Phase I Study of Decitabine, Vorinostat, and Cytarabine in Acute Myeloid Leukemia
I. To determine the maximum tolerated dose (MTD) of the combination of decitabine,
vorinostat, and cytarabine in patients with relapsed/refractory acute myeloid leukemia (AML)
and select subsets of high risk leukemia/myelodysplastic syndromes (MDS).
II. To define the specific toxicities and the dose limiting toxicity (DLT) of the
I. To develop a platform for specifically targeting MLL PTD, for future efficacy studies.
II. To determine the overall response rate (ORR) of this regimen in relapsed/ refractory
III. To examine the role of decitabine and vorinostat in re-expression of MLL- WT in
patients with MLL PTD via correlative studies specific to patients with MLL PTD and the
preliminary relationship of this to clinical response in patients with MLL PTD+ AML.
IV. To correlate the biological activity of decitabine as demethylating agent (changes in
target gene methylation and gene expression, DNMT1 protein expression, global methylation)
with clinical endpoints V. To explore the biologic role of microRNAs in determining clinical
response to the combination and achievement of the other pharmacodynamic endpoints.
OUTLINE: This is a dose-escalation study of cytarabine.
INDUCTION THERAPY: Patients receive decitabine IV over 1 hour on days 1-10; oral vorinostat
on days 5-10; and high-dose cytarabine IV over 2 hours on days 12, 14, and 16 in the absence
of disease progression or unacceptable toxicity. Patients who achieve complete response (CR)
proceed to maintenance therapy. Patients who achieve CR with incomplete blood count recovery
undergo bone marrow aspiration and biopsy at count recovery or day 42 before proceeding to
MAINTENANCE THERAPY: Patients receive decitabine IV over 1 hour on days 1-5 and oral
vorinostat on days 5-10. Treatment repeats every 28 days for up to 11 courses in the absence
of disease progression or unacceptable toxicity.
Blood samples and additional bone marrow aspirate and biopsy are collected at baseline and
during study for re-expression of mixed lineage leukemia-wild-type, changes in target gene
methylation and gene expression, DNMT1 protein expression, global methylation, and other
After completion of study therapy, patients are followed up for 30 days.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
MTD of decitabine and vorinostat, determined according to incidence of DLT graded using NCI CTCAE version 4.0
Ohio State University
United States: Food and Drug Administration
|Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center||Columbus, Ohio 43210-1240|
|M D Anderson Cancer Center||Houston, Texas 77030|