Irinotecan, Fluorouracil, And Leucovorin In Treating Patients With Advanced Gastrointestinal Cancer

Study Overview

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

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.

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.

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

CDR0000592931
P30CA015083 (U.S. NIH Grant/Contract)
MC064G (OTHER Identifier) (OTHER: Mayo Clinic Cancer Center)
NCI-2009-01216 (REGISTRY Identifier) (REGISTRY: CTRP)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2008-04-04	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2017-05-23
First Submitted that Met QC Criteria 2008-04-04	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2017-05-25
First Posted (ACTUAL) 2008-04-07	Results First Posted N/A	Last Verified 2016-09

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Randomized

Interventional Model:
Single Group

Masking:
N/A

Arms and Interventions

Participant Group/Arm	Intervention/Treatment

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

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

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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

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

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)

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)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

National Cancer Institute (NCI)

Investigators

PRINCIPAL_INVESTIGATOR: Robert McWilliams, MD, Mayo Clinic

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

No publications available

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Resources

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Clinical Trial Record