A Phase I and Pharmacologic Study of the Proteasome Inhibitor PS-341 in Combination With Paclitaxel and Carboplatin in Patients With Advanced Malignancies
A Phase I and Pharmacologic Study of the Proteasome Inhibitor PS-341 in Combination With Paclitaxel and Carboplatin in Patients With Advanced Malignancies
Phase I trial to study the effectiveness of combining PS-341 and combination chemotherapy in treating patients who have advanced solid tumors. PS-341 may stop the growth of tumor cells by blocking the enzymes necessary for tumor cell growth. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining PS-341 and chemotherapy may kill more tumor cells
PRIMARY OBJECTIVES:
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 these patients.
III. Determine the clinical toxic effects and pharmacokinetics of this regimen in these patients.
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 months.
Inclusion Criteria:
Histologically confirmed malignancy for which no known standard therapy that is potentially curative or definitely capable of extending life expectancy exists
No hematologic malignancies
No symptomatic CNS metastases
Performance status - ECOG 0-2
At least 12 weeks
Absolute neutrophil count at least 1,500/mm^3
Platelet count at least 100,000/mm^3
Bilirubin no greater than 1.5 times upper limit of normal (ULN)
AST no greater than 2.5 times ULN
Creatinine no greater than 1.5 times ULN
No New York Heart Association class III or IV heart disease
HIV negative
No peripheral neuropathy grade 2 or greater
No uncontrolled infection
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
More than 4 weeks since prior biologic therapy
More than 4 weeks since prior immunotherapy
No prior bone marrow transplantation
No concurrent immunotherapy
More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
No other concurrent chemotherapy
More than 4 weeks since prior radiotherapy
No prior radiotherapy to more than 30% of bone marrow
No concurrent radiotherapy
No concurrent investigational ancillary therapy
No concurrent enrollment in another study involving a pharmacologic agent (e.g., drugs, biologics, immunotherapy, or gene therapy) for symptom control or therapeutic intents