Bortezomib, Fluorouracil, Leucovorin, and Oxaliplatin in Treating Patients With Advanced or Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as fluorouracil, leucovorin, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It may also help the chemotherapy drugs work better by making tumor cells more sensitive to the drugs. Giving bortezomib with fluorouracil, leucovorin, and oxaliplatin may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of bortezomib when given with fluorouracil, leucovorin, and oxaliplatin in treating patients with advanced or metastatic colorectal cancer.

Detailed Description
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OBJECTIVES: Primary Determine the dose-limiting toxicity and maximum tolerated dose of bortezomib when administered with fluorouracil, leucovorin calcium, and oxaliplatin in patients with advanced or metastatic colorectal cancer. Determine the recommended phase II dose of bortezomib in patients treated with this regimen. Secondary Determine response in patients with measurable disease treated with this regimen. OUTLINE: This is an open-label, non-randomized, multicenter, dose-escalation study of bortezomib. Patients receive bortezomib IV over 3-5 seconds on days 1, 8, and 15; oxaliplatin IV over 2 hours on days 1 and 15; and leucovorin calcium IV over 2 hours and fluorouracil IV over 22 hours on days 1, 2, 15, and 16. Courses repeat every 28 days 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. Additional patients receive treatment at the MTD to a maximum of 12 patients at that dose level. Patients are followed every 8 weeks until disease progression or start of a new anticancer treatment. PROJECTED ACCRUAL: Not specified.

Official Title
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Phase I Study of PS-341 (VELCADE) in Combination With 5FU/LV Plus Oxaliplatin in Patients With Advanced Colorectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: bortezomib
* Drug: fluorouracil
* Drug: leucovorin calcium
* Drug: oxaliplatin


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed advanced or metastatic colorectal cancer Amenable to first-line treatment with oxaliplatin, fluorouracil, and leucovorin calcium for advanced or metastatic disease No symptomatic or radiologic evidence of brain metastases PATIENT CHARACTERISTICS: Age Over 18 Performance status ECOG 0-1 Life expectancy Not specified Hematopoietic Absolute neutrophil count ≥ 2,000/mm^3 Platelet count ≥ 100,000/mm^3 Hepatic Bilirubin ≤ 1.5 times upper limit of normal (ULN) Alkaline phosphatase ≤ 2.5 times ULN (5 times ULN if liver metastases are present) AST and ALT ≤ 2.5 times ULN (5 times ULN if liver metastases are present) Renal Creatinine ≤ 1.7 mg/dL Cardiovascular No ischemic heart disease within the past 6 months No clinically significant ECG changes Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No baseline neuropathy > grade 1 No other prior or concurrent malignancy except cone-biopsied carcinoma of the cervix or adequately treated basal cell or squamous cell skin cancer No unstable systemic disease No active uncontrolled infection No psychological, familial, sociological, or geographical condition that would preclude study participation No hypersensitivity to bortezomib, boron, or mannitol PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy No prior oxaliplatin No prior chemotherapy for advanced or metastatic disease At least 6 months since prior adjuvant chemotherapy Endocrine therapy Not specified Radiotherapy More than 4 weeks since prior radiotherapy Surgery More than 14 days since prior major surgery

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: bortezomib|nan|
|Drug: fluorouracil|nan|
|Drug: leucovorin calcium|nan|
|Drug: oxaliplatin|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose and recommended dose of bortezomib as measured by CTC v3.0 |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as measured by CTC v3.0 |  |  | 
| Response as measured by RECIST every 8 weeks |  |  | 
| Time to progression as measured by Kaplan Meier and RECIST every 8 weeks |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage III colon cancer, stage IV colon cancer, stage III rectal cancer, stage IV rectal cancer, recurrent colon cancer, recurrent rectal cancer