A Phase I Study of Vorinostat (Suberoylanilide Hydroxamic Acid [SAHA]) in Combination With Temozolomide in Patients With Malignant Gliomas
I. Determine the maximum tolerated dose (MTD) of vorinostat in combination with temozolomide
in patients with malignant gliomas.
II. Characterize the safety profile of vorinostat in combination with temozolomide in these
I. Characterize the pharmacokinetics of vorinostat (SAHA) in combination with temozolomide
in these patients.
II. Determine efficacy of vorinostat (SAHA) in combination with temozolomide as measured by
objective response in these patients.
I. Correlate response to treatment with the molecular phenotype of the tumor in these
OUTLINE: This is a 2-part, multicenter, dose-escalation study of vorinostat.
PART 1: Patients receive oral vorinostat once or twice daily on days 1-7 and 15-21 OR once
or twice daily on days 1-7. Patients also receive oral temozolomide once daily on days 1-5.
Treatment repeats every 28 days for up to 13 courses in the absence of disease progression
or unacceptable toxicity. Beginning in course 2, some patients may receive a higher dose of
temozolomide. Treatment may continue beyond 13 courses at the discretion of the
Cohorts of 3-6 patients receive escalating doses of vorinostat during course 1 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 dose-limiting toxicity. At least 6 patients are
treated at the MTD.
PART 2: Patients receive vorinostat and temozolomide as in part 1*.
[Note: *Beginning in course 2, all patients receive a higher dose of temozolomide.]
Cohorts of 3-6 patients receive de-escalating doses of vorinostat (beginning at the MTD
determined in part 1) during courses 1 and 2 until the MTD for part 2 is determined. The MTD
is defined as in part 1. An additional 6 patients are treated at the MTD.
After completion of study treatment, patients are followed periodically for survival.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
MTD of SAHA with Temozolomide defined as the dose at which less than one-third of patients experience DLT based on the CTC severity grading (Phase I)
North American Brain Tumor Consortium
United States: Food and Drug Administration
|Dana-Farber Cancer Institute||Boston, Massachusetts 02115|
|University of Wisconsin Hospital and Clinics||Madison, Wisconsin 53792-0001|
|University of Pittsburgh||Pittsburgh, Pennsylvania 15261|
|M D Anderson Cancer Center||Houston, Texas 77030|
|University of California San Francisco Medical Center-Mount Zion||San Francisco, California 94115|
|University of California at Los Angeles (UCLA )||Los Angeles, California 90095|
|North American Brain Tumor Consortium||Watertown, Massachusetts 02472|