Dual inhibition of the vascular endothelial growth factor pathway: A phase 1 trial evaluating bevacizumab and AZD2171 (cediranib) in patients with advanced solid tumors
| Autor: | Gerald Steven Falchook, Luis H. Camacho, Goldy C. George, David S. Hong, Siqing Fu, Wen Liu, Kirk S. Culotta, Aung Naing, Kenna Lynn Anderes, Sarina Anne Piha-Paul, Jennifer J. Wheler, Susan Percy Ivy, Stacy Moulder, Suhendan Ekmekcioglu, Razelle Kurzrock, Yuejin Wen, Apostolia Maria Tsimberidou, Ignacio Garrido-Laguna, Darren W. Davis |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
medicine.medical_specialty Bevacizumab business.industry Area under the curve Cancer medicine.disease Gastroenterology Inflammatory breast cancer Surgery Cediranib Vascular endothelial growth factor chemistry.chemical_compound Oncology Pharmacokinetics chemistry Tumor progression Internal medicine Medicine business medicine.drug |
| Zdroj: | Cancer. 120:2164-2173 |
| ISSN: | 0008-543X |
| Popis: | BACKGROUND The current study was conducted to evaluate the safety and biological activity of dual inhibition of the vascular endothelial growth factor (VEGF) pathway with combined bevacizumab and cediranib (a VEGF receptor tyrosine kinase inhibitor). METHODS This was a 3 + 3 dose escalation study in patients with advanced solid tumors. Cediranib was given orally daily for 21 days and bevacizumab intravenously every 2 weeks. Pharmacokinetics and correlates (nitric oxide synthase, nitrate oxide, and circulating tumor cells) were assessed. RESULTS Fifty-one patients were treated. Dose-limiting toxicities (DLTs) (grade 3-4; graded according to the National Cancer Institute Common Terminology Criteria of Adverse Events [version 3.0]) observed included 1 patient with chest pain, 1 patient with fatigue, 2 patients with thrombocytopenia, 3 patients with hypertension (1 with intracranial hemorrhage), and 1 patient with grade 5 hemoptysis. Moreover, 2 patients presented with grade 3 intracranial bleeding beyond the DLT window. Dose level 2 (cediranib at a dose of 20 mg/day and bevacizumab at a dose of 5 mg/kg every 2 weeks) was selected as the recommended phase 2 dose (RP2D); 17 patients were treated at dose level 2 with 1 DLT and no intracranial bleeding or severe hypertension reported. Pharmacokinetics of cediranib at dose level 3 demonstrated a 46% to 77% increase in area under the curve (0-24 hours) on cycle 1 day 1 compared with historical controls. Four patients attained partial remissions: inflammatory breast cancer (-54%), basal cell carcinoma (-33%), alveolar soft part sarcoma (-33%), and synovial sarcoma (-32%). Patients with a lower circulating tumor cell count ( |
| Databáze: | OpenAIRE |
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