A Phase I and Pharmacologic Study of the Proteasome Inhibitor PS-341 in Combination With Paclitaxel and Carboplatin in Patients With Advanced Malignancies
I. Determine the maximum tolerated dose of bortezomib and paclitaxel administered in
combination with carboplatin in patients with advanced solid tumors.
II. Compare the tolerability and efficacy of the different sequences of this regimen in
III. Determine the clinical toxic effects and pharmacokinetics of this regimen in these
IV. Determine, preliminarily, the therapeutic activity of this regimen in these patients.
V. Evaluate p53 accumulation as a marker of PS-341 activity, and the effect of
paclitaxel/carboplatin on PS-341 induced accumulation of p53.
VI. Exam the effect of PS-341 on the levels of other proteasome targets, e.g. mdm2, p27,
p21, cyclins B, D1,E; IκB and other ubiquitinated proteins in tumor tissue, when available.
OUTLINE: This is a dose-escalation study of bortezomib and paclitaxel. Patients are assigned
to 1 of 2 treatment groups.
Group A: Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on
day 1 and bortezomib IV over 3-5 seconds on days 2, 5, and 8.
Group B: Patients receive bortezomib IV over 3-5 seconds on days 1, 4, and 8 and paclitaxel
IV over 3 hours and carboplatin IV over 30 minutes on day 2.
Treatment in both groups repeats every 3 weeks in the absence of disease progression or
unacceptable toxicity. After 6 courses of paclitaxel and carboplatin, patients with stable
or responding disease may continue with bortezomib alone at the discretion of the
investigator. Cohorts of 3-6 patients in each group receive escalating doses of bortezomib
and paclitaxel until the maximum tolerated dose (MTD) is determined. The MTD is defined as
the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity.
Patients are followed at 3 months.
PROJECTED ACCRUAL: A total of 24-96 patients will be accrued for this study within 25
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
MTD of paclitaxel, bortezomib, and carboplatin defined as the highest safely-tolerated dose where =< 1 patient experience dose-limiting toxicity (DLT) with the next higher dose having at least 2 patients who experience DLT as assessed by CTC version 2.0
United States: Food and Drug Administration
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