase II Study of Epigenetic Priming Using Decitabine With Induction Chemotherapy in Patients With Acute Myelogenous Leukemia (AML)

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Complete remission rate (CR1) [ Time Frame: After 1 course of decitabine-primed induction chemotherapy ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Complete remission rate (CR1 + CR2) [ Time Frame: After up to 2 courses of decitabine-primed induction chemotherapy ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: Time from entry on study to time of death from any cause, assessed up to 10 years ] [ Designated as safety issue: No ]
  • Relapse-free survival [ Time Frame: Time from CR documentation to either AML relapse or death from any cause, assessed up to 10 years ] [ Designated as safety issue: No ]
  • Event-free survival [ Time Frame: Time from entry on study until treatment failure (no CR with up to two study induction cycles), AML relapse, or death from any cause, assessed up to 10 years ] [ Designated as safety issue: No ]
  • Time to complete response determined according to the International Working Group (IWG) criterion [ Time Frame: Time from entry on study until documentation of CR, up to second course of induction chemotherapy ] [ Designated as safety issue: No ]
    95% confidence limits will be provided.

  • Remission duration [ Time Frame: Time from CR documentation to either AML relapse, assessed up to 10 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 180
Study Start Date: September 2011
Estimated Primary Completion Date: October 2022 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (daunorubicin hydrochloride, cytarabine)
Patients receive induction chemotherapy comprising daunorubicin hydrochloride IV daily on days 1-3 and cytarabine IV continuously on days 1-7 in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a CR after the first induction-chemotherapy course receive a second identical induction course.
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
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Experimental: Arm II (decitabine, daunorubicin hydrochloride, cytarabine)
Patients receive decitabine IV over 1 hour on days -5 to -1. Patients then receive induction chemotherapy as in arm I in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a CR after the first induction-chemotherapy course receive a second identical induction course.
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: decitabine
Given IV
Other Names:
  • 5-aza-dCyd
  • 5AZA
  • DAC
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Detailed Description:

OBJECTIVES: Primary I. To "Pick a Winner" by deciding whether further development of epigenetic priming with decitabine prior to standard "7+3" induction chemotherapy should be pursued.

Secondary I. To determine whether epigenetic priming with decitabine prior to standard cytarabine and daunorubicin hydrochloride "7+3" induction chemotherapy has sufficient efficacy to warrant further development as assessed by an overall CR1 rate ≥ 50%.

II. To establish the safety and expected toxicities of decitabine when used as priming for cytarabine and daunorubicin hydrochloride "7+3" induction chemotherapy in acute myeloid leukemia (AML).

III. To assess the pharmacodynamics of deoxyribonucleic acid (DNA) hypomethylation when decitabine is administered as a short infusion.

IV. To investigate, in selected cases, the molecular and cellular consequences of decitabine-induced hypomethylation by assessing the effects of decitabine-mediated hypomethylation on transcriptional patterns in AML cells, and by determining the effect of hypomethylation on the differentiation and/or apoptosis of leukemic blasts. (exploratory) V. To identify biomolecular correlates of treatment response (biomarkers) to induction chemotherapy in AML based upon the epigenetic pattern of DNA methylation in AML specimens obtained prior to treatment. (exploratory)

OUTLINE: This is a multicenter study. Patients are stratified according to age (less than 50 years vs 50-65 years), white blood cell count (≤ 30 K/mL vs greater than 30 K/mL), cytogenetic risk group (intermediate vs adverse risk), and antecedent hematological condition preceding the diagnosis of acute myeloid leukemia (yes vs no). Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients receive induction chemotherapy comprising daunorubicin hydrochloride intravenously (IV) daily on days 1-3 and cytarabine IV continuously on days 1-7 in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a complete remission (CR) after the first induction-chemotherapy course receive a second identical induction course.

Arm II: Patients receive decitabine IV over 1 hour on days -5 to -1. Patients then receive induction chemotherapy as in arm I in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a CR after the first induction-chemotherapy course receive a second identical induction course.

Patients undergo blood, bone marrow, and oral mucosa cells sample collection at baseline, prior to induction therapy, and after treatment for DNA methylation studies and pharmacodynamic studies.

After completion of study treatment, patients are followed up for up to 10 years.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of acute myeloid leukemia (AML) as defined by the World Health Organization
  • Molecular AML-risk group is less-than-favorable as defined by any of the following criteria:

    • The absence of good-risk karyotype t(8;21), inv(16), t(16;16), or t(15;17)identified by metaphase karyotype
    • The absence of t(8;21), inv(16), t(16;16), or t(15;17) identified by fluorescent in situ hybridization(FISH)
    • The absence of the corresponding fusion transcripts, AML1-eight-twenty-one corepressor (ETO), core-binding factor, beta subunit (CBFβ)-smooth muscle myosin heavy chain (SMMHC), or progressive multifocal leukoencephalopathy (PML)-retinoic acid receptor alpha (RARa), identified by reverse transcriptase-polymerase chain reaction (RT-PCR)
    • Patient does not have acute promyelocytic leukemia (APL, French-American-British [FAB] M3)
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
  • Adequate cardiac function as defined by either of the following:

    • An echocardiogram demonstrating an ejection fraction within normal limits
    • A multi gated acquisition (MUGA) scan demonstrating an ejection fraction within normal limits
  • Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 times institutional upper limit of normal (ULN)
  • Creatinine ≤ 2 mg/dL OR creatinine clearance ≥ 50 mL/min
  • Total bilirubin ≤ 2 times ULN

    • Patients with documented diagnosis of Gilbert syndrome resulting in elevated total bilirubin levels will be eligible, provided all other eligibility criteria are met
    • Patients with a total bilirubin of 2-3 mg/dL and direct (conjugated) bilirubin in the normal range will be eligible, provided all other eligibility criteria are met
  • Pregnant and nursing subjects may not be enrolled and pregnancy must be avoided; women of child-bearing potential—defined as a sexually active woman who has not undergone hysterectomy and who has had menses any time within the preceding 24 months—must have a negative serum or urine pregnancy test within 7 days prior to registration; women and men of childbearing potential must either commit to continued abstinence from heterosexual intercourse or commit to two acceptable methods of birth control—one highly effective method (e.g., IUD, oral or non-oral hormonal contraceptive, tubal ligation or partner's vasectomy) and one additional effective method (e.g., latex condom, diaphragm or cervical cap) at the same time from the time of screening through final Treatment Response Assessment

    • NOTE: should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, the subject should inform their treating phy-sician immediately
    • NOTE: the effects of decitabine on the developing human fetus are unknown but it is a know teratogen in mammals (mice)
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Chemotherapy (other than hydroxyurea) or radiation within the 2 weeks prior to planned therapy on this study or ongoing adverse events due to agents administered more than 2 weeks earlier
  • Concurrent treatment with other investigational agents is not permitted
  • Cumulative lifetime dose of anthracycline chemotherapeutic > 80 mg/m^2
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition of decitabine, cytarabine or daunorubicin
  • Uncontrolled intercurrent illness considered by the investigator to constitute an unwarranted high risk for investigational drug treatment; examples include, but not limited to the following:

    • Uncontrolled serious infection; or
    • Unstable angina pectoris; or
    • Uncontrolled cardiac arrhythmia; or
    • Active second malignancy requiring treatment; or
    • Symptomatic congestive heart failure
  • HIV-positive subjects with a CD4 count < 200 cells/μL are excluded due to the increased risk of lethal infections when treated with marrow-suppressive chemotherapy(87)

    • NOTE: subjects with HIV infection and a CD4 count >= 200 cells/μL are eligible but combination antiretroviral therapy should be held during administration of chemotherapy due to the potential for pharmacokinetic interactions with decita-bine, cytarabine or daunorubicin. Antiretroviral therapy may be resumed 24 hours after completion of the last dose of induction chemotherapy
  • Subject has a psychiatric disorder, altered mental status or social situation that would preclude understanding of the informed consent process and/or limit compliance with study requirements
  • Subject has an inability or unwillingness, in the opinion of the investigator, to comply with the protocol requirements
  • Subjects with central nervous system (CNS) (or leptomeningeal) infiltration by AML may be considered for treatment at the Investigator's discretion and following discussion with the Principle Investigator; all neurologic deficits must be noted prior to enrollment on study
  • Subject has circulating blast count > 50,000/μL (subjects may be enrolled if circulating blast count is controlled by hydroxyurea and/or, if clinically indicated, by leukophoresis)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01627041

Locations
United States, Maine
Lafayette Family Cancer Center-EMMC Recruiting
Brewer, Maine, United States, 04412
Contact: Thomas H. Openshaw    207-973-7478    topenshaw@emhs.org   
Principal Investigator: Thomas H. Openshaw         
United States, New York
Albert Einstein College of Medicine Active, not recruiting
Bronx, New York, United States, 10461
Montefiore Medical Center - Moses Campus Active, not recruiting
Bronx, New York, United States, 10467-2490
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Joseph M. Scandura    212-746-1848    jms2003@med.cornell.edu   
Principal Investigator: Joseph M. Scandura         
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Martin S. Tallman    212-639-3245    m-tallman@northwestern.edu   
Principal Investigator: Martin S. Tallman         
Weill Medical College of Cornell University Recruiting
New York, New York, United States, 10065
Contact: Joseph M. Scandura    212-746-1848      
Principal Investigator: Joseph M. Scandura         
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Mark G. Frattini    212-305-8615      
Principal Investigator: Mark G. Frattini         
United States, Ohio
Case Western Reserve University Recruiting
Cleveland, Ohio, United States, 44106
Contact: Brenda W. Cooper    800-641-2422      
Principal Investigator: Brenda W. Cooper         
Ohio State University Medical Center Active, not recruiting
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
Investigators
Principal Investigator: Joseph Scandura Weill Medical College of Cornell University
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01627041     History of Changes
Other Study ID Numbers: NCI-2012-01959, NCI-2012-01959, CDR0000712322, 1106011736, 8854, N01CM62204
Study First Received: June 21, 2012
Last Updated: September 16, 2014
Health Authority: United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on September 18, 2014