INTRODUCTION: PTK/ZK is a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors, platelet-derived growth factor receptor, colony-stimulating factor 1 receptor, and cytokine stem cell factor receptor. Cetuximab is a monoclonal antibody against epidermal growth factor (EGF) receptor. Combining inhibition of VEGF and EGF signaling might act additive or synergistically. METHODS: In phase 1 design, patients with advanced solid tumors were treated with PTK/ZK daily (cohort 1, 750 mg once daily; cohort 2, 1250 mg once daily; cohort 3, 250 mg [morning] and 500 mg [evening]; and cohort 4, 500 mg [morning] and 750 mg [evening]) in combination with cetuximab 250 mg/m(2) weekly in cycles of 28 days in cohorts of three patients. Toxicity was evaluated conform the Common Terminology Criteria for Adverse Events classification 3.0. Pharmacokinetics and pharmacodynamics consisting of circulating endothelial (progenitor) cell (CE[P]C) analysis by flow cytometry were performed. RESULTS: Safety and tolerability was evaluated in 16 patients. The most frequently reported adverse events were acne, dry skin, fatigue, nausea, dizziness, vomiting, headache, and diarrhea. One dose-limiting toxicity occurred in cohort 3 consisting of a grade 3 transaminitis. Pharmacokinetic analysis revealed no significant changes in PTK/ZK exposure on coadministration with cetuximab and in bioavailability at equivalent total daily doses. Biomarker analysis showed no significant change in the number of CE(P)Cs during treatment. One of 14 evaluable patients showed a partial response for at least 11.5 months, and 7 patients (50%) stable disease for at least 2 months. CONCLUSIONS: This study shows that the combination of PTK/ZK and cetuximab is well tolerated with only slightly overlapping toxicity profiles and has antitumor activity.
INTRODUCTION:PTK/ZK is a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors, platelet-derived growth factor receptor, colony-stimulating factor 1 receptor, and cytokine stem cell factor receptor. Cetuximab is a monoclonal antibody against epidermal growth factor (EGF) receptor. Combining inhibition of VEGF and EGF signaling might act additive or synergistically. METHODS: In phase 1 design, patients with advanced solid tumors were treated with PTK/ZK daily (cohort 1, 750 mg once daily; cohort 2, 1250 mg once daily; cohort 3, 250 mg [morning] and 500 mg [evening]; and cohort 4, 500 mg [morning] and 750 mg [evening]) in combination with cetuximab 250 mg/m(2) weekly in cycles of 28 days in cohorts of three patients. Toxicity was evaluated conform the Common Terminology Criteria for Adverse Events classification 3.0. Pharmacokinetics and pharmacodynamics consisting of circulating endothelial (progenitor) cell (CE[P]C) analysis by flow cytometry were performed. RESULTS: Safety and tolerability was evaluated in 16 patients. The most frequently reported adverse events were acne, dry skin, fatigue, nausea, dizziness, vomiting, headache, and diarrhea. One dose-limiting toxicity occurred in cohort 3 consisting of a grade 3 transaminitis. Pharmacokinetic analysis revealed no significant changes in PTK/ZK exposure on coadministration with cetuximab and in bioavailability at equivalent total daily doses. Biomarker analysis showed no significant change in the number of CE(P)Cs during treatment. One of 14 evaluable patients showed a partial response for at least 11.5 months, and 7 patients (50%) stable disease for at least 2 months. CONCLUSIONS: This study shows that the combination of PTK/ZK and cetuximab is well tolerated with only slightly overlapping toxicity profiles and has antitumor activity.
Authors: P Therasse; S G Arbuck; E A Eisenhauer; J Wanders; R S Kaplan; L Rubinstein; J Verweij; M Van Glabbeke; A T van Oosterom; M C Christian; S G Gwyther Journal: J Natl Cancer Inst Date: 2000-02-02 Impact factor: 13.506
Authors: F Ciardiello; R Bianco; V Damiano; G Fontanini; R Caputo; G Pomatico; S De Placido; A R Bianco; J Mendelsohn; G Tortora Journal: Clin Cancer Res Date: 2000-09 Impact factor: 12.531
Authors: J Baselga; D Pfister; M R Cooper; R Cohen; B Burtness; M Bos; G D'Andrea; A Seidman; L Norton; K Gunnett; J Falcey; V Anderson; H Waksal; J Mendelsohn Journal: J Clin Oncol Date: 2000-02 Impact factor: 44.544
Authors: Maura N Dickler; Hope S Rugo; Carey A Eberle; Edi Brogi; James F Caravelli; Katherine S Panageas; Jeff Boyd; Benjamin Yeh; Diana E Lake; Chau T Dang; Teresa A Gilewski; Jacqueline F Bromberg; Andrew D Seidman; Gabriella M D'Andrea; Mark M Moasser; Michele Melisko; John W Park; Janet Dancey; Larry Norton; Clifford A Hudis Journal: Clin Cancer Res Date: 2008-12-01 Impact factor: 12.531
Authors: R M Shaheen; S A Ahmad; W Liu; N Reinmuth; Y D Jung; W W Tseng; K E Drazan; C D Bucana; D J Hicklin; L M Ellis Journal: Br J Cancer Date: 2001-08-17 Impact factor: 7.640
Authors: Wesley Hayes; Sibylle Tschumi; Simon C Ling; Janusz Feber; Michael Kirschfink; Christoph Licht Journal: Pediatr Nephrol Date: 2014-11-22 Impact factor: 3.651
Authors: Ana P S Silva; Priscila V Coelho; Maristella Anazetti; Patricia U Simioni Journal: Hum Vaccin Immunother Date: 2016-11-10 Impact factor: 3.452