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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
178
Lafayette Family Cancer Center-EMMC
Brewer, Maine, United States
Roswell Park Cancer Institute
Buffalo, New York, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York, New York, United States
Memorial Sloan Kettering Cancer Center
New York, New York, United States
NYP/Weill Cornell Medical Center
New York, New York, United States
Montefiore Medical Center-Weiler Hospital
The Bronx, New York, United States
Montefiore Medical Center - Moses Campus
The Bronx, New York, United States
Case Western Reserve University
Cleveland, Ohio, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
Complete remission rate (CR1)
Time frame: After 1 course of decitabine-primed induction chemotherapy
Complete remission rate (CR1 + CR2)
Time frame: After up to 2 courses of decitabine-primed induction chemotherapy
Overall survival
Time frame: Time from entry on study to time of death from any cause, assessed up to 10 years
Relapse-free survival
Time frame: Time from CR documentation to either AML relapse or death from any cause, assessed up to 10 years
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
Time to complete response determined according to the International Working Group (IWG) criterion
95% confidence limits will be provided.
Time frame: Time from entry on study until documentation of CR, up to second course of induction chemotherapy
Remission duration
Time frame: Time from CR documentation to either AML relapse, assessed up to 10 years
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