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

Abstract

Summary 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.

First‐in‐human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors

“…Reasons for TEAE‐related dose interruptions included nausea (n = 3), vomiting (n = 2), anorexia (n = 2), nasopharyngitis (n = 1), and decreased neutrophil count (n = 1). Selective FGFR inhibition has been associated with an increased risk of hyperphosphatemia and eye toxicity, including retinal detachment . In the present study, there were nine AE of hyperphosphatemia and three AE of retinal detachment, but all were <grade 3 in severity and did not lead to dose reduction or discontinuation.…”

“…FGFR signaling is involved in the regulation of FGF23 expression, and increased FGF23 production has been implicated in the development of several hypophosphatemic diseases . Selective FGFR inhibitors are typically associated with on‐target toxicities such as hyperphosphatemia, which appears to play a role in FGF23 signaling and eye toxicity such as macular edema and retinal detachment, as reported previously . No clear relationship between these toxicities and the inhibition of FGFR has been found.…”

“…A phase I study of the selective FGFR1‐3 inhibitor AZD4547 in patients with squamous cell lung cancers confirmed target inhibition but failed to achieve its efficacy endpoint . In Japanese patients with advanced solid tumors, AZD4547 was well tolerated, with best response being stable disease (duration ≥4 weeks) . BGJ398, another selective FGFR1‐3 inhibitor, showed antitumor activity in several tumor types and had a tolerable safety profile in a phase I study in patients with advanced solid tumors, whereas JNJ‐42756493, a pan‐FGFR inhibitor recently approved by the FDA for urothelial carcinoma, showed a clinical response with acceptable safety in a similar patient population .…”

Discovery and Biological Evaluation of a Series of Pyrrolo[2,3-<em>b</em>]pyrazines as Novel FGFR Inhibitors

“…Compounds 11-28 were prepared with a similar procedure as that used for 8. [2,3-b] [2,3-b]pyrazine (11) [2,3-b]pyrazine (14). [2,3-b]pyrazine (15) [2,3-b]pyrazine (16) [2,3-b]pyrazine (17 [2,3-b]pyrazine (18 …”

“…Aberrant FGFR signaling could be caused by different mechanisms, including activating mutations in FGFRs, oncogenic fusion of FGFRs and over-expression of FGFRs [10]. Currently, several FGFR-targeted agents, mostly are small molecules binding to the kinase domain, are evaluated in clinical trials for cancer treatment, and most intriguing and advanced evaluated are FGFR-selective inhibitors, such as AZD4547 (1) [11], NVP-BGJ398 (2) [12] and JNJ-42756493 (3) [13]. As investigated by Patani et al [14], due to the landscape of activated mutations in FGFR kinases, the above-mentioned FGFR inhibitors (1, 2, 3) showed distinct effects towards different mutants, which indicated that developing FGFR inhibitors with novel scaffold are highly demanded as they may provide unique therapeutic benefits towards certain patients.…”