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

Invest New Drugs. 2017 Aug;35(4):451-462. doi: 10.1007/s10637-016-0416-x. Epub 2017 Jan 10.

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.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Asian Continental Ancestry Group
  • Benzamides / adverse effects
  • Benzamides / blood
  • Benzamides / pharmacokinetics
  • Benzamides / therapeutic use*
  • Female
  • Half-Life
  • Humans
  • Male
  • Middle Aged
  • Neoplasms / blood
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Piperazines / adverse effects
  • Piperazines / blood
  • Piperazines / pharmacokinetics
  • Piperazines / therapeutic use*
  • Pyrazoles / adverse effects
  • Pyrazoles / blood
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / therapeutic use*
  • Receptors, Fibroblast Growth Factor / antagonists & inhibitors*
  • Treatment Outcome

Substances

  • AZD4547
  • Antineoplastic Agents
  • Benzamides
  • Piperazines
  • Pyrazoles
  • Receptors, Fibroblast Growth Factor

Associated data

  • ClinicalTrials.gov/NCT01213160