A Phase I Study of Suberoylanilide Hydroxamic Acid (SAHA) in Combination With Flavopiridol in Advanced Solid Tumors
I. Determine the maximum tolerated dose of vorinostat (SAHA) when given in combination with
flavopiridol (alvocidib) in patients with advanced solid tumors.
II. Obtain preliminary data on the therapeutic activity of SAHA and flavopiridol in these
III. Evaluate the role of p21, p53, and apoptotic markers relative to treatment response in
patients treated with this regimen.
OUTLINE: This is a multicenter, open label, non-randomized, dose-escalation study of
Before beginning course 1 of study therapy, patients receive oral SAHA on days 1-3 in order
to ensure tolerability of the drug. Beginning 1 week later, patients receive oral SAHA once
daily on days 1-3 and 8-10 and fixed-dose alvocidib intravenously (IV) over 1 hour on days
2 and 9. Treatment repeats every 21 days in the absence of disease progression or
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 6 patients
experience dose-limiting toxicity. An additional 10 patients are treated at the MTD of SAHA
in combination with fixed-dose alvocidib. Once the MTD of SAHA in combination with
fixed-dose alvocidib is determined, patients receive oral SAHA at one dose level below the
MTD once daily on days 1-3 and 8-10 and divided-dose alvocidib IV over 30 minutes followed
by alvocidib IV over 4 hours on days 2 and 9. Treatment repeats every 21 days in the absence
of disease progression or unacceptable toxicity. If this schedule is well-tolerated, the MTD
of SAHA in combination with divided-dose flavopiridol is determined as above. An additional
10 patients are treated at the MTD of SAHA in combination with divided-dose alvocidib.
Patients undergo blood draws on days 1 and 9 of course 1 for pharmacokinetic analysis.
After completion of study treatment, patients are followed for 4 weeks.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose of vorinostat when administered in combination with a fixed dose of weekly flavopiridol
Defined as the dose one level below the dose at which two or more of the patients in the initial cohort experience dose limiting toxicities (DLT) during the first treatment course. Graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 Term.
Memorial Sloan-Kettering Cancer Center
United States: Food and Drug Administration
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