Abstract A165: Result of a phase 1 (dose-escalation stage), first-in-human study of ASP5878, an oral FGFR inhibitor, in patients with advanced solid tumors
Authors: Shimizu Toshio , Doi Toshihiko , Yamamoto Noboru , Murakami Haruyasu , Furuse Junji , Kawai Koji , Nishiyama Hiroyuki , Morita Satoshi , Takahashi Shunji , Bahceci Erkut , Steinberg Joyce , Ball Howard A. , Kunieda Futoshi , Takeda Kentaro , Kita Aya , Takeshita Shigeru 
Published: May 2016

Background: ASP5878 is an orally available, novel Fibroblast Growth Factor Receptor (FGFR) inhibitor against FGFR 1, 2, 3, and 4. It demonstrated potent in vitro and in vivo inhibitory effects on a variety of human tumor cell lines and xenograft models with FGFR alterations. Deregulated activation of FGFR signaling has been implicated in several human cancers. Method:This first-in-human phase I study consists of dose escalation (P1a) and expansion (P1b) stages. The primary objectives of P1a are to determine the safety and tolerability and to establish dose limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended P1b dose (RP1bD). The secondary objectives are to determine pharmacokinetics (PK) and pharmacodynamics (PD) of ASP5878. The exploratory objective is to determine antitumor activity of ASP5878. ASP5878 was orally administered on Cycle 0 (a single oral dose once daily followed by 2 days interruption), Cycle 1 and subsequent cycles (continuous daily dosing once (qd) or twice daily (bid)) consist of 28 days each. Dose escalation was planned in a step-wise manner, by using the Bayesian Continual Reassessment Method. Three to four patients (pts) with advanced solid tumors (unselected for FGFR alteration) were planned to be enrolled per cohort in P1a. Results: As of 12 March 2015, 25 pts with advanced solid tumors (lung cancer, hepatocellular carcinoma, etc.) had received at least 1 dose of ASP5878 in 7 dose cohorts (0.5 - 2.0 mg qd, 2.0 - 10.0 mg bid continuous dosing). Twenty three (92.0%) pts experienced at least a single AE. AEs reported by 20 (80%) pts were considered to be study-drug related by the investigators. SAEs were reported in 3 pts (grade 3 hepatic dysfunction in the 1.0 mg qd cohort, grade 3 dyspnea in the 2.0 mg bid cohort and grade 3 urinary tract infection (UTI) in the 2.0 mg bid cohort). Of these, only the UTI was considered to be possibly related to ASP5878 exposure. No DLT was observed, up to the 10 mg bid cohort. Common possibly or probably drug-related AEs (mostly grade 1/2) were hyperphosphatemia (HP) (12/25, 48%), serous retinal detachment (SRD) (8/25, 32%), and diarrhea (8/25, 32%). HP was transient and reversible, and was mostly manageable by appropriate measures (e.g.; low phosphate diet, oral phosphate adsorbent, and/or temporary study drug interruption). The vast majority of SRD did not cause any affect on visual perception and resolved after brief study drug interruption. Preliminary PK analyses revealed that plasma concentrations of ASP5878 were increased in a dose proportional manner with median tmax of 1-3 hr and median t1/2of 2-6 hr. Preliminary data on 3 pts enrolled at a 20mg bid dose indicate that HP was observed in all 3 pts with 2 of the 3 patient's HP considered a DLT by the investigators/sponsor. One partial response was observed in a bladder cancer patient with an FGFR gene alteration in the 20 mg bid cohort. In the presentation, further updates will be presented. Conclusions: ASP5878 was well tolerated with manageable, mostly grade 1/2 AEs. Tumor shrinkage was observed in a bladder cancer patient with an FGFR gene alteration. RP1bD has not yet been established. Further dose exploration is ongoing (NCT02038673).

Citation Format: Toshio Shimizu, Toshihiko Doi, Noboru Yamamoto, Haruyasu Murakami, Junji Furuse, Koji Kawai, Hiroyuki Nishiyama, Satoshi Morita, Shunji Takahashi, Erkut Bahceci, Joyce Steinberg, Howard A. Ball, Futoshi Kunieda, Kentaro Takeda, Aya Kita, Shigeru Takeshita. Result of a phase 1 (dose-escalation stage), first-in-human study of ASP5878, an oral FGFR inhibitor, in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A165.