467P FGFR INHIBITOR AND CHEMOTHERAPY IN GASTRIC CANCER (FACING): PHASE I RESULTS FROM AN ECMC COMBINATIONS ALLIANCE PHASE I/II TRIAL OF AZD4547 IN COMBINATION WITH CISPLATIN AND CAPECITABINE (CX)

C. Lindsay, Fiona Thistlethwaite, A Gupta, W Mansoor, Liz-anne Lewsley, Richard Hubner, K Chan, C McDowell, S Campbell, C Bray, M Ranson, Caroline Dive, MR Middleton, Donal Landers, T. R Jeffery Evans

Research output: Contribution to journalArticle

Abstract

Aim: Fibroblast growth factors (FGFs) and their receptors (FGFRs) control a wide range of biological functions, and are implicated in the pathogenesis of diverse tumour types including gastro-oesophageal adenocarcinoma (OGA). AZD4547 is a potent, selective, small molecule inhibitor of FGFR 1, 2, & 3 tyrosine kinases. The aims of the phase I component of this study were to determine the safety, MTD, & PK profile of AZD4547 when administered with cisplatin (C) and capecitabine (X). Methods: Eligible patients (pts) with refractory advanced solid tumors, adequate performance status (PS), haematologic, renal, hepatic function received 1 of 3 escalating doses of AZD4547 in a “rolling six” dose escalation design. AZD4547 was administered orally (po) bid days 1-14 in combination with C (80 mg/m2 i/v) and X (1000 mg/m2 po bid days 1–14) in 3-weekly cycles. DLTs were based on cycle 1 toxicities which were assessed weekly (clinical, haematologic, biochemical) with ophthalmic assessment and echocardiogram at 4 weeks. Plasma AZD4547 was measured in blood over 24 hrs (day 1). Disease (CT scan) was assessed 9-weekly. Results: 19 pts (11 M, 8F), median age 57 (range: 40-78) were enrolled; 16 with PS 0 (9) or 1 (7) were evaluable for toxicity at 40mg BD (4 pts), 60mg BD (6), or 80mg BD (6) dose levels. Median duration of treatment was 3 cycles (range: 1-6). 4 DLTs occurred in 3 pts: 3 DLTs at 80mg BD (grade 3/4 neutropenia with fever; & > 2 week dose interruption for cardiac toxicity; - 1 pt; grade 3 LFT elevation – 1 pt); 1 DLT at 60mg BD (grade 3 oral mucositis). Cumulative (worst grade, all cycles) grade 3/4 toxicities (excluding DLTs) included hypomagnesaemia (5 pts), electrolyte disturbance (4) neutropenia (3), pulmonary embolism (3), elevated AST / ALT (3), nausea (2), febrile neutropenia (1). 1 partial response (basaloid cervical cancer) was observed at 40mg BD. Stable disease was observed in 7 pts at 9 weeks and in 3 pts at 18 weeks. Conclusions: The recommended dose of AZD4547 is 60mg BD when combined with CX. A randomised phase IIa study of CX + AZD4547 or placebo is on-going in patients with advanced OGA and polysomy or amplification of FGFRs. Disclosure: D. Landers: Employee of AstraZeneca UK Limited, involved in development of the reported drug. All other authors have declared no conflicts of interest.
Original languageEnglish
Article numberiv146-iv164. 10.1093/annonc/mdu331
Pages (from-to)iv155-iv156
Number of pages1
JournalAnnals of Oncology
Volume25
Issue number4
Publication statusPublished - 1 Sept 2014

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  • Manchester Cancer Research Centre

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