ZD 1839 Plus Combination Chemotherapy in Treating Patients With Locally Advanced, Locally Recurrent, or Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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Phase I trial to study the effectiveness of ZD 1839 combined with irinotecan, leucovorin, and fluorouracil in treating patients who have locally advanced, locally recurrent, or metastatic colorectal cancer. Biological therapies such as ZD 1839 may interfere with the growth of tumor cells and slow the growth of the tumor. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining ZD 1839 with combination chemotherapy may kill more tumor cells.

Detailed Description
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OBJECTIVES: I. 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. II. Determine the dose-limiting toxicity of this regimen in these patients. III. Determine the pharmacokinetics of this regimen in these patients. IV. Determine the objective response rate in patients treated with this regimen. V. 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.

Official Title
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A Phase I Study Of ZD1839 (Iressa) In Combination With Irinotecan, Leucovorin, And 5-Fluorouracil In Previously Untreated, Stage IV Colorectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: fluorouracil
* Drug: gefitinib
* Drug: irinotecan hydrochloride
* Drug: leucovorin calcium


Participation Criteria
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Eligibility Criteria
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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: At least 12 months since prior immunotherapy Chemotherapy: At least 12 months since prior fluorouracil No prior chemotherapy for advanced colorectal cancer No prior irinotecan Radiotherapy: 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: 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

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>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. | Drug: fluorouracil<br> <br> Drug: gefitinib<br> <br> Drug: irinotecan hydrochloride<br> <br> Drug: leucovorin calcium<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

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