A UGT1A1 genotype-directed phase I study of irinotecan (CPT-11) combined with fixed dose of capecitabine in patients with metastatic colorectal cancer (mCRC)

2554 Background: The risk of severe toxicity of CPT-11 can be in part explained by polymorphism of UGT1A1. The most common polymorphism in Whites is UGT1A1*28. UGT1A1*6 is another common polymorphism in Asians. We designed a phase I study to investigate UGT1A1 genotype-directed maximum tolerated dose (MTD) of CPT-11 plus fixed dose of capecitabine in patients (pts) with Korean mCRC. Methods: Pts with mCRC screened UGT1A1 genotyping (*28 and *6) and were stratified into one of 3 groups according to the number of defective allele (DA): 0 (none of *28 or *6 allele), 1(only one of *28 or *6 allele), and 2 (*28/*28, *6/*6, or double heterozygous for *28 and *6). The dose of CPT-11 was escalated as following: Level -I:200, I:240, II:280, III:320, IV: 350, V: 380 mg/m2 (IV, once every 3 weeks). Capecitabine (1,000 mg/m2 PO BID) was administered on days 2–15 every 3 weeks. Dose limiting toxicity (DLT) and pharmacokinetic analyses was determined at cycle 1. Results: Forty-two pts, median age 50 years, EOOG performance ≤1 were recruited: 0 DA group (18 pts), 1 DA (18), and 2 DA (6). In 0 DA group, two of six pts experienced DLT at 380 mg/m2 with grade III asthenia (1 pts) and febrile neutropenia (1). In 1 DA group, all of two pts experienced DLT at 380 mg/m2 with grade III asthenia. In 2 DA group, two of three pts experienced DLT at 240 mg/m2 with febrile neutropenia (1) and grade IV neutropenia (1). The MTD was defined as CPT-11 350 mg/m2 for pts with 0 and 1 DA group and CPT-11 200 mg/m2 for pts with 2 DA group, with capecitabine. Median SN-38G/SN-38 AUC was 10.45, 8.78, and 1.66 in pts with 0, 1, and 2 DA group, respectively. Conclusions: CPT-11 dosing by UGT1A1*28 and *6 genotypes is feasible in Korean pts with mCRC. A dose of CPT-11 350 mg/m2 IV for pts with 0 and 1 DA group and CPT-11 200 mg/m2 for pts with 2 DA group, with capecitabine every 3 weeks, is recommended for further study. [Table: see text] No significant financial relationships to disclose.