A Pharmacogenetic-Based Phase I Trial of Irinotecan, 5-Fluorouracil, and Leucovorin (FOLFIRI) in Patients With Advanced Gastrointestinal Cancer
- 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]).
- 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
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.
Primary Purpose: Treatment
Maximum tolerated dose of genotype-based dosing of FOLFIRI with or without monoclonal antibody therapy
Robert McWilliams, MD
United States: Federal Government
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