Phase I trial to study the effectiveness of combining bortezomib with paclitaxel in treating patients who have advanced or metastatic solid tumors. Bortezomib may stop the growth of cancer cells by blocking the enzymes necessary for their growth. Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Combining bortezomib with paclitaxel may kill more tumor cells.
PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose of bortezomib when given in combination with paclitaxel in patients with locally advanced or metastatic solid tumors. OUTLINE: This is a multicenter, dose-escalation study of bortezomib. Patients receive bortezomib IV on days 2 and 9 and paclitaxel IV over 1 hour on days 1 and 8. For the first course only, patients do not receive paclitaxel on day 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 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 or greater than 80% 20S proteasome inhibition. Once the MTD is determined, an additional 6-9 patients are accrued and treated at that dose. Patients are followed at 21 days. PROJECTED ACCRUAL: A total of 45 patients will be accrued for this study.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
45
Ohio State University Medical Center
Columbus, Ohio, United States
Dose-limiting toxicity (DLT) defined as Common Terminology Criteria (CTC) version 2.0 grade 3 or greater non-hematologic toxicity or grade 4 hematologic toxicity with the exception of asymptomatic neutropenia [ANC < 500]
Time frame: 21 days
Maximum-tolerated dose (MTD) based on the incidence of DLT
Time frame: 21 days
Dose of PS-341 that results in not more than 70% to 80% 20S proteasome inhibition [20S-PI] in combination with a paclitaxel
Time frame: At baseline and at 1 hour of weeks 1, 2 and 4
Response according to the Response Evaluation Criteria in Solid Tumors (RECIST) Committee
Reported descriptively using all eligible patients and evaluable patients separately. Response rates will include 95% confidence limits.
Time frame: Up to 21 days
Change in the level of p27 and Bax proteins in peripheral blood mononuclear cells
Descriptive data will be computed and compared using analysis of variance and non-parametric rank equivalents for continuous data and chi-square or Fisher's exact test for discrete data.
Time frame: From baseline to 6 hours of day 1 (week 1) and day 2 (week 2)
Change in plasma levels of TNF, IL-1, IL-6, and C-reactive protein
Descriptive data will be computed and compared using analysis of variance and non-parametric rank equivalents for continuous data and chi-square or Fisher's exact test for discrete data.
Time frame: From baseline to 6 hours of day 2 (weeks 1 and 2)
Change in NF-kb biomarkers TRAP I and c-IAP-2 in tumor tissue blocks
Descriptive data will be computed and compared using analysis of variance and non-parametric rank equivalents for continuous data and chi-square or Fisher's exact test for discrete data.
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Time frame: From baseline to 6 hours of day 2 (weeks 1 and 2)
Change in phosphorylation of c-Jun and JNK in tumor tissue blocks
Descriptive data will be computed and compared using analysis of variance and non-parametric rank equivalents for continuous data and chi-square or Fisher's exact test for discrete data.
Time frame: From baseline to 6 hours of day 2 (weeks 1 and 2)