Phase I evaluation of cediranib, a selective VEGFR signalling inhibitor, in combination with gefitinib in patients with advanced tumours

van Cruijsen, Hester; Voest, Emile E.; Punt, Cornelis J.A.; Hoekman, Klaas; Witteveen, Petronella O.; Meijerink, Martijn R.; Puchalski, Thomas A.; Robertson, Jane; Saunders, Owain; Jürgensmeier, Juliane M.; van Herpen, Carla M.L.; Giaccone, Giuseppe

doi:10.1016/j.ejca.2009.12.023

« Previous Next »European Journal of Cancer
Volume 46, Issue 5 , Pages 901-911, March 2010

Phase I evaluation of cediranib, a selective VEGFR signalling inhibitor, in combination with gefitinib in patients with advanced tumours

Hester van Cruijsen
- Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
Emile E. Voest
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
Cornelis J.A. Punt
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
Klaas Hoekman
- Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
Petronella O. Witteveen
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
Martijn R. Meijerink
- Department of Radiology, VU University Medical Center, Amsterdam, The Netherlands
Thomas A. Puchalski
- AstraZeneca, Wilmington, DE, USA
- Present address: Centocor, Chesterbrook, PA, USA.
Jane Robertson
- AstraZeneca, Alderley Park, Macclesfield, UK
Owain Saunders
- AstraZeneca, Alderley Park, Macclesfield, UK
Juliane M. Jürgensmeier
- AstraZeneca, Alderley Park, Macclesfield, UK
Carla M.L. van Herpen
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
Giuseppe Giaccone
- Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
- Corresponding author: Address: Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Building 10, Room 12N226, 10 Center Drive, Bethesda, MD 20892-190, USA. Tel.: +1 301 496 4916; fax: +1 301 402 0172.

Received 23 September 2009; received in revised form 7 December 2009; accepted 14 December 2009. published online 11 January 2010.

Abstract

Aim

Cediranib is a highly potent inhibitor of vascular endothelial growth factor receptor (VEGFR) signalling. Preclinical and clinical data suggest that inhibition of the VEGFR and epidermal growth factor receptor (EGFR) pathways may be synergistic. Combination treatment with cediranib and gefitinib, an EGFR signalling inhibitor, was evaluated in patients with advanced solid tumours.

Patients and methods

Ninety patients received treatment in this four-part, open-label study (NCT00502060). The patients received once-daily oral doses of cediranib (20–45mg) and gefitinib 250mg (part A1; n=16) or 500mg (part B1; n=44). A cohort expansion phase investigated the potential pharmacokinetic interaction of cediranib 30mg with gefitinib 250mg (part A2; n=15) or 500mg (part B2; n=15). The primary objective was to assess the safety and tolerability of cediranib with gefitinib. Secondary assessments included pharmacokinetics, efficacy and pharmacodynamics.

Results

Combination treatment was generally well tolerated; the protocol-defined maximum-tolerated dose of cediranib was 30mg/day with gefitinib 250mg/day (part A1) and cediranib 45mg/day was the maximum dose investigated with gefitinib 500mg/day (part B1). The most common adverse events were diarrhoea (84 [93%]), anorexia (63 [70%]) and fatigue (60 [67%]). Cediranib pharmacokinetic parameters were not substantially different when given alone or in combination with gefitinib. Gefitinib pharmacokinetic parameters were similar to those seen previously with gefitinib monotherapy. Efficacy results included eight (9%) confirmed partial responses (6 renal; 1 lung; 1 osteosarcoma) and 38 (42%) patients with stable disease. Pharmacodynamic assessments demonstrated changes in levels of VEGF and soluble VEGFR-2 following treatment.

Conclusions

Combination treatment was generally well tolerated and showed encouraging antitumour activity in patients with advanced solid tumours. These results merit further exploration.

Keywords: VEGFR-1, VEGFR-2, VEGFR-3, EGFR, Angiogenesis inhibitors, Clinical trial, Phase I