Trial Information

Phase II Study of Maintenance Therapy With Decitabine (NSC #127716, IND #50733) Following Standard Induction and Cytogenetic Risk-Adapted Intensification in Previously Untreated Patients With AML < 60 Years

PRIMARY OBJECTIVES:

I. To determine the efficacy, feasibility, and toxicities when one year of maintenance
therapy with decitabine is given to patients < 60 years with untreated AML who achieve and
maintain first CR following an established induction and intensification regimen.

II. To determine the 1-year disease free survival rate for AML patients in first CR treated
with maintenance decitabine.

SECONDARY OBJECTIVES:

I. To measure biologic response to decitabine in evaluable patients with fusion genes to
determine eradication of minimal residual disease.

II. To measure surrogates for DNA demethylation including downregulation of DNMT1 and
induction of fetal hemoglobin.

III. To examine the significance of gene re expression following ex vivo decitabine exposure
in primary AML cells taken at the time of diagnosis on clinical outcome and on gene
expression at the time of relapse after in vivo decitabine exposure.

IV. To continue to evaluate the effectiveness of a cytogenetically risk-adapted approach for
consolidation therapy for patients with CBF or non-CBF AML.

V. To continue the investigation begun in CALGB 19808 aimed at correlation of the rate of
relapse and toxicity with IV busulfan pharmacokinetics when busulfan and etoposide are used
as the preparative regimen for autologous stem cell transplantation for AML patients in
first CR.

VI. To correlate outcome measures such as CR, DFS, EFS, and OS, with pretreatment
characteristics such as age, sex, race, blood counts, morphology, immunophenotype,
cytogenetics, and molecular features of AML.

OUTLINE: This is a multicenter study.

REMISSION INDUCTION THERAPY: Patients receive cytarabine IV over 168 hours on days 1-7 and
daunorubicin hydrochloride IV over 5-10 minutes and etoposide IV over 2 hours on days 1-3.
Patients undergo bone marrow biopsy on day 14. Patients with residual leukemia proceed to
second remission induction therapy. Patients achieving complete remission (CR) proceed to
intensification therapy.

SECOND REMISSION INDUCTION THERAPY: Patients receive cytarabine IV over 120 hours on days
1-5 and daunorubicin hydrochloride IV and etoposide IV over 2 hours on days 1 and 2.
Patients undergo bone marrow biopsy on day 42. Patients with residual leukemia are removed
from the study. Patients achieving CR proceed to intensification therapy.

INTENSIFICATION THERAPY: Patients are stratified and receive intensification therapy
according to cytogenetic findings (favorable cytogenetics [t(8;21)(q22q22),
inv(16)(p13;q22), or t(16;16)(p13;q22) by cytogenetic and/or molecular analysis] vs
unfavorable cytogenetics [all other cytogenetic findings, including normal cytogenetics]).

FAVORABLE CYTOGENETICS: Within 2-4 weeks after achieving CR, patients receive high-dose
cytarabine IV over 3 hours twice daily on days 1, 3, and 5.

Treatment repeats every 28 days for up to 3 courses.

UNFAVORABLE CYTOGENETICS: Peripheral blood stem cell (PBSC) mobilization: Within 2-4 weeks
after achieving CR, patients receive etoposide IV over 96 hours and high-dose cytarabine IV
over 2 hours twice daily on days 1-4 and filgrastim (G-CSF) subcutaneously (SC) once daily
beginning on day 14 and continuing until blood counts recover. Patients then proceed to
transplantation.

PBSC OR BONE MARROW TRANSPLANTATION: Patients receive busulfan IV over 2 hours 4 times daily
on days -7 to -4 and etoposide IV over 4 hours on day -3. Patients undergo autologous PBSC
or bone marrow transplantation on day 0 and receive G-CSF SC once daily beginning on day 0
and continuing until blood counts recover.

UNFAVORABLE CYTOGENETICS AND UNABLE TO UNDERGO PBSC TRANSPLANTATION: Within 2-4 weeks after
achieving CR, patients receive etoposide, high-dose cytarabine, and G-CSF as in unfavorable
cytogenetics (PBSC mobilization) followed by 2 courses of high-dose cytarabine as in
favorable genetics.

MAINTENANCE THERAPY: Within 60-90 days after completion of intensification therapy, patients
receive decitabine IV over 1 hour on days 1-5. Treatment repeats every 6 weeks for up to 8
courses.

Blood and bone marrow samples are obtained periodically during study therapy for cytogenetic
analysis.

After completion of study treatment, patients are followed up every 2 month for 1 year,
every 6 months for 3 years, and then at 1 year.