Abstract OT2-02-09: Phase II study of trimebutine maleate and probiotics for abemaciclib-induced diarrhea in patients with ER-positive and HER2-negative advanced breast cancer (MERMAID) WJOG11318B
Authors: Masuda Hiroko , Iwasa Tsutomu , Mukohara Toru , Tokunaga Shinya , Matsumoto Koji , Niikura Naoki , Sagara Yasuaki , Miyoshi Yasuo , Shimomura Akihiko , Takahashi Masato , Nagashima Takeshi , Doi Mihoko , Futamura Manabu , Yoshimura Kenichi , Takano Toshimi , Tsurutani Junji 
Published: March 2020

Abstract
Background: The standard treatment for estrogen receptor-positive, HER2-negative inoperable and/or recurrent breast cancers is a combination of endocrine therapy and a CDK4/6 inhibitor (abemaciclib). When abemaciclib is administered, 80%-90% of patients experience diarrhea, resulting in the reduction of patient QOL and compliance. Loperamide is recommended for abemaciclib-induced diarrhea as well as chemotherapy induced diarrhea. However, previous reports showed that approximately 40% patients had constipation due to supportive treatment of loperamide. Moreover, the side effects of molecular targeted drugs, including abemaciclib, are not clear in the mechanism, and the effectiveness of coping therapy similar to chemotherapy and the treatment for side effects have not been clearly established. Thus developing new measures to effectively manage abemaciclib-induced diarrhea is an important clinical task, especially prevention of diarrhea without increasing adverse events such as constipation will be important to maintain QOL of patients receiving abemaciclib. Trial Design: This is a multicenter, randomized, open-label Phase II study to evaluate the efficacy and safety of probiotics (bifidobacterial formulation) and trimebutine maleate in treatment of abemaciclib-induced diarrhea. Both Arms A and B will receive hormone therapies (selected by physician in charge*) as directed along with abemaciclib 150 mg bid over the course of 28 days, and simultaneously to initiation of abemaciclib administration, will be given two pills of Biofermin® tid in Both Arms. Once patients experience diarrhea that is grade 6 or greater on the Bristol scale (higher grade than loose stool), salvage therapy using loperamide will be administered in Arm A. In contrast, participants from Arm B will be administered 100 mg trimebutine maleate. Thereafter, following meals, trimebutine maleate tid will be given throughout the trial period of 28 days. Eligibility Criteria: Key eligibility criteria for this trial are: Histologically diagnosed estrogen receptor-positive, HER2-negative breast cancer. Stage IIIB/IIIC breast cancer that is not subjected to surgery for curative intent, Stage IV breast cancer suitable for endocrine therapy. No prior treatment with CDK 4/6 inhibitors, and any type and number of previous treatments will be allowed in the selection criteria except CDK4/6 inhibitors. Specific Aims: The primary endpoint is the percentage of patients who experienced Grade 2 or greater diarrhea during the trial duration of 28 days and key secondary endpoints include safety, frequency and duration of all-grade diarrhea, frequency of emesis and constipation, comparative usage of loperamide in Arms A and B, and QOL/PRO in the 28-day study duration Statistical Design: By using the 40% threshold as the null hypothesis, appropriate statistical analysis will be performed based on a binomial distribution. The significance level will be 2.5%, determined using a one-tailed test. Interval estimation will be appropriately deduced from a binomial distribution. If either arm shows a significant reduction compared with the threshold value, as secondary validation, intergroup comparison of the primary endpoint percentage of diarrhea onset will be performed. In this case, the significance level will be 10%, determined using a two-tailed test. Target Accrual: A total of 50 patients will be enrolled and duration of enrollment will be 1 year. This trial will open to accrual in September 2019. Contact Information: Hiroko Masuda, Showa University Hospital, Tokyo, Japan, hmasuda@med.showa-u.ac.jp
Citation Format: Hiroko Masuda, Tsutomu Iwasa, Toru Mukohara, Shinya Tokunaga, Koji Matsumoto, Naoki Niikura, Yasuaki Sagara, Yasuo Miyoshi, Akihiko Shimomura, Masato Takahashi, Takeshi Nagashima, Mihoko Doi, Manabu Futamura, Kenichi Yoshimura, Toshimi Takano, Junji Tsurutani. Phase II study of trimebutine maleate and probiotics for abemaciclib-induced diarrhea in patients with ER-positive and HER2-negative advanced breast cancer (MERMAID) WJOG11318B [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-02-09.