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

Sponsor

Mayo Clinic (Other)

Overall Status

Completed

CT.gov ID

NCT00654160

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

54.1

Actual Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: fluorouracil Drug: irinotecan hydrochloride Drug: leucovorin calcium Other: pharmacogenomic studies Other: pharmacological study	Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

7 participants

Allocation:

Randomized

Intervention Model:

Single Group Assignment

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jun 1, 2008

Actual Primary Completion Date :

Nov 1, 2010

Actual Study Completion Date :

Dec 3, 2012

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose of genotype-based dosing of FOLFIRI with or without monoclonal antibody therapy []

Secondary Outcome Measures

Response rate of genotype-based dosing in the subset of patients that has colorectal cancer []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)