Abstract CT121: Phase I dose-escalation study of TAS-120, a highly selective, covalently bound FGFR inhibitor, in patients with advanced solid tumors
Authors: Bahleda Rastislav , Meric-Bernstam Funda , Goyal Lipika , Tran Ben , He Helen , Winkler Robert , Hierro Cinta , Arkenau Hendrik-Tobias 
Published: August 2018

Abstract
Background: Fibroblast growth factor receptor (FGFR) gene abnormalities are present in hard to treat cholangiocarcinoma (CCA), glioblastoma, and urothelial carcinomas. TAS-120 is a highly potent and selective, covalently bound small-molecule inhibitor of FGFR1-4. This Phase I dose-escalation study investigated the safety, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and/or recommended Phase II dose (RP2D) of TAS-120 in patients (pts) with advanced solid tumors (NCT02052778).
Methods: Pts aged ≥18 years with advanced solid tumors (without FGFR abnormalities in lower doses and with FGFR abnormalities in higher doses) who had failed all standard therapies were enrolled. TAS-120 was administered 3 times a week (QOD; escalating dose levels, 8-200 mg) or once daily (QD; escalating dose levels, 4-24 mg) continuously in 21-day cycles. Primary objective was to evaluate the safety and determine the MTD and/or RP2D of TAS-120; secondary objective was preliminary antitumor activity.
Results: Of 86 enrolled pts, 42 were in the 9 QOD cohorts and 44 in the 5 QD cohorts; 34 pts (17 in each cohort) had ≥4 prior lines of anticancer therapy. The most common tumor types were CCA (7 QOD pts [16.7%]; 18 QD pts [40.9%]) and breast cancer (7 QOD pts [16.7%]; 5 QD pts [11.4%]). Grade ≥3 treatment-emergent AEs (TEAEs) were reported in 24 QOD pts (57.1%) and 27 QD pts (61.4%). The most common TEAEs (≥30%) in any of the QOD and QD cohorts were hyperphosphatemia (50.0% and 68.2%), diarrhea (40.5% and 31.8%), nausea (31.0% and 27.3%), dry mouth (33.3% and 25.0%), constipation (26.2% and 38.6%), and anemia (33.3% and 18.2%), respectively. Treatment-related grade ≥3 TEAEs were reported in 10 QOD pts (23.8%) and 17 QD pts (38.6%). The most common treatment-related TEAEs (≥20%) in QOD and QD cohorts were hyperphosphatemia (50.0% and 68.2%), diarrhea (33.3% and 25.0%), and dry mouth (26.2% and 22.7%), respectively. DLTs were reported in 3 of 9 evaluable pts at 24 mg QD (1 each had grade 3 elevated ALT, elevated ALT and AST, blood bilirubin increase) and 1 of 6 evaluable pts at 8 mg QOD (grade 4 creatinine kinase increase). Median treatment duration was 49.0 days (range 8-359) and 68.5 days (range 1-414) in the QOD and QD cohorts, respectively. Stable disease was reported for 22 QOD pts (52.3%) and 20 QD pts (45.4%), with partial response in 3 QD pts (all had CCA with FGFR2 fusions, 2 pts were in 16 mg, and 1 pt in 24 mg cohorts). Based on these data, the MTD and RP2D for TAS-120 is 20 mg QD.
Conclusions: In the dose-escalation phase, TAS-120 demonstrated a very tolerable safety profile and preliminary antitumor activity in heavily pretreated pts with CCA harboring FGFR2 fusions. The dose-expansion phase in pts with tumors harboring FGFR aberrations is ongoing and a Phase II study at 20 mg QD will be initiated in CCA pts with FGFR2 fusions.
Citation Format: Rastislav Bahleda, Funda Meric-Bernstam, Lipika Goyal, Ben Tran, Helen He, Robert Winkler, Cinta Hierro, Hendrik-Tobias Arkenau. Phase I dose-escalation study of TAS-120, a highly selective, covalently bound FGFR inhibitor, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT121.