Makoto Ueno1, Chigusa Morizane2, Masayuki Furukawa3, Daisuke Sakai4, Yoshito Komatsu5, Yousuke Nakai6, Masahiro Tsuda7, Masato Ozaka8, Nobumasa Mizuno9, Manabu Muto10, Akira Fukutomi11, Masafumi Ikeda12, Akihito Tsuji13, Akio Katanuma14, Toshikazu Moriwaki15, Takeshi Kajiwara16, Hiroshi Ishii17, Yuji Negoro18, Satoshi Shimizu19, Noriko Nemoto20, Shingo Kobayashi20, Keigo Makino20, Junji Furuse21. 1. Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, Kanagawa, Japan. 2. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. 3. Department of Hepato-Biliary-Pancreatology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan. 4. Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, Japan. 5. Division of Cancer Center, Hokkaido University Hospital, Hokkaido, Japan. 6. Department of Gastroenterology, Department of Endoscopy and Endoscopic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 7. Department of Gastroenterological Oncology, Hyogo Cancer Center, Hyogo, Japan. 8. Hepato-Biliary-Pancreatic Medicine Department, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan. 9. Department of Gastroenterology, Aichi Cancer Center Hospital, Aichi, Japan. 10. Department of Clinical Oncology, Kyoto University Hospital, Kyoto, Japan. 11. Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan. 12. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Chiba, Japan. 13. Department of Clinical Oncology, Faculty of medicine, Kagawa University, Kagawa, Japan. 14. Center for Gastroenterology, Teine-keijinkai hospital, Hokkaido, Japan. 15. Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan. 16. Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Ehime, Japan. 17. Clinical Research Center, Chiba Cancer Center, Chiba, Japan. 18. Division of Clinical Oncology, Kochi Health Sciences Center, Kochi, Japan. 19. Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan. 20. Pharmaceutical Research & Development Department, Yakult Honsha Co., Ltd., Tokyo, Japan. 21. Department of Medical Oncology, Faculty of Medicine, Kyorin University, Tokyo, Japan.
Abstract
PURPOSE: Effective second-line chemotherapy options are limited in treating advanced biliary tract cancers (BTCs). Resminostat is an oral histone deacetylase inhibitor. Such inhibitors increase sensitivity to fluorouracil, the active form of S-1. In the phase I study, addition of resminostat to S-1 was suggested to have promising efficacy for pre-treated BTCs. This study investigated the efficacy and safety of resminostat plus S-1 in second-line therapy for BTCs. METHODS: Patients were randomly assigned to receive resminostat or placebo (200 mg orally per day; days 1-5 and 8-12) and S-1 group (80-120 mg orally per day by body surface area; days 1-14) over a 21-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), response rate (RR), disease control rate (DCR), and safety. RESULTS: Among 101 patients enrolled, 50 received resminostat+S-1 and 51 receivedplacebo+S-1. Median PFS was 2.9 months for resminostat+S-1 vs. 3.0 months for placebo+S-1 (HR: 1.154, 95% CI: 0.759-1.757, p = 0.502); median OS was 7.8 months vs. 7.5 months, respectively (HR: 1.049, 95% CI: 0.653-1.684, p = 0.834); the RR and DCR were 6.0% vs. 9.8% and 70.0% vs. 78.4%, respectively. Treatment-related adverse events (TrAEs) of grade ≥ 3 occurring more frequently (≥10% difference) in the resminostat+S-1 than in the placebo+S-1 comprised platelet count decreased (18.0% vs. 2.0%) and decreased appetite (16.0% vs. 2.0%). CONCLUSIONS:Resminostat plus S-1 therapy improved neither PFS nor OS for patients with pre-treated BTCs. Addition of resminostat to S-1 was associated with higher incidence of TrAEs, but these were manageable (JapicCTI-183883).
RCT Entities:
PURPOSE: Effective second-line chemotherapy options are limited in treating advanced biliary tract cancers (BTCs). Resminostat is an oral histone deacetylase inhibitor. Such inhibitors increase sensitivity to fluorouracil, the active form of S-1. In the phase I study, addition of resminostat to S-1 was suggested to have promising efficacy for pre-treated BTCs. This study investigated the efficacy and safety of resminostat plus S-1 in second-line therapy for BTCs. METHODS:Patients were randomly assigned to receive resminostat or placebo (200 mg orally per day; days 1-5 and 8-12) and S-1 group (80-120 mg orally per day by body surface area; days 1-14) over a 21-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), response rate (RR), disease control rate (DCR), and safety. RESULTS: Among 101 patients enrolled, 50 received resminostat+S-1 and 51 received placebo+S-1. Median PFS was 2.9 months for resminostat+S-1 vs. 3.0 months for placebo+S-1 (HR: 1.154, 95% CI: 0.759-1.757, p = 0.502); median OS was 7.8 months vs. 7.5 months, respectively (HR: 1.049, 95% CI: 0.653-1.684, p = 0.834); the RR and DCR were 6.0% vs. 9.8% and 70.0% vs. 78.4%, respectively. Treatment-related adverse events (TrAEs) of grade ≥ 3 occurring more frequently (≥10% difference) in the resminostat+S-1 than in the placebo+S-1 comprised platelet count decreased (18.0% vs. 2.0%) and decreased appetite (16.0% vs. 2.0%). CONCLUSIONS: Resminostat plus S-1 therapy improved neither PFS nor OS for patients with pre-treated BTCs. Addition of resminostat to S-1 was associated with higher incidence of TrAEs, but these were manageable (JapicCTI-183883).