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

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.

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