s-1-(combination) and resminostat

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.. 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.. 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%).. 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).

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Deoxycytidine; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; Gemcitabine; Humans; Hydroxamic Acids; Japan; Male; Middle Aged; Oxonic Acid; Placebos; Platinum Compounds; Progression-Free Survival; Sulfonamides; Tegafur; Young Adult

Resminostat is an oral hydroxamate inhibitor of class I, IIb, and IV histone deacetylases. S-1 is widely used to treat biliary tract cancer and pancreatic cancer in Japan. We performed a phase I study of resminostat combined with S-1 as second-line or later therapy in Japanese patients with biliary tract or pancreatic cancer. A total of 27 patients were enrolled. We determined the optimal regimen for resminostat/S-1 therapy in part 1, and investigated its safety and efficacy in part 2. In part 1, 17 patients were enrolled. One DLT (anorexia and stomatitis, respectively) occurred with each of regimens 2 and 3. In part 2, an additional 10 patients received regimen 3, which was selected in part 1. Regimen 3 was resminostat (200 mg/day on Days 1 to 5 and Days 8 to 12: 5 days on/2 days off) plus S-1 (80-120 mg/day according to body surface area on Days 1 to 14) repeated every 21 days. A total of 16 patients (13 with biliary tract cancer and 3 with pancreatic cancer) received regimen 3 and it was well tolerated. The most frequent treatment-related adverse events were thrombocytopenia and anorexia (11 patients each, 69%). The disease control rate was 81.3% (84.6% for biliary tract cancer and 66.7% for pancreatic cancer, respectively). Median progression-free survival was 3.1 months (5.5 and 2.3 months), while median overall survival was 8.8 months (10.2 and 4.7 months). In conclusion, regimen 3 was well tolerated by patients with pre-treated biliary tract or pancreatic cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Drug Combinations; Female; Follow-Up Studies; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Male; Maximum Tolerated Dose; Middle Aged; Oxonic Acid; Pancreatic Neoplasms; Prognosis; Sulfonamides; Tegafur; Tissue Distribution