Oxaliplatin, Irinotecan, and Capecitabine in Treating Patients With Advanced or Metastatic Colorectal Cancer That Cannot Be Removed By Surgery

OBJECTIVES:

Primary

• Determine the maximum tolerated dose and recommended phase II dose of capecitabine administered in combination with oxaliplatin and irinotecan in patients with unresectable advanced or metastatic colorectal cancer. (Phase I)
• Determine the efficacy of this regimen in these patients. (Phase II)

Secondary

• Determine the tolerability of this regimen in these patients. (Phase II)

OUTLINE: This is a multicenter, phase I dose-escalation study of capecitabine followed by a phase II study.

• Phase I: Patients receive oxaliplatin IV over 2 hours on days 1 and 15, irinotecan IV over 1 hour on days 8 and 22, and oral capecitabine twice daily on days 1-29. Treatment repeats every 5 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of capecitabine 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.

• Phase II: Patients receive capecitabine at the MTD and irinotecan and oxaliplatin as in phase I.

After completion of study treatment, patients are followed every 2 months for 1 year and then every 4 months thereafter.

PROJECTED ACCRUAL: A total of 23-32 patients (3-12 for the phase I portion and 20 for the phase II portion) will be accrued for this study within 2.75 years

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed unresectable advanced or metastatic colorectal cancer
• Measurable disease (phase II only)

• At least 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan or MRI
• No presence or history of CNS metastases

PATIENT CHARACTERISTICS:

Age

• 18 to 70

Performance status

• WHO 0-1

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• Bilirubin ≤ 1.25 times upper limit of normal (ULN) (1.5 times ULN if liver metastases are present)
• AST and ALT ≤ 3 times ULN (5 times ULN if liver metastases are present)

Renal

• Creatinine clearance > 60 mL/min

Cardiovascular

• No New York Heart Association class III-IV congestive heart failure
• No symptomatic coronary artery disease
• No uncontrolled cardiac arrhythmia
• No myocardial infarction within the past year
• No other clinically significant cardiac disease

Immunologic

• No active autoimmune disease
• No uncontrolled infection
• No prior severe reaction to fluoropyrimidine therapy or known hypersensitivity to fluorouracil
• No known hypersensitivity to any component of study drugs

Other

• Not pregnant or nursing
• Negative pregnancy test
• Patients must use effective contraception during and for 1 year after study participation
• No other malignancy within the past 5 years except adequately treated carcinoma in situ of the cervix or localized nonmelanoma skin cancer
• No peripheral neuropathy > grade 1 of any origin (e.g., alcohol or diabetes)
• No nausea, vomiting, or malabsorption syndrome that would preclude ingestion or absorption of oral medication
• No psychiatric disability that would preclude study compliance
• No uncontrolled diabetes
• No other serious underlying medical condition that would preclude study participation
• No known dihydropyrimidine dehydrogenase deficiency

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent prophylactic hematopoietic growth factors

Chemotherapy

• More than 6 months since prior adjuvant fluoropyrimidine chemotherapy
• No other prior chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No concurrent radiotherapy

• Concurrent radiotherapy of a single painful lesion allowed

Surgery

• Not specified

Other

• More than 30 days since prior clinical trial participation
• No other concurrent experimental drugs
• No other concurrent anticancer therapy
• No concurrent sorivudine or its chemically-related analogues (e.g., lamivudine)