A Phase 1 Study of Suberoylanilide Hydroxamic Acid (Vorinostat, SAHA) in Combination With Idarubicin in Relapsed or Refractory Leukemia
I. Determine the maximum tolerated dose and dose-limiting toxicities of vorinostat (SAHA) in
combination with standard-dose idarubicin in patients with relapsed or refractory acute
myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndromes, acute promyelocytic
leukemia, or chronic myelogenous leukemia in blastic phase.
II. Describe the clinical activity of this regimen in these patients. III. Determine the in
vivo molecular effects of this regimen, including the effects on DNA topoisomerase IIα mRNA
expression and on the induction of γH2AX, histone H3 and H4 acetylation, as well as changes
in the gene expression profile.
IV. Determine the pharmacokinetic characteristics of this regimen in these patients.
This is a randomized, dose-escalation study of vorinostat (SAHA). Patients are randomized to
1 of 2 treatment arms.
ARM I: Patients receive oral SAHA three times daily on days 1-14 and idarubicin IV over 15
minutes once daily on days 1-3. Treatment repeats every 21 days for 6 courses in the absence
of disease progression or unacceptable toxicity.*
ARM II: Patients receive oral SAHA three times daily and idarubicin IV over 15 minutes once
daily on days 1-3. Treatment repeats every 21 days for 6 courses in the absence of disease
progression or unacceptable toxicity.*
Note: *Patients completing 6 courses of therapy or who reach the maximum cumulative dose of
idarubicin or an equivalent anthracycline and achieve clinical benefit may continue
treatment with SAHA alone 3 times daily on days 1-14 of each course, in the absence of
disease progression or unacceptable toxicity.
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 2 of 3 or 2 of 6
patients experience a dose-limiting toxicity. An additional 10 patients are treated at the
Patients undergo blood collection and bone marrow biopsies periodically during the study for
pharmacologic, biomarker, and genetic studies.
After completion of study treatment, patients are followed at 4 weeks and then periodically
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum-tolerated dose (MTD) of vorinostat determined by dose-limiting toxicities (DLT) as measured by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.3.0
M.D. Anderson Cancer Center
United States: Food and Drug Administration
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