Irinotecan, Fluorouracil, and Leucovorin in Treating Patients With Advanced Gastrointestinal Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as irinotecan, fluorouracil, and leucovorin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of irinotecan when given together with fluorouracil and leucovorin in treating patients with advanced gastrointestinal cancer.

Detailed Description
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OBJECTIVES: Primary To determine the maximum tolerated dose of irinotecan hydrochloride in FOLFIRI for each respective UGT1A1 TA indel genotype grouping (group 1 [7/7, 7/8, 8/8], group 2 [6/7, 5/7, 5/8 ,6/8], and group 3 [6/6, 5/6, 5/5]). Secondary Determine the molecular basis of toxicity, other than UGT1A1 variants, in FOLFIRI-treated cancer patients. Determine the pharmacodynamic molecular profiles of cell signaling pathways associated with the development and severity of early and late specific toxicities in cancer patients treated with FOLFIRI. OUTLINE: This is a dose-escalation study of irinotecan hydrochloride. Patients are stratified according to genotype of UGT1A1 TA indel. Group 1 ( TA genotype 7/7, 7/8, 8/8): Patients receive irinotecan hydrochloride IV over 90 minutes and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV bolus over 5 minutes followed by IV continuously over 46 hours on days 1-3. Group 2 (TA genotype 6/7, 6/7, 5/8, 6/8): Patients receive treatment as in group 1 with a higher initial dose of irinotecan hydrochloride. Group 3 (TA genotype 5/5, 5/6, 6/6): Patients receive treatment as in group 2. In all groups, treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood collection at baseline and periodically during study for pharmacokinetics, dihydropyridine deaminase enzyme assay, and pathway expression analysis. After completion of study treatment, patients are followed every 6 weeks for up to 2 years.

Official Title
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A Pharmacogenetic-Based Phase I Trial of Irinotecan, 5-Fluorouracil, and Leucovorin (FOLFIRI) in Patients With Advanced Gastrointestinal Cancer

Conditions
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Anal Cancer, Carcinoma of the Appendix, Colorectal Cancer, Esophageal Cancer, Extrahepatic Bile Duct Cancer, Gallbladder Cancer, Gastric Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumor, Liver Cancer, Pancreatic Cancer, Small Intestine Cancer

Intervention / Treatment
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* Drug: fluorouracil
* Drug: irinotecan hydrochloride
* Drug: leucovorin calcium
* Other: pharmacogenomic studies
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Biopsy confirmed diagnosis of gastrointestinal cancer Advanced, unresectable disease Confirmation of UGT1A1 TA indel genotype Measurable or evaluable (non-measurable) disease Measurable disease is defined as ≥ 1 lesion that can be accurately measured (longest diameter to be recorded) as ≥ 2.0 cm with conventional techniques or as ≥ 1.0 cm with spiral CT scan Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules, palpable lymph nodes) Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung The following are considered non-measurable disease: Bone lesions Leptomeningeal disease Ascites Pleural/pericardial effusions Lymphangitis cutis/ pulmonis Inflammatory breast disease Abdominal masses (not followed by CR scan or MRI) Cystic lesions All other lesions (or sites of disease), including small lesions (longest diameter < 2.0 cm with conventional techniques or as < 1.0 cm with spiral CT) No known central nervous system metastases or carcinomatous meningitis PATIENT CHARACTERISTICS: Inclusion criteria Life expectancy ≥ 12 weeks. ECOG performance status 0-2 ANC ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ SGOT ≤ 2.5 times upper limit of normal (ULN) (≤ 5 times ULN if liver metastases) Total Bilirubin ≤ ULN for patients in group 3 and ≤ 2.0 times ULN for patients in groups 1 and 2 Hemoglobin ≥ 9.0 g/dL Creatinine ≤ 1.5 times ULN or creatinine clearance ≥ 60 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception for the duration of study treatment Willing to provide blood samples for mandatory translational studies Exclusion criteria Known allergy to irinotecan hydrochloride-related agents (e.g., topotecan), 5-fluorouracil, and/or leucovorin calcium Active or uncontrolled infection Evidence of serious intercurrent illness (e.g., unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) PRIOR CONCURRENT THERAPY: Recovered from all toxicities More than 4 weeks since prior major surgery More than 2 weeks since completion of prior radiotherapy No prior radiotherapy to > 25% of bone marrow More than 2 week since prior cytotoxic chemotherapy, biologic therapy, or immunotherapy No concurrent sargramostim (GM-CSF)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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
Allocation: Randomized
Intervention Model: Single Group Assignment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: fluorouracil|nan|
|Drug: irinotecan hydrochloride|nan|
|Drug: leucovorin calcium|nan|
|Other: pharmacogenomic studies|nan|
|Other: pharmacological study|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of genotype-based dosing of FOLFIRI with or without monoclonal antibody therapy |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate of genotype-based dosing in the subset of patients that has colorectal cancer |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IIIB anal cancer, stage IV anal cancer, recurrent anal cancer, carcinoma of the appendix, stage III colon cancer, stage IV colon cancer, recurrent colon cancer, stage III rectal cancer, stage IV rectal cancer, recurrent rectal cancer, stage III esophageal cancer, stage IV esophageal cancer, recurrent esophageal cancer, recurrent extrahepatic bile duct cancer, unresectable extrahepatic bile duct cancer, unresectable gallbladder cancer, recurrent gallbladder cancer, stage III gastric cancer, stage IV gastric cancer, recurrent gastric cancer, metastatic gastrointestinal carcinoid tumor, recurrent gastrointestinal carcinoid tumor, regional gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, advanced adult primary liver cancer, localized unresectable adult primary liver cancer, recurrent adult primary liver cancer, stage II pancreatic cancer, stage III pancreatic cancer, stage IV pancreatic cancer, recurrent pancreatic cancer, recurrent small intestine cancer, small intestine adenocarcinoma, small intestine leiomyosarcoma, small intestine lymphoma