Safety, tolerability and pharmacokinetics of the fibroblast growth factor receptor inhibitor AZD4547 in Japanese patients with advanced solid tumours: a Phase I study

Abstract

Background AZD4547 is a potent, oral, highly selective fibroblast growth factor receptor (FGFR) inhibitor in clinical development for treating tumours with a range of FGFR aberrations, including FGFR mutations, amplifications and fusions. Methods This open-label, Phase I, multicentre study (NCT01213160) evaluated the safety, pharmacokinetics, and preliminary antitumour efficacy (RECIST v1.1) of AZD4547 monotherapy in Japanese patients with advanced solid tumours. Part A was a dose-escalation part; Part B was a dose-expansion part in patients with FGFR-amplified tumours, confirmed by fluorescence in situ hybridization. Results Thirty patients enrolled in Part A (dose range: 40 mg twice daily [bid] to 120 mg bid; 160 mg once daily [qd]), four in Part B (80 mg bid). No dose-limiting toxicities were observed and maximum tolerated dose was not determined. Most common adverse events (AEs; any grade) were: dysgeusia (50% of patients); stomatitis (41%); diarrhoea (38%); hyperphosphataemia (38%); dry mouth (35%). Common grade ≥3 AEs were nausea (12% of patients) and neutropenia (9%). No complete or partial responses were observed: 21/30 patients had stable disease ≥4 weeks in Part A, and 1/4 patients had stable disease ≥10 weeks in Part B. Following single and multiple dosing, absorption rate appeared moderate; peak plasma concentrations generally occurred 3-4 h post-dose, then declined biphasically with terminal half-life ~30 h. Steady state was reached by day 8. Compared with single dosing, plasma concentrations were, on average, 2.4- and 3.3- to 5.4-fold higher after qd and bid dosing, respectively. Conclusions AZD4547 was well tolerated in Japanese patients, with best response of stable disease ≥4 weeks.

Keywords: AZD4547; FGFR; Japanese; Pharmacokinetics; Phase I; Safety.

Fig. 1

AZD4547 Japanese Phase I study design. Part A was a dose-escalation study with a 5- to 10-day washout period followed by bid dosing. Part B was a dose-escalation study in patients with FGFR-amplified tumours with an RP2D of 80 mg bid. *Cohort 4 dose was based on PK modelling data and was consistent with the latest tolerated exposures from AZD4547 bid dosing in Western patients [16], as well as emerging safety data from Japanese patients (this study); ^†In schedule 2, it was planned that dose assessment could extend over multiple cohorts; however, no cohorts exceeded the 160 mg qd dosing level due to emerging data from the study in Western patients and a decision from the clinical project team. RP2D, recommended Phase II dose

Fig. 2

Plasma concentration–time profiles of AZD4547 after a single dosing and b multiple dosing. Geometric mean plasma concentrations are shown against time for the dosing levels 40 mg bid, 80 mg bid (combined from cohorts dosed at the 80 mg bid level across both Parts A and B), 120 mg bid, and 160 mg qd