A Dose Finding Phase I Trial of the Combination of Topotecan and PS-341, a Novel Proteasome Inhibitor, in Advanced Malignancies
I. Determine the safety of the combination of PS-341 and topotecan. II. Determine the dose
limiting toxicities and maximum tolerated dose as well as the recommended phase II doses of
III. Assess the pharmacokinetics of topotecan alone and in combination with PS-341.
I. Estimate the objective response rate of a combination of PS-341 and topotecan delivered
on days 1-5 every three weeks as defined by the RECIST criteria.
II. Assess the pharmacodynamics of topo I levels. III. Determine the expression of the DNA
repair enzyme XRCC1 in tumor biopsies.
OUTLINE: This is a dose-escalation study.
Patients receive topotecan IV over 30 minutes on days 1-5. Beginning with course 2, patients
also receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 3
weeks in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of topotecan and bortezomib until the
maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which no more
than 1 of 6 patients experience dose-limiting toxicity.
PROJECTED ACCRUAL: A total of 20-25 patients will be accrued for this study.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Dose limiting toxicities
Up to 3 years
United States: Food and Drug Administration
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