Resminostat is an oral hydroxamate-type inhibitor of class I, IIb, and IV histone deacetylases. S-1 is preferably used in biliary tract (BTC) and pancreatic cancer (PC) in Japan. However, patients (pts) with high thymidylate synthase (TS) expression are known to show resistance to S-1. Resminostat down-regulates TS expression and has shown additive effects to S-1 in preclinical studies. Thus, resminostat besides its antitumor activity, may overcome S-1 resistance by down-regulating TS. We report a Japanese phase I study of resminostat + S-1 combination therapy in a 2nd-line or later setting for BTC/PC.
In the first stage, we determined the optimal dosing schedule for resminostat + S-1 combination therapy, investigating its safety and efficacy in the second stage. In the former, pts were treated with one of the following 3 regimens (R): R1, resminostat 200 mg/day on Day 1 to 14 every 21 days; R2, resminostat 200 mg/day + S-1 80 to 120 mg/day according to BSA on Day 1 to 14 every 21 days; or R3, resminostat 200 mg/day on Day 1 to 5 and Day 8 to 12 (“5 + 2” dosing schedule) + S-1 80 to 120 mg/day according to BSA on Day 1 to 14 every 21 days. In the latter, additional 10 pts were treated with the regimen selected in the first stage. Dose-limiting toxicities (DLTs) were evaluated according to adverse drug reactions observed during the first cycle in the first stage.
A total of 27 pts were enrolled (first stage: R1, 6 pts; R2, 5 pts; R3, 6 pts; second stage: 10 pts). Two DLTs were observed: one (Grade 2 anorexia) in a patient treated with R2 and one (Grade 3 stomatitis) in another patient treated with R3. Dose modification due to gastrointestinal toxicities was implemented frequently in pts treated with R2. Therefore, R3 was selected as the regimen for the second stage. A total of 16 pts (BTC 13 pts; PC 3 pts) were treated with R3 and it was well tolerable. Disease control rate was 81.3% (BTC 84.6%; PC 66.7%). The median progression-free survival was 3.1 months (BTC 5.5 months; PC 2.3 months).
The data revealed that R3 (“5 + 2” dosing schedule of resminostat in combination with S-1) was well tolerated in advanced BTC/PC pts. Further investigations are warranted for its efficacy especially in advanced BTC pts.
Clinical trial identification
JAPIC Clinical Trials Information (JapicCTI-152864)
Legal entity responsible for the study
Yakult Honsha Co., Ltd.
Yakult Honsha Co., Ltd.
C. Morizane: Consulting or Advisory Role: AstraZeneca, Yakult, Novartis, Taiho Honoraria: Pfizer, Novartis, Yakult Honsha, Lilly, Nobelpharma, Fujifilm Research Funding: GlaxoSmithKline, Pfizer, Nobelpharma, Eisai, Yakult, Ono Pharmaceutical, Taiho. I. Ohno: Consulting or Advisory Role: Merck Serono. H. Ueno: Honoraria: Taiho, Chugai, Yakult Research Funding: Taiho, Eli Lilly, NanoCarrier, Baxalta, Yakult. S. Mitsunaga: Honoraria: Ono pharmaceutical, Toray Research Funding: Bayer Yakuhin, Chugai Pharmaceutical, Merck Serono, Aslan Pharmaceuticals, Ajinomoto. Y. Hashimoto: Honoraria: Taiho pharmaceuticals, Boston scientific, Olympus Medical Research funding: Taiho pharmaceuticals Travel, Accomodations, Expenses: Taiho pharmaceuticals, M.I.Tech. T. Okusaka: Research funding from Yakult Honsha Co., Ltd. S. Kondo: Research funding: Astrazeneca, Eli Lilly, Pfizer, Bayer, MSD, ASLAN. H. Takahashi: Honoraria: Taiho Pharmaceutical Research funding: Bayer Pharmaceutical, Bristol-Myers Squibb Travel, Accomodations, Expenses: Pfizer Inc. R. Hara: Employee and stock owner at Yakult. S. Kobayashi, O. Nakamura: Employee of Yakult. M. Ikeda: Honoraria: Novartis, Taiho, Chugai, Daiichi Sankyo, Lilly, Yakult Membership on an advisory board: Nano Carrier Corporate-sponsored research: Yakult, Taiho, Ono, Eisai, AstraZeneca, Zeria, Merck Serono, Baxter, Nano Carrier. All other authors have declared no conflicts of interest.