Dual Inhibition of the Vascular Endothelial Growth Factor Pathway

作者：Hong David S^*; Garrido Laguna Ignacio; Ekmekcioglu Suhendan; Falchook Gerald S; Naing Aung; Wheler Jennifer J; Fu Siqing; Moulder Stacy L; Piha Paul Sarina; Tsimberidou Apostolia M; Wen YueJin; Culotta Kirk S; Anderes Kenna; Davis Darren W; Liu Wen; George Goldy C; Camacho Luis H; Ivy Susan Percy; Kurzrock Razelle

来源：Cancer, 2014, 120(14): 2164-2173.

DOI：10.1002/cncr.28701

• angiogenesis
• phase 1
• bevacizumab
• cediranib

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 313 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 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 (<30) at the predose period had a longer time to tumor progression (P=.024, log-rank test). CONCLUSIONS: Cediranib at a dose of 20 mg/day and bevacizumab at a dose of 5 mg/kg every 2 weeks was found to be the RP2D. Activity in several tumor types was noted. Central nervous system bleeding and severe hypertension were observed at doses above the RP2D.

• 出版日期2014-7-15