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

Colorectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00654160
• Other study ID #: CDR0000592931
• Secondary ID: P30CA015083MC064
• Status: Completed
• Phase: Phase 1
• First received: April 4, 2008
• Last updated: May 23, 2017
• Start date: June 2008
• Est. completion date: December 3, 2012

Study information

• Verified date: September 2016
• Source: Mayo Clinic
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 7
• Est. completion date: December 3, 2012
• Est. primary completion date: November 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

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)

Related Conditions & MeSH terms

• Anal Cancer
• Anus Neoplasms
• Appendiceal Neoplasms
• Bile Duct Neoplasms
• Carcinoid Tumor
• Carcinoma of the Appendix
• Colorectal Cancer
• Colorectal Neoplasms
• Esophageal Cancer
• Esophageal Neoplasms
• Extrahepatic Bile Duct Cancer
• Gallbladder Cancer
• Gallbladder Neoplasms
• Gastric Cancer
• Gastrointestinal Carcinoid Tumor
• Gastrointestinal Neoplasms
• Gastrointestinal Stromal Tumor
• Gastrointestinal Stromal Tumors
• Intestinal Neoplasms
• Liver Cancer
• Liver Neoplasms
• Malignant Carcinoid Syndrome
• Neoplasms
• Neuroendocrine Tumors
• Pancreatic Cancer
• Pancreatic Neoplasms
• Small Intestine Cancer
• Stomach Neoplasms

Intervention

Drug:
• fluorouracil

• irinotecan hydrochloride

• leucovorin calcium

Other:
• pharmacogenomic studies

• pharmacological study

Locations

Country	Name	City	State
United States	Mayo Clinic	Rochester	Minnesota

Sponsors (2)

Lead Sponsor	Collaborator
Mayo Clinic	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose of genotype-based dosing of FOLFIRI with or without monoclonal antibody therapy
Secondary	Response rate of genotype-based dosing in the subset of patients that has colorectal cancer