Dual inhibition of the vascular endothelial growth factor pathway: A phase 1 trial evaluating bevacizumab and AZD2171 (cediranib) in patients with advanced solid tumors

David S. Hong, Ignacio Garrido-Laguna, Suhendan Ekmekcioglu, Gerald S. Falchook, Aung Naing, Jennifer Jane Wheler, Siqing Fu, Stacy L. Moulder, Sarina Piha-Paul, Apostolia M. Tsimberidou, Yuejin Wen, Kirk S. Culotta, Kenna Anderes, Darren W. Davis, Wen Liu, Goldy C. George, Luis H. Camacho, Susan Percy Ivy, Razelle Kurzrock

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

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 (< 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.

Original languageEnglish (US)
Pages (from-to)2164-2173
Number of pages10
JournalCancer
Volume120
Issue number14
DOIs
StatePublished - Jan 1 2014

Keywords

  • angiogenesis
  • bevacizumab
  • cediranib
  • phase 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Dual inhibition of the vascular endothelial growth factor pathway: A phase 1 trial evaluating bevacizumab and AZD2171 (cediranib) in patients with advanced solid tumors'. Together they form a unique fingerprint.

  • Cite this