Dysregulation of the FGF/FGFR signaling pathway has been associated with many developmental disorders and varieties of cancers. TAS-120 is an oral, highly selective covalent FGFR inhibitor with potent antitumor activity in vitro and in vivo models with FGFR pathway aberration.
This FIH study consists of dose escalation phase (DE) and expansion phase (EX). The objectives of this study are to determine the maximum tolerated dose (MTD)/recommended dose (RD) and to investigate the safety, pharmacokinetics, pharmacodynamics, and efficacy. In DE, the first three cohorts were evaluated by a single patient then a 3 + 3 design is used which is currently ongoing. Pts with FGFR abnormalities can be enrolled to EX during the evaluation of DE with dose lower than maximum administered dose under evaluation. TAS-120 was administered orally three times weekly (Monday-Wednesday-Friday) in a 21day cycle.
As of 3 Apr 2017, 36 pts (34% FGFR with genetic abnormalities) were enrolled (DE; 26 pts, EX; 10 pts). Tumor types enrolled were bladder cancer (n = 8), colorectal cancer (n = 7), biliary tract cancer (n = 4), gastric, esophageal and pancreas cancer (n = 3 each), and others (n = 8). Pts were treated in 8 dose cohorts of 8 -160 mg. MTD has not been reached. The most common drug-related AEs (all AEs ≥10%) were hyperphosphatemia (79%), and anorexia (12%). Grade ≥3 hyperphosphatemia has never been observed. Hyperphosphatemia was managed with dose interruption or reduction in addition of phosphate binders. Drug-related SAE has not occurred. TAS-120 exposure increased with dosage. Mean Cmax and AUC0-48 at 160 mg were 1,192 ng/mL and 9,972 ng*h/mL, respectively, with a mean Tmax of 2.67 hrs and apparent T1/2 of 6.06 hrs. Two pts showed the clinical response, one of them was gastric cancer with FGFR2 amplification at 80 mg, and the other was esophageal cancer (FGFR status is under evaluation) at 120 mg. Moreover, two biliary tract cancer with FGFR2 fusion at 56 mg, and one bladder cancer at 36 mg (FGFR status is unknown) had stable disease > 24 weeks.
TAS-120 was well-tolerated, and the safety profile was confirmed up to 120 mg. The ongoing DE and EX are still under evaluation and RD will be determined.
Clinical trial identification
Clinical trial information: JapicCTI-142552
Legal entity responsible for the study
TAIHO Pharmaceutical co., LTD.
TAIHO Pharmaceutical co., LTD.
Y. Kuboki: Honoraria: Taiho Pharmaceutical, Bayer. N. Matsubara: Advisory Board: Janssen, AstraZeneca. Corporate-sponsored research: Janssen, Bayer. Honoraria: Taiho Pharmaceutical. Speakers’ Bureau: Janssen, AstraZeneca, Sanofi. H. Bando: Corporate-sponsored research: AstraZeneca, Sysmex, FALCO Biosystems. Speakers’ Bureau: Taiho Pharmaceutical, Lilly, Takeda, Merck Serono, Chugai, Yakult. K. Shitara: Advisory Board: Bayer, Chugai, Lilly, Takeda. Corporate-sponsored research: Bayer, Chugai, Dainippon Sumitomo, Lilly, MSD, Sanofi, Daiichi Sankyo, Taiho, Yakult. Honoraria: Bayer, Chugai, Bristol-Myers Squibb, Novartis, Takeda. K. Yoh: Corporate-sponsored research: AstraZeneca, Lilly, Taiho Pharmaceutical, Pfizer. Honoraria: AstraZeneca, Chugai, Boehringer Ingelheim, Lilly, Bristol-Myers Squibb, Taiho Pharmaceutical, Ono Pharmaceutical. T. Kojima: Corporate-sponsored research: AstraZeneca, Ono Pharmaceutical, Shionogi, MSD, Merck Serono, Taiho Pharmaceutical. Speakers’ Bureau: Chugai. I. Ohno: Advisory Board: Merck Serono. H. Takahashi: Corporate-sponsored research: Bayer, Bristol-Myers Squibb. Honoraria: Taiho Pharmaceutical. S. Kondo: Corporate-sponsored research: AstraZeneca, Lilly, Pfizer, ASLAN, Merck Serono. H. Hirai: Employee: Taiho Pharmaceutical. C. Morizane: Advisory Board: AstraZeneca, Yakult, Novartis, Taiho. Corporate-sponsored research: GlaxoSmithKline, Pfizer, Nobelpharma, Eisai, Yakult, Ono, Taiho. Honoraria: Pfizer, Novartis, Yakult, Lilly, Nobelpharma, Fujifilm. T. Doi: Advisory Board: Lilly, Chugai, Kyowa Hakko Kirin, Novartis, MSD, Daiichi Sankyo, Amgen. Corporate-sponsored research: Taiho, Merck, Astellas, Janssen, Takeda, Pfizer, Lilly, Sumitomo Group, Bayer, Chugai, Kyowa Hakko Kirin, Boehringer, Novartis, MSD, Daiichi Sankyo, Celgene. All other authors have declared no conflicts of interest.