Phase I/II study of combination therapy with S-1 and CPT-11 for metastatic colorectal cancer

Abstract

Abstract. We conducted a Phase I/II study of combination therapy using CPT-11 and S-1 as a first-line treatment for metastatic colorectal cancer. The 28-day treatment cycle consisted of S-1 administered orally from day 1 to 21 and CPT-11 administered intravenously on days 1 and 15. In the Phase I portion, the dose of S-1 was fixed at 80 mg/m 2 /day, while CPT-11 was administered at a starting dose of 60 mg/m 2 then stepped up in 20 mg/m 2 increments. The maximumtolerated dose was achieved at 80 mg/m 2 of CPT-11, and the recommended dose was determined to be 60 mg/m 2 of CPT-11. In the Phase II portion, this therapy exhibited a response rate of 58%, a median progression-free survival of 8.4 months, and a median overall survival of 18.7 months. Toxicity was generally mild and manageable. No patient showed grade 4 toxicity, and grade 3 toxicity was observed in only 18% of patients. The most frequently observed grade 3 toxicity was diarrhea, at a rate of 6%. The mean relative dose intensity of CPT-11 and S-1 was as high as 98 and 97%, respectively. In conclusion, combination therapy with CPT-11 and S-1 according to our treatment schedule is effective, safe and highly feasible for metastatic colorectal cancer patients. These data suggest that assessing this combination therapy in a Phase III study would be worthwhile.

Random-effects meta-analysis of Phase I dose-finding studies using stochastic process priors

“…The results of 10 studies on combination therapy of irinotecan and S-1 (tegafur/gimeracil/oteracil). For each dose considered in each trial, the numbers of patients experiencing DLT events and the total numbers of exposed patients are given Ogata et al (2009) 0/3 0/3 3/4 Inokuchi et al (2006) 0/3 10/42 0/3 2/3 Goya et al (2012) 0/3 0/3 3/5 Takiuchi et al (2005) 1/6 0/3 0/4 3/6 Ishimoto et al (2009) 0/3 0/3 0/3 2/4 Kusaba et al (2010) 0 / 6 2 / 3 Nakafusa et al (2008) 7/39 2/3 Shiozawa et al (2009) 1/6 2/6 2/6 2/3 Yoda et al (2011) 0 / 3 3 / 6 Komatsu et al (2010) 1/9 1/9 0/3…”

CpG island methylation of BNIP3 predicts resistance against S-1/CPT-11 combined therapy in colorectal cancer patients

“…Nine of the cancer related genes, CHFR, p16, RUNX3, E-cadherin, MGMT, hMLH1, ABCG2, UGT1A1 and BNIP3, were chosen for methylation analysis, because frequent gene methylation has been reported in solid cancers, including CRC (5)(6)(7)(8)(10)(11)(12)(13)(14)(15)(16)(17)(20)(21)(22)(23)(24). A significant correlation between gene methylation or expression and chemosensitivity to 5-FU, S-1 and CPT-11 has been reported for p16 (11), MGMT (29), hMLH1 (12), ABCG2 (16,30), UGT1A1 (14) and BNIP3 (31).…”

“…A phase I/II study assessed the toxicity and efficacy of S-1/CPT-11 combined therapy for metastatic CRC (13,25). The result showed that a response to the S-1/CPT-11 combined therapy was obtained in 19 of 33 (58%) patients without any significant toxicity, suggesting the efficacy of S-1/CPT-11 against metastatic CRC (13).…”

“…The pretreatment regimens included tegafur-uracil/leucovorin (LV) therapy (7 cases), l-LV/5-FU therapy (5 cases), S-1 monotherapy (2 cases), tegafur-uracil monotherapy (1 case), and doxifluridine (5'-DFUR)/CPT-11 therapy (1 case). The treatment regimens and details were previously reported (13).…”

“…We recently reported that a phase I/II study of Tegafur, gimeracil, oteracil potassium (S-1) plus CPT-11 therapy in 33 metastatic CRC patients demonstrated a response rate of 58% (13). The present study examined DNA methylation of 9 cancer related genes using primary CRC tissues from 27 patients.…”