A genotype-directed phase I study of irinotecan in advanced cancer patients

Abstract

2502 Background: The risk of severe toxicity of irinotecan is in part related to the presence of common polymorphisms in UGT1A1, which codes for the enzyme responsible for the inactivation of SN-38, the active metabolite of irinotecan. The most common polymorphism in non-Asian populations is an extra TA repeat in the promoter (7 vs. 6), which reduces the enzyme expression. The three most common genotypes are: 6/6 (40–50%), 6/7 (40–50%), and 7/7 (10–15%). The 7/7 genotype confers the highest risk of toxicity, and it has been suggested that dose reduction is appropriate for patients with this genotype. As one published study has suggested that doses up to 500 mg/m2 q3w can be tolerated by some patients, we hypothesized that higher doses can be safely administered based on genotype by excluding patients with the 7/7 genotype. This study seeks to find the maximum tolerated dose (MTD) in patients with 6/6 and 6/7 genotypes. Methods: Advanced cancer patients (5 SCLC, 4 esophageal, 5 other tumors) have been genotyped for the UGT1A1 polymorphism. 6/6 and 6/7 patients have been treated with 700–850 mg (flat dose, corresponding to about 400–500 mg/m2) of q3w irinotecan. Dose-limiting toxicity (DLT) at cycle 1 is defined as grade =3 nonhematological toxicity, grade 4 neutropenia lasting more than 4 days, and febrile neutropenia. Results: Three 6/6 patients tolerated 700 mg (no grade >2 toxicity). Three additional 6/6 patients have been treated at 850 mg, and one DLT (grade 4 neutropenia lasting more than 4 days) was observed; 3 additional 6/6 patients will be enrolled at 850. Six 6/7 patients have been treated at 700 mg, with only one DLT (febrile neutropenia). Two additional 6/7 patients have been treated at 850, and one DLT (febrile neutropenia) has been observed. Conclusions: Higher doses of irinotecan can be safely administered in patients with selected UGT1A1 genotypes. On the basis of these interim results, a phase II trial in metastatic colorectal cancer patients with 6/6 and 6/7 genotypes has been designed to evaluate the efficacy of higher doses of irinotecan. [Table: see text]