Combination Chemotherapy in Treating Patients With Colorectal Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known if the effectiveness of irinotecan combined with fluorouracil in treating colorectal cancer varies depending on the patient's racial background. PURPOSE: Phase III trial to study the effectiveness of irinotecan combined with fluorouracil in treating patients from different racial backgrounds who have colorectal cancer that is advanced, recurrent, metastatic or has not responded to treatment with fluorouracil.

Detailed Description
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OBJECTIVES: Determine the interracial differences in the pharmacokinetics of irinotecan in combination with fluorouracil in terms of SN-38 glucuronidation and biliary index, and gastrointestinal (GI) toxicity in patients with metastatic, locally advanced, or recurrent colorectal cancer. Determine if there is a significant relationship between UGT1A1 genotype (promoter and/or coding region mutation) and CYP3A4 promoter genotype, vs GI toxicity, bone marrow toxicity, and pharmacokinetics of irinotecan in this patient population. OUTLINE: Patients are stratified according to race (Asian or Pacific Islander vs black vs Hispanic vs white). Patients receive irinotecan IV over 90 minutes, leucovorin calcium IV, and fluorouracil IV on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for a total of 5 courses in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 1 year and then every 6 months thereafter. PROJECTED ACCRUAL: A total of 400 patients (100 per stratum) will be accrued for this study within 3 years.

Official Title
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Interracial Study of CPT-11 (Irinotecan) Pharmacokinetics in 5-Fluorouracil Refractory Colorectal Cancer: A Population Pharmacokinetic/Pharmacodynamic Study of CPT-11

Conditions
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Colorectal Cancer

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


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma of the colon or rectum Metastatic, locally advanced, or recurrent disease Patients must have at least 2 generations (parents and grandparents) who belong to one of the following racial groups: Asian or Pacific Islander (e.g., China, Japan, Korea, the Philippine Islands, or Samoa) Black (originating from the black racial groups of Africa) Hispanic (originating from Mexico, Puerto Rico, Cuba, Central or South America, or other Spanish culture) White (originating from the peoples of Europe, North Africa, or the Middle East) No patients with parents or grandparents of mixed race or race other than that of the patient PATIENT CHARACTERISTICS: Age: Not specified Performance status: CTC 0-2 Life expectancy: Not specified Hematopoietic: Granulocyte count at least 1,500/mm3 Platelet count at least 100,000/mm3 Hepatic: Bilirubin no greater than 1.5 mg/dL AST no greater than 3 times upper limit of normal Renal: Creatinine no greater than 1.5 mg/dL Other: Not pregnant or nursing Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: Prior adjuvant fluorouracil allowed if relapse occurred at least 6 months after completion of fluorouracil At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) No prior irinotecan No other concurrent chemotherapy Endocrine therapy: No concurrent hormones except steroids for adrenal failure, hormones for nondisease related conditions (e.g., insulin for diabetes), or intermittent dexamethasone as an antiemetic No concurrent prednisone Radiotherapy: At least 4 weeks since prior radiotherapy (except to bone or soft tissue involving less than 25% of bone marrow) No concurrent radiotherapy Surgery: At least 4 weeks since prior major surgery Other: No concurrent phenobarbital, valproate, or cyclosporine None of the following concurrently during first course of therapy: Macrolide antibiotics (e.g., azithromycin, erythromycin, clarithromycin, troleandomycin, dapsone) Azole antibiotics (e.g., fuconazole, miconazole, itraconazole, ketoconazole) Triazobenzodiazepines (e.g., alprazolam, midazolam, triazolam) Antidepressants (e.g., fluoxetine, setraline hydrochloride, fluoxamine, nefazodone hydrochloride) Quinolone antimicrobials (e.g., ciprofloxacin, ofloxacin) Imidazole antibiotics (e.g., clotrimazole) Anti-ulcer medications (e.g., omeprazole, lansoprazole) Ethinyl estradiol Diltiazem Cimetidine hydrochloride Cisapride Terfenadine Rifampin Glucocorticoids Antiepileptics Grapefruit juice
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: irinotecan + leucovorin + fluorouracil<br>Patients receive irinotecan IV over 90 minutes, leucovorin calcium IV, and fluorouracil IV on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for a total of 5 courses in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 1 year and then every 6 months thereafter. | Drug: fluorouracil<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 |
| --- | --- | --- |
| overall survival |  | Up to 10 years | 

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