HGCSG1301: A multicenter, double-blind, randomized control phase II trial comparing Hange-shashin-to versus placebo to prevent diarrhea in patients with metastatic colorectal cancer under IRIS/Bev second-line treatment

Abstract

Introduction: S‐1 plus irinotecan (IRIS) showed non‐inferiority to fluorouracil and folinic acid plus irinotecan (FOLFIRI) by FIRIS study. Therefore, IRIS is widely used with bevacizumab (IRIS/Bev) as the second‐line chemotherapy in patients with colorectal cancer. The most frequent non‐hematological adverse event shown at the study was diarrhea. Baicalin contained within Hange‐shashin‐to is a potent competitive inhibitor of beta‐glucuronidase which cleaves conjugated SN‐38‐glucuronide to SN‐38 which causes cytotoxic diarrhea as an active metabolite from irinotecan. We conducted to evaluate the usefulness of prophylactic administration of Hange‐shashin‐to to prevent diarrhea in patients receiving IRIS/Bev. Methods: This trial was designed as a multicenter, randomized, double‐blind, placebocontrolled study. We administrated Hange‐shashin‐to 2.5g or placebo PO t.i.d. until 3 months from the first treatment cycle of IRIS/Bev. The primary endpoint is proportion of Grade 3 or worse diarrhea assessed by CTCAE v4.0. This study is registered with UMIN‐CTR, number UMIN000012276. Results: Between Jan 1, 2014 and Mar 31, 2017, 59 patients with colorectal cancer in need of second‐line chemotherapy from 11 institutes in japan were randomly assigned to receive Hange‐shashin‐to (n=28, Group H) or placebo (n=29, Group P). The patients' characteristics were well‐balanced. The median relative dose intensities of S‐1, irinotecan and bevacizumab were 0.89 vs 0.89, 0.89 vs 0.89 and 0.89 vs 0.86 in groupH vs group P. The proportions of Grade 3 or worse diarrhea were 10.7% (3 of 28) in Group H and 13.8% (4 of 29) in Group P (p=1.00). Those of any grade diarrhea were 64.3% (18 of 28) in Group Hand 72.4% (21 of 29) in Group P (p=0.58). The other major adverse events (grade 3 or worse) were fatigue (3.6% vs 10.3%), anorexia (14.3% vs 10.3%), nausea (0.0% vs 3.4%) in Group Hvs Group P. The overall response rate in group H vs group P was 13.6% vs 7.7% (p=0.65), and the disease control rate was 86.4% vs 80.8% (p=0.71), respectively. Conclusion: Our study to examine the diarrhea control effect by Hange‐shashin‐to induced by IRIS/Bev did not show any significant difference between two groups.