A phase I study of irinotecan and 5'-DFUR in patients with metastatic colorectal cancer: With consideration of gene polymorphism

Abstract

3630 Background: 5-Fluorouracil plus irinotecan (CPT-11) is standard 1st-line therapy in patients (pts) with metastatic colorectal cancer (MCRC). 5'-DFUR is a tumor-activated oral fluoropyrimidine. We conduct a phase I trial of CPT-11 and 5'-DFUR to determine the maximum tolerated dose (MTD) and toxicities of this regimen. However, detoxification of SN-38 (active form of CPT-11) is depending on UGT1A1 polymorphism. Here we report the results from a phase I study to determine the significance of UGT1A1 polymorphism on toxicity in pts with MCRC. Patients and methods: Eligibility criteria were as follows; histologically proven CRC with unresectable metastatic lesions, PS 0–2, age<75, adequate organ functions, and written informed consent. 5'-DFUR was administered orally (level 1 and 2; 600 mg/body, level 2b and 3; 800 mg/body) on 5 consecutive days with 2 days' rest for 12 weeks, and CPT-11 was infused (level 1, 2, 2b, and 3: 50, 70, 70, 100 mg/m2, respectively) on days 1, 15, 29, 43, 57, and 71. Dose limiting toxicities were determined as grade 3 hematological and grade 3 non-hematological during 12 weeks. Genotypes were determined by analyzing the sequence of TATA box of UGT1A1 of genomic DNA from the pts. Results: Fifteen pts were registered (3 pts each in level 1 to 2b and 6 in level 3). No toxicity of grade 3 or over was observed at level 1 to 2b. At level 3, the planned therapy was discontinued in 3 pts because of grade 3 neutropenia and/or diarrhea, which settled the MTD on this level. Polymorphism of UGT1A1 is characterized by (TA)7, instead of (TA)6. The frequency of genotypes was as follows: 6/6–10/15(67%), 6/7–5/15(33%) and 7/7–0/15(0%). Three pts who had grade 3 toxicities on level 3 had abnormal allele (6/7). On the other hand, three pts who had normal allele (6/6) had no toxicity of grade 2 or over on level 3. Conclusions: The recommended doses are CPT-11 70 mg/m2 and 5' -DFUR 800 mg/body. However, pts who had normal allele (6/6) could tolerate on level 3, so MTD and RD for pts with normal allele should be settled by further examinations. The RD in the phase I study may be changed, when the gene polymorphism is taken into consideration. No significant financial relationships to disclose.