title: Dual antiangiogenic inhibition: a phase I dose escalation and expansion trial targeting VEGF-A and VEGFR in patients with advanced solid tumors.
abstract: OBJECTIVE
  Angiogenesis plays a pivotal role in tumor growth and metastasis. Sorafenib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR), combined with bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF-A), would vertically inhibit VEGF/VEGFR signaling. A phase I trial was performed to assess safety, maximum tolerated dose (MTD), and clinical correlates.
  
  
  METHODS
  Patients with advanced solid tumors refractory to standard therapy were eligible. In cohorts of escalating doses, patients received sorafenib daily for 28 days and bevacizumab every two weeks. Clinical correlates included VEGF polymorphisms. Expansion cohorts of responding tumor types were enrolled.
  
  
  RESULTS
  One hundred fifteen patients were treated, and the MTD was identified as 200 mg twice daily sorafenib and 5 mg/kg bevacizumab every two weeks. Median number of prior therapies was four. Twenty-nine patients (25 %) achieved stable disease ≥6 months; six patients (5 %) achieved a partial response (total SD ≥ 6 months/PR=35 (30 %)). 76 patients (66 %) experienced adverse events of grade 2 or higher, most commonly hand and foot syndrome (n = 27, 24 %) and hypertension (n = 24, 21 %). Dose-limiting toxicity occurred in eight patients (7 %), and 45 patients (39 %) required dose reduction for toxicity. Grade 3 and 4 hypertension was associated with longer time to treatment failure, overall survival, and higher response rate.
  
  
  CONCLUSIONS
  Combination sorafenib and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with advanced solid tumors.
authors.affiliation: Sarah Cannon Research Institute at HealthONE, Presbyterian/St. Luke's Medical Center, 1800 Williams Street, Suite 300, Denver, CO, 80218, USA, gerald.falchook@scresearch.net.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Falchook
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wheler
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.forename: Sarina A
authors.initials: SA
authors.lastname: Piha-Paul
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.forename: Apostolia M
authors.initials: AM
authors.lastname: Tsimberidou
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.forename: Ralph
authors.initials: R
authors.lastname: Zinner
authors.forename: Yunfang
authors.initials: Y
authors.lastname: Jiang
authors.forename: Mei
authors.initials: M
authors.lastname: Huang
authors.forename: Quan
authors.initials: Q
authors.lastname: Lin
authors.forename: Kristin
authors.initials: K
authors.lastname: Parkhurst
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D000077157:Sorafenib; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D010671:Phenylurea Compounds; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000068258:Bevacizumab; D000077157:Sorafenib; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D040262:Receptors, Vascular Endothelial Growth Factor; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human