Abstract CT106: Ph I/II study of FGF401 in adult pts with HCC or solid tumors characterized by FGFR4/KLB expression
Authors: Chan Stephen L. , Yen Chia-Jui , Schuler Martin , Lin Chia-Chi , Choo Su Pin , Weiss Karl-Heinz , Geier Andreas , Okusaka Takuji , Lim Ho Yeong , Macarulla Teresa , Zhu Andrew X. , Kakizume Tomoyuki , Gu Yi (Gary) , Porta Diana Graus , Myers Andrea P. , Delord Jean-Pierre 
Published: July 2017

Abstract
Background: The fibroblast growth factor 19 (FGF19)-fibroblast growth factor receptor 4 (FGFR4)-Klotho β (KLB) signaling pathway regulates bile acid synthesis and is also a key driver in certain subtypes of hepatocellular carcinoma (HCC). FGF401 is a highly selective FGFR4 inhibitor with antitumor activity in several HCC models. This first-in-human study was designed to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of FGF401 in patients (pts) with advanced cancers and FGFR4/KLB expression.
Methods: An ongoing Phase (Ph) I/II, open-label study (NCT02325739) is evaluating FGF401 in pts with HCC or solid tumors with positive FGFR4 and KLB expression (RT-qPCR prescreening). Based on the known effect of FGF19 signaling on bile acid synthesis, the safety of FGF401 was explored under fasted and fed states, and dose escalation was guided by a Bayesian hierarchical model which estimates dose-toxicity relationships at each state. The primary objective was to determine the maximum tolerated doses (MTDs) and recommended Phase II doses (RP2Ds). Pre- and on-treatment specimens (blood, tumor) were collected for PK monitoring and evaluation of PD markers, including 7-alpha-hydroxy-4-cholesten-3-1, total bile acids, total cholesterol, and FGF19. The Ph II part will explore safety and preliminary efficacy of FGF401 in 3 pt groups.
Results: Data are presented from the Ph I dose escalation part of the study (n=67; data cut-off Nov 30, 2016). Median age was 61 years (range, 23-80), 81% of pts were male, and the primary tumor type was HCC in 79% of pts. Dose levels were 50 mg once daily (QD), 80 mg QD, 120 mg QD, and 150 mg QD under fasted conditions, and 80 mg QD and 120 mg QD under fed conditions. Dose-limiting toxicities were observed in 6 pts (1 × 50 mg dose, 2 × 120 mg, 3 × 150 mg): ALT increased (↑) in 2 pts, AST↑ in 4 pts, and blood bilirubin↑ in 1 pt. The most common (&gt;15%) adverse events (AE) suspected to be related to FGF401 were diarrhea (70%; Grade 1/2, 67%), AST↑ (46%), and ALT↑ (40%). Grade 3/4 AEs (&gt;5%) were AST↑ (16%) and ALT↑ (12%). The RP2D was declared for the fasting cohort as 120 mg QD based on all data, including safety, PK, PD, and efficacy evaluations; updated PK and PD data will be presented. The RP2D for the fed cohort is under evaluation; MTDs have not been determined for either cohort. At the data cut-off of Nov 14, 2016, the overall response rate across doses in Ph I pts with HCC (N=53) was 8% and stable disease was seen in 53% of pts. Median time to progression was 4.1 months with one-sided 90% CI: (2.8, NE). Objective responses were seen in both FGF19-positive and -negative pts.
Conclusions: Preliminary data suggest FGF401 has a manageable safety profile that is consistent with FGFR4 pathway inhibition. Promising clinical activity was observed in pts with advanced HCC in this dose escalation part of the study. Studies to further evaluate FGF401 as a single agent and in combination are ongoing.
Citation Format: Stephen L. Chan, Chia-Jui Yen, Martin Schuler, Chia-Chi Lin, Su Pin Choo, Karl-Heinz Weiss, Andreas Geier, Takuji Okusaka, Ho Yeong Lim, Teresa Macarulla, Andrew X. Zhu, Tomoyuki Kakizume, Yi (Gary) Gu, Diana Graus Porta, Andrea P. Myers, Jean-Pierre Delord. Ph I/II study of FGF401 in adult pts with HCC or solid tumors characterized by FGFR4/KLB expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT106. doi:10.1158/1538-7445.AM2017-CT106