747P - phase I study of resminostat/S-1 combination in patients with pre-treated biliary tract or pancreatic cancer

Date 09 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Cytotoxic agents
Clinical research
Hepatobiliary Cancers
Pancreatic Cancer
Gastrointestinal Cancers
Basic Scientific Principles
Biological therapy
Presenter Chigusa Morizane
Citation Annals of Oncology (2017) 28 (suppl_5): v209-v268. 10.1093/annonc/mdx369
Authors C. Morizane1, I. Ohno2, H. Ueno1, S. Mitsunaga2, Y. Hashimoto2, T. Okusaka1, S. Kondo1, M. Sasaki2, Y. Sakamoto1, H. Takahashi2, R. Hara3, S. Kobayashi3, O. Nakamura3, M. Ikeda2
  • 1Department Of Hepatobiliary And Pancreatic Oncology, National Cancer Center Hospital, 104-0045 - Tokyo/JP
  • 2Department Of Hepatobiliary And Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa/JP
  • 3Pharmaceutical Research & Development Department, Yakult Honsha Co., Ltd., 104-0061 - Tokyo/JP



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.