Phase I Trial of Vorinostat (NSC-701852, Suberoylanilide Hydroxamic Acid) and Doxorubicin (NSC-123127, Adriamycin)
I. Determine the safety and tolerability of vorinostat (SAHA) and doxorubicin hydrochloride
in patients with metastatic or locally advanced solid tumors.
II. Determine the maximum tolerated dose of vorinostat when administered with doxorubicin
hydrochloride in patients treated with this regimen.
I. Determine the response rate (complete response [CR] and partial response [PR]) and
clinical benefits rate (CR, PR, and stable disease > 12 weeks) in patients treated with this
II. Determine the pharmacokinetics and pharmacodynamics of vorinostat and doxorubicin
hydrochloride and their interaction.
III. Determine the effects of vorinostat on histone acetylation in peripheral blood
mononuclear cells and tumors.
IV. Determine the effects of vorinostat on DNA damage induced by doxorubicin hydrochloride
as a function of topoisomerase II expression.
V. Determine the effects of vorinostat on genes and proteins crucial for the maintenance of
OUTLINE: This is a non-randomized, open-label, dose-escalation study of vorinostat.
Patients receive oral vorinostat twice daily for 5 doses on days 1-3, 8-10, and 15-17 and
doxorubicin hydrochloride IV on days 3, 10, and 17. Treatment repeats every 28 days for up
to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with
responding or stable disease after 6 courses of treatment may continue to receive vorinostat
alone in the absence of disease progression.
Cohorts of 3-6 patients receive escalating doses of vorinostat 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. Up to15 patients are treated at the MTD.
Mandatory biopsies are required in these patients. Patients undergo blood collection and
tumor biopsies periodically during the study for pharmacologic, pharmacokinetic,
pharmacodynamic, and biomarker correlative studies.
After completion of study treatment, patients are followed for at least 30 days.
PROJECTED ACCRUAL: A total of 40 patients will be accrued to this study.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Safety and tolerability as assessed by NCI CTCAE v3.0
Up to 30 days after completion of treatment
H. Lee Moffitt Cancer Center and Research Institute
United States: Food and Drug Administration
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