467P - FGFR inhibitor and chemotherapy in gastric cancer (FACING): Phase I results from an ECMC combinations alliance phase I/II trial of AZD4547 in combi...

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Drug Development
Gastric Cancer
Presenter Colin Lindsay
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors C. Lindsay1, F. Thistlethwaite2, A. Gupta3, W. Mansoor4, L. Lewsley5, R. Hubner2, C.A. Hopkins1, K. Chan2, C. McDowell6, S. Campbell1, L. Douglas5, C. Bray5, M. Ranson7, C. Dive8, M.R. Middleton3, D. Landers9, T.R..J. Evans10
  • 1Medical Oncology, Beatson West of Scotland Cancer Centre Gartnavel General Hospital, G12 0YN - Glasgow/GB
  • 2Medical Oncology, The Christie NHS Foundation Trust, M20 4BX - Manchester/GB
  • 3Medical Oncology, The Oxford Cancer Centre, Churchill Hospital, Oxford Radcliffe Hospitals NHS Trust, OX3 7LJ - Oxford/GB
  • 4Histopathology, The Christie NHS Foundation Trust, M20 4BX - Manchester/GB
  • 5Cancer Research Uk Clinical Trials Unit, Cancer Research UK, G12 0YN - Glasgow/GB
  • 6Cruk Drug Development Office, Cancer Research UK, EC1V 4AD - London/GB
  • 7Department Of Medical Oncology, Formerly at University of Manchester Christie Hospital NHS Trust, Manchester/GB
  • 8Institute Of Cancer Sciences, Paterson Institute for cancer research University of Manchester, M20 4BX - Manchester/GB
  • 9Early Clinical Development In Oncology, Astrazeneca UK Limited, SK10 4TG - Macclesfield/GB
  • 10University Of Glasgow, Institute of Cancer Sciences, Glasgow/GB

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.