3602 Background: 5-Fluorouracil plus CPT-11 is one of the standard 1st-line therapies in patients (pts) with metastatic colorectal cancer (MCRC). Although it has been reported that individuals carrying the (TA) 7 allele in the TATAA promoter of UGT1A1 increased risk of severe toxic event occurrence after CPT-11 administration, there is no report about phase I study based on the polymorphism of UGT1A1. Here we report the results from a genetic UGT1A1 polymorphism oriented phase I study of CPT-11 and 5’-DFUR to determine the maximum tolerated dose (MTD) and the recommend doses (RD) for each UGT1A1 genotypes. Methods: Eligibility criteria were as follows; histologically proven CRC with unresectable metastatic lesions, PS 0–2, age<76, adequate organ functions, and written informed consent. CPT-11 was infused (level 1, 2, 3 and 4: 70, 100, 120, 150 mg/m2, respectively) biweekly and 5’-DFUR was administered orally (800 mg/body, <1.39 m2; 600 mg/body) on 5 consecutive days with 2 days’ rest for more than 12 weeks. DLT were determined as grade 3 hematological and non-hematological toxicities. Genotypes were determined by analyzing the sequence of TATA box of UGT1A1 of genomic DNA from pts. Results: Eighteen pts with wild 6/6 allele and 9 pts with mutated 6/7 allele were registered. In pts with 6/6 allele, MTD was not observed up to level 4 (150 mg/m2). In pts with mutated 6/7 allele, on the other hand, MTD was observed at level 2 (100 mg/m2). We recommend doses of 70 mg/m2 of CPT-11 for pts with mutated 6/7 allele and 150 mg/m2 of CPT-11 for pts with wild 6/6 allele, respectively. Conclusions: The recommended phases II/III starting doses of biweekly CPT-11 administration are 150 mg/m2 for pts with wild 6/6 allele and 70 mg/m2 of CPT-11 for pts with mutated 6/7 allele, and 5’ -DFUR 800 mg/body on every 5 days per week. This combination therapy may be administered safely for all pts according to the TATAA promoter polymorphism of UGT1A1. The gene polymorphism should be taken into consideration to provide more precise information to guess the individual toxicities. No significant financial relationships to disclose.
Trifluridine/tipiracil in combination with oxaliplatin and either bevacizumab or nivolumab in metastatic colorectal cancer: a dose-expansion, phase I study
