Randomized Phase Ii Trial of Hange-Shasin-To Versus Placebo to Prevent Diarrhea in Patients with Metastatic Colorectal Cancer Under Iris+Bev Second-Line Treatment (Hgcsg1301)

Abstract

ABSTRACT Background: Combined chemotherapy with irinotecan, S-1 (IRIS) showed non-inferiority to FOLFIRI, and IRIS with bevacizumab (IRIS/Bev) showed a promising efficacy and a well-tolerated safety profile in our phase II trial. However diarrhea is one of dose-limiting factors of IRIS and its incidence of grade 3 or more is over 20% in patients receiving this regimen (FIRIS study). Hange-shashin-to is an herbal medicine, which contains baicalin, a beta-glucuronidase inhibitor, reported to alleviate diarrhea induced by irinotecan. Aim of this study is to evaluate the usefulness of prophylactic administration of Hange-shashin-to for prevention of diarrhea induced by IRIS/BV, for 2nd line chemotherapy in patients with metastatic colorectal cancer, and also to evaluate efficacy and safety of IRIS/Bev as 2nd-line treatment. Trial design: This study is a multicenter, randomized, double blind, placebo-controlled phase II trial. The primary endpoint is incidence of grade 3 or more diarrhea until the end of 3rd cycle. The secondary endpoints are response rate, progression free survival, time to treatment failure, overall survival, incidence of adverse events, and compliance. Patients are balanced regarding the center, the presence of stoma, history of grade 2 or higher diarrhea in the prior therapies, and the use of opioid medications. The main eligibility criteria are as follows: histologically confirmed adenocarcinoma, unresectable or recurrent colorectal cancer, age of 20 years or older, ECOG performance status of 0-2, measurable or evaluable lesions by RECIST criteria, received prior oxaliplatin-containing chemotherapy, adequate organ functions, written informed consent. Patients are randomly assigned to IRIS/Bev with placebo (arm A) or with Hange-shashin-to (arm B). The sample size was calculated to be 170 (85 patients per arm), with a one-sided alpha of 30%, a power of 80% (randomized phase II screening design), assumed incidence of grade 3 or more diarrhea of 17% in arm A and of 8.5% in arm B, an accrual period of 3 years, and a follow-up period of 2 years. This trial was registered as UMIN 000012276 and was activated in November 2013. Disclosure: Y. Sakata: Fees of testimony, judgment and comment from Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd. Yakult Honsha Co., Ltd., Otsuka Pharmaceutical Co., Ltd. Merck Serono Co., Ltd., Bristol-Myers Squibb Co.; Y. Komatsu: Research expenses from Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd. Yakult Honsha Co., Ltd., Chugai Pharmaceutical Co., Ltd Pfizer Japan Inc., GlaxoSmithKline K.K., Novartis Pharma K.K. All other authors have declared no conflicts of interest.