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

• Published in: European journal of cancer (1990) Vol. 46; no. 5; pp. 901 - 911
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.03.2010; Elsevier
• Subjects: Adult; Aged; Angiogenesis inhibitors; Anorexia - chemically induced; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Clinical trial; Diarrhea - chemically induced; Drug Therapy, Combination; EGFR; Fatigue - chemically induced; Female; Hematology, Oncology and Palliative Medicine; Humans; Male; Medical sciences; Middle Aged; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Netherlands; Pharmacology. Drug treatments; Phase I; Quinazolines - administration & dosage; Quinazolines - adverse effects; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; Treatment Outcome; Tumors; VEGFR-1; VEGFR-2; VEGFR-3; Young Adult; Netherlands; Phase I; VEGFR-3; VEGFR-2; VEGFR-1; Clinical trial; Angiogenesis inhibitors; EGFR; Antineoplastic agent; Quinazoline derivatives; Epidermal growth factor receptor; Vascular endothelium growth factor receptor; Signal transduction; Cancerology; Advanced stage; Tumor; Antiangiogenic agent; Gefitinib; Vascular endothelial growth factor receptor 2; Protein-tyrosine kinase; Vascular endothelial growth factor receptor 3; Cediranib; Vascular endothelial growth factor receptor 1; Human; Drug combination; Enzyme; Tyrosine kinase inhibitor; Transferases; Enzyme inhibitor
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2009.12.023

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 (20–45 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 A1) 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.