This phase I trial studies the side effects and best dose of bortezomib when given together with fluorouracil and leucovorin calcium in treating patients with solid tumors that are metastatic or cannot be removed by surgery. Bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fluorouracil and leucovorin calcium, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bortezomib together with chemotherapy may be an effective treatment for solid tumors.
PRIMARY OBJECTIVES: I. To determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of PS-341 (bortezomib) 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 nuclear factor kappa-light chain enhancer of activated B cells (NFkB) inhibition in blood of patients treated with intravenous PS-341 combined with weekly fluorouracil (5-FU) and leucovorin calcium (LV). SECONDARY OBJECTIVES: 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 clinical toxicity. 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 dose-escalation study of bortezomib. Patients receive bortezomib intravenously (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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
30
University of Southern California
Los Angeles, California, United States
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
Time frame: Up to 21 days
Incidence of adverse events, graded according to NCI CTC version 2.0
The toxicities observed at each dose level will be summarized in terms of type, severity, time of onset, duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and course.
Time frame: Up to 7 years
Survival
Will be summarized with Kaplan-Meier plots.
Time frame: Up to 7 years
Time to failure
Will be summarized with Kaplan-Meier plots.
Time frame: Up to 7 years
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