title: Dual inhibition of the vascular endothelial growth factor pathway: a phase 1 trial evaluating bevacizumab and AZD2171 (cediranib) in patients with advanced solid tumors.
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.
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.forename: Ignacio
authors.initials: I
authors.lastname: Garrido-Laguna
authors.forename: Suhendan
authors.initials: S
authors.lastname: Ekmekcioglu
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Falchook
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wheler
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Moulder
authors.forename: Sarina
authors.initials: S
authors.lastname: Piha-Paul
authors.forename: Apostolia M
authors.initials: AM
authors.lastname: Tsimberidou
authors.forename: YueJin
authors.initials: Y
authors.lastname: Wen
authors.forename: Kirk S
authors.initials: KS
authors.lastname: Culotta
authors.forename: Kenna
authors.initials: K
authors.lastname: Anderes
authors.forename: Darren W
authors.initials: DW
authors.lastname: Davis
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.forename: Goldy C
authors.initials: GC
authors.lastname: George
authors.forename: Luis H
authors.initials: LH
authors.lastname: Camacho
authors.forename: Susan
authors.initials: S
authors.lastname: Percy Ivy
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D002543:Cerebral Hemorrhage / Q000139:chemically induced; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D009360:Neoplastic Cells, Circulating; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012509:Sarcoma / Q000188:drug therapy / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007211:Indoles
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; C467484:VEGFA protein, human; C500926:cediranib; D007211:Indoles
keywords: angiogenesis; bevacizumab; cediranib; phase 1