期刊
EUROPEAN JOURNAL OF CANCER
卷 46, 期 5, 页码 901-911出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2009.12.023
关键词
VEGFR-1; VEGFR-2; VEGFR-3; EGFR; Angiogenesis inhibitors; Clinical trial; Phase I
类别
资金
- AstraZeneca
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 (20-45 mg) and gefitinib 250 mg (part A1; n = 16) or 500 mg (part B1; n = 44). A cohort expansion phase investigated the potential pharmacokinetic interaction of cediranib 30 mg with gefitinib 250 mg (part A2; n = 15) or 500 mg (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 30 mg/day with gefitinib 250 mg/day (part Al) and cediranib 45 mg/day was the maximum dose investigated with gefitinib 500 mg/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. (C) 2009 Elsevier Ltd. All rights reserved.
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