A Phase I/II Study of Vorinostat [Suberoylanilide Hydroxamic Acid (SAHA)] in Combination With Azacitidine in Patients With the Myelodysplastic Syndrome (MDS)
I. To evaluate the safety and toxicity of vorinostat in combination with azacitidine in
patients with MDS and some select patients with AML (step 1).
II. To identify doses of both vorinostat and Azacitidine for safe combination of the 2
agents that can be administered in repetitive cycles over time for use in phase II studies.
III. To determine the response rate of patients treated with the combination of SAHA and
azacitidine at the doses established as safe and effective in Step 1 in an expanded cohort
of patients with MDS.
IV. To obtain preliminary data on the effects of treatment with the combination of
VORINOSTAT and Aza C in patients with MDS on a series of biologic surrogate markers
including: DNA methylation of specific genes (e.g. p15); histone acetylation; hematopoietic
progenitor growth and differentiation; the fate of the MDS clone and changes in gene
expression by array profiling.
I. Determine effect of treatment with the combination on time to response, time to leukemic
transformation and frequency of transformation to leukemia in patients with MDS during the
phase II segment of the study.
OUTLINE: This is a multicenter, phase I, dose-escalation study followed by an open-label
phase II study.
PHASE I: Patients receive azacitidine subcutaneously (SC) once daily on days 1-7 and
vorinostat (SAHA) orally (PO) 2-3 times daily on days 3-5, 3-9, or 3-16. Treatment repeats
every 28 days for at least 4 courses in the absence of disease progression or unacceptable
toxicity. Cohorts of 3-6 patients receive escalating doses of azacitidine and vorinostat
(SAHA) until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose
preceding that at which at least 2 of 6 patients experience dose-limiting toxicity.
PHASE II: Patients receive azacitidine and vorinostat (SAHA) at the safe dose and duration
determined in phase I.
After completion of study treatment, patients are followed monthly for 6 months and then
every 2 months thereafter.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Incidence of toxicities of vorinostat (SAHA) in combination with azacitidine graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 (Phase I)
Exact 95% confidence intervals around the toxicity proportions will be calculated to assess the precision of the obtained estimates.
Up to 1 month post-treatment
Montefiore Medical Center
United States: Food and Drug Administration
|Albert Einstein College of Medicine||Bronx, New York 10461|
|Weill Medical College of Cornell University||New York, New York 10021|
|Mount Sinai Medical Center||New York, New York 10029|
|Montefiore Medical Center||Bronx, New York 10467-2490|
|University of Maryland Greenebaum Cancer Center||Baltimore, Maryland 21201|