OBJECTIVES:

• Determine the maximum tolerated dose of ZD 1839 in combination with irinotecan, leucovorin calcium, and fluorouracil in patients with locally advanced, locally recurrent, or metastatic colorectal cancer.
• Determine the dose-limiting toxicity of this regimen in these patients.
• Determine the pharmacokinetics of this regimen in these patients.
• Determine the objective response rate in patients treated with this regimen.
• Correlate epidermal growth factor receptor expression with the probability of objective tumor response in these patients.

OUTLINE: This is a multicenter, dose-escalation study of ZD 1839.

Patients receive oral ZD 1839 daily. Beginning on day 15, patients receive irinotecan IV over 90 minutes, leucovorin calcium IV over 15 minutes, and fluorouracil IV weekly on weeks 1-2. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of ZD 1839 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. Once the MTD is determined, 10 additional patients are accrued to receive treatment at the MTD.

Patients are followed for 30 days.

PROJECTED ACCRUAL: Approximately 3-22 patients will be accrued for this study within 1-6 months.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed adenocarcinoma of the colon or rectum

  • Locally advanced, locally recurrent, or metastatic disease
  • Not curable by surgery and/or not amenable to radiotherapy with curative intent
  • Histological or cytological confirmation of metastatic cancer not required for patients with prior surgically resected colorectal cancer if more than 5 years elapsed between primary surgery and development of metastatic disease OR if primary cancer was stage I or II
• Prior adjuvant therapy with fluorouracil or immunotherapy for resected stage II, III, or IV disease allowed
• Measurable disease
• No known brain metastases

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-1

Life expectancy:

• More than 12 weeks

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 normal
• AST/ALT no greater than 5 times upper limit of normal

Renal:

• Creatinine normal

Cardiovascular:

• No uncontrolled high blood pressure
• No unstable angina
• No symptomatic congestive heart failure
• No myocardial infarction within the past 6 months
• No serious uncontrolled cardiac arrhythmia
• No New York Heart Association class III or IV heart disease

Other:

• No active or uncontrolled infection
• No predisposing colonic or small bowel disorders with uncontrolled symptoms as indicated by more than 3 loose stools daily in patients without a colostomy or ileostomy
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or adequately treated noninvasive carcinomas
• No other concurrent medical or psychiatric condition that would preclude study
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• See Disease Characteristics
• At least 12 months since prior immunotherapy

Chemotherapy:

• See Disease Characteristics
• At least 12 months since prior fluorouracil
• No prior chemotherapy for advanced colorectal cancer
• No prior irinotecan

Endocrine therapy:

• Not specified

Radiotherapy:

• See Disease Characteristics
• No prior radiotherapy to more than 15% of bone marrow
• At least 4 weeks since prior major radiotherapy (e.g., chest or bone palliative radiotherapy)
• No concurrent radiotherapy

Surgery:

• See Disease Characteristics
• At least 4 weeks since prior major surgery (e.g., laparotomy) and recovered
• At least 2 weeks since prior minor surgery and recovered
• No concurrent ophthalmic surgery

Other:

• No prior ZD 1839
• No other concurrent investigational or commercial agents or therapies for malignancy
• No concurrent combination antiretroviral therapy for HIV
• No concurrent oral retinoids
• No concurrent prochlorperazine on day of irinotecan administration