OBJECTIVES:

• Determine the recommended phase II dose of gefitinib when administered in combination with oxaliplatin in patients with metastatic or locally recurrent colorectal cancer.
• Determine the dose-limiting toxicity of this regimen in these patients.
• Compare the time to progression, objective response rate, and median and overall survival in patients treated with oxaliplatin with or without gefitinib.
• Compare the toxicity of these regimens in these patients.

OUTLINE: This is a phase I dose-escalation study of gefitinib followed by a phase II randomized, multicenter study. Patients are stratified according to ECOG performance status (0 vs 1-2).

• Phase I: Patients receive oxaliplatin IV over 2 hours on day 1 and oral gefitinib once daily on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of gefitinib 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 are randomized to one of two treatment arms.

  • Arm I: Patients receive oxaliplatin IV over 2 hours on day 1.
  • Arm II: Patients receive oxaliplatin as in arm I and oral gefitinib once daily at the MTD on days 1-21.

In both arms, treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients in arm II with stable or responding disease after 6 courses may continue to receive gefitinib alone until disease progression.

PROJECTED ACCRUAL: Approximately 77 patients (9 for phase I and 68 for phase II) will be accrued for this study within 12-14 months.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed adenocarcinoma of the colon or rectum that is not amenable to potentially curative surgical resection
• Metastatic or locally recurrent disease
• Tumor in liver or lung accessible to needle biopsy by ultrasound or CT scan guidance

• At least 1 measurable lesion

  • At least 20 mm by conventional techniques, including physical examination, CT scan, or MRI OR
  • At least 10 mm by spiral CT scan
  • Lesions on colonoscopic examination or barium studies, bone metastases, CNS lesions, and ascites are not considered measurable
• Failed prior therapy with fluorouracil, leucovorin calcium, and irinotecan given either sequentially or in combination
• No known brain metastases

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-2

Life expectancy:

• At least 3 months

Hematopoietic:

• WBC at least 3,000/mm^3
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin no greater than 1.5 mg/dL
• AST/ALT no greater than 2.5 times upper limit of normal

Renal:

• Creatinine no greater than 1.5 mg/dL OR
• Creatinine clearance at least 60 mL/min

Cardiovascular:

• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No peripheral neuropathy greater than grade 1
• No other concurrent uncontrolled illness that would preclude study
• No concurrent psychiatric illness or social situation that would preclude study
• No ongoing or active infection
• No prior allergic reaction to compounds of similar chemical or biologic composition to oxaliplatin or gefitinib
• No other concurrent malignancy except non-melanoma skin cancer or carcinoma in situ of the cervix unless considered to be at less than 30% risk of relapse after completion of therapy

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior epidermal growth factor inhibitor
• At least 24 hours since prior colony-stimulating factors
• No concurrent colony-stimulating factors during first course of study therapy

Chemotherapy:

• See Disease Characteristics
• No more than 2 prior chemotherapy regimens for metastatic disease
• Prior adjuvant chemotherapy allowed
• At least 4 weeks since prior cytotoxic chemotherapy and recovered
• No prior cisplatin or oxaliplatin

Endocrine therapy:

• Not specified

Radiotherapy:

• At least 4 weeks since prior radiotherapy and recovered

Surgery:

• See Disease Characteristics
• At least 4 weeks since prior surgery

Other:

• At least 30 days since prior investigational agents
• Recovered from prior therapy
• No concurrent anti-retroviral therapy for HIV
• No other concurrent investigational or commercial agents or therapies for malignancy