Phase I Study of Vorinostat (Suberoylanilide Hydroxamic Acid, or SAHA) in Combination With Cytosine Arabinoside (Ara-C) and Etoposide for Patients With Relapsed and/or Refractory Acute Leukemias, Myelodysplasias and Myeloproliferative Disorders
I. Determine the feasibility, tolerability, and toxicities, in terms of the maximum
tolerated dose (MTD), of the sequential combination of vorinostat (SAHA) followed by
cytarabine and etoposide in patients with relapsed and/or refractory acute leukemia or
transforming myelodysplastic syndromes or myeloproliferative disorders.
II. Determine whether the addition of SAHA to cytarabine and etoposide chemotherapy improves
outcome, in terms of complete response rate, duration of response, and overall survival, in
III. Determine the effects of SAHA on induction of tumor necrosis factor-related
apoptosis-inducing ligand (TRAIL)-death receptors DR4 and DR5 and other pro-apoptotic
mediators in patient-derived cancer cells (leukemia blast cells) and somatic cells (buccal
mucosa cells, using pre-SAHA and on SAHA treatment samples).
IV. Determine the ability of SAHA to block leukemia blast cells in the G1 phase of the cell
cycle (leukemia blast cells, using pre-SAHA and on SAHA treatment samples).
V. Determine the effects of SAHA on the expression of P-glycoprotein/MDR1/ABCB1, and the
breast cancer resistance protein (BCRP/ABCG2), using functional and mRNA/protein assays for
these transporters (leukemia blast cells, using pre-SAHA and on SAHA treatment samples).
OUTLINE: This is a dose-escalation study of vorinostat (SAHA).
Patients receive oral SAHA two or three times daily on days 1-7 and cytarabine intravenously
(IV) over 3 hours twice daily and etoposide IV over 1 hour once daily on days 11-14.
Treatment repeats approximately every 6-7 weeks for up to 3 courses in the absence of
disease progression or unacceptable toxicity.
Patients who achieve complete response after 1 course of therapy may receive 1 or 2 more
courses of therapy. Patients who achieve partial response after 1 course of therapy may
receive 1 more course of therapy. Cohorts of 3-6 patients receive escalating doses of SAHA
until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose
preceding that at which 1 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once
the MTD is determined, an additional 10 patients are treated at that dose. Blood, buccal
cells, and bone marrow samples are collected prior to and during treatment. Samples are used
for pharmacokinetic and pharmacodynamic studies, protein expression studies, and gene
expression profiling. After completion of study treatment, patients are followed within 30
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose (MTD) of vorinostat (SAHA) in combination with cytarabine and etoposide
Based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
University of Maryland Greenebaum Cancer Center
United States: Food and Drug Administration
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