A Phase I Study of PS-341 in Combination With 5-FU/LV in Solid Tumors
I. To determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of PS-341
when administered as a bolus injection two times a week (on days 1 and 4) for 2 weeks
followed by one week of rest.
II. To evaluate the pharmacodynamics of PS-341 by determining the 20S proteasome and NFkB
inhibition in blood of patients treated with intravenous PS-341 combined with weekly 5-FU
I. To identify any objective tumor response in patients treated with intravenous PS-341.
II. To evaluate the relationship between inhibition of the 20S proteasome and NFkB and
III. To obtain preliminary data on molecular correlates of response to PS-341 and 5-FU and
LV including genes involved in apoptosis, cell cycle control, transcriptional regulation and
adhesion/angiogenesis based on the mechanisms of PS-341 IV. To examine the pharmacokinetics
of 5-FU when co-administered with PS-341.
OUTLINE: This is a multicenter, dose-escalation study of bortezomib.
Patients receive bortezomib IV on days 1 and 4 and fluorouracil IV and leucovorin calcium IV
on day 1 weekly for 2 weeks. Treatment repeats every 3 weeks in the absence of disease
progression or unacceptable toxicity.
Cohorts of 3 to 6 patients receive escalating doses of bortezomib 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.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
MTD, defined as the highest dose tested in which none or only one patient experienced DLT attributable to the study drug(s), when at least 6 patients were treated at that dose and are evaluable for toxicity, graded according to the NCI CTC version 2.0
Up to 21 days
University of Southern California
United States: Food and Drug Administration
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