title: Phase II study evaluating the efficacy, safety, and pharmacodynamic correlative study of dual antiangiogenic inhibition using bevacizumab in combination with sorafenib in patients with advanced malignant melanoma.
abstract: OBJECTIVE
  Melanomas are vascular tumors with a high incidence of BRAF mutations driving tumor proliferation. Complete inhibition of vascular endothelial growth factor (VEGF) signaling has potential for enhanced antitumor efficacy.
  
  
  METHODS
  Patients with advanced melanoma and adequate organ function were eligible. Sorafenib was given orally at 200 mg BiD for 5 days every week; bevacizumab was administered 5 mg/kg intravenously every 14 days. The primary objective was to determine clinical biological activity. The secondary objectives were safety, tolerability, and time to progression (TTP). Pharmacodynamic analysis included serum VEGF and soluble VEGF receptor-1 and VEGF receptor-2 performed at baseline, C1D15 and C2D1. The study was terminated during the first stage of a Simon two-stage design, after 14 of planned 21 subjects were enrolled.
  
  
  RESULTS
  Of the 14 patients who received treatment, no objective tumor responses were observed. Stable disease (SD) ≥16 weeks was observed in 57 % patients, including three patients with SD lasting ≥1 year. Median TTP was 32 weeks. The most frequently reported drug-related adverse events (AEs) were hand-foot syndrome (57.1 %), fatigue (57.1 %), hypertension (64.3 %), and proteinuria (35.7). Grade 3/4 drug-related AEs were hypertension (14.2 %), hand-foot syndrome, proteinuria, and thrombocytopenia (7 % each). Patients with low VEGF (<300 pg/ml) experienced longer TTP than those with high VEGF [median 50 vs. 15 weeks, p = 0.02). A similar pattern was seen for VEGFR1 and VEGFR2, although it did not reach statistical significance.
  
  
  CONCLUSIONS
  Combined VEGF/VEGFR blockade using bevacizumab with sorafenib shows clinical activity. The linkage between VEGF levels and time to tumor progression needs further exploration.
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA, Mahalingam@uthscsa.edu.
authors.forename: Devalingam
authors.initials: D
authors.lastname: Mahalingam
authors.forename: Laeeq
authors.initials: L
authors.lastname: Malik
authors.forename: Muralidhar
authors.initials: M
authors.lastname: Beeram
authors.forename: Jordi
authors.initials: J
authors.lastname: Rodon
authors.forename: Kamalesh
authors.initials: K
authors.lastname: Sankhala
authors.forename: Alain
authors.initials: A
authors.lastname: Mita
authors.forename: Daniel
authors.initials: D
authors.lastname: Benjamin
authors.forename: Norma
authors.initials: N
authors.lastname: Ketchum
authors.forename: Joel
authors.initials: J
authors.lastname: Michalek
authors.forename: Anthony
authors.initials: A
authors.lastname: Tolcher
authors.forename: John
authors.initials: J
authors.lastname: Wright
authors.forename: John
authors.initials: J
authors.lastname: Sarantopoulos
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; 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; D015415:Biomarkers / Q000097:blood; D018450:Disease Progression; D016903:Drug Monitoring; D057239:Early Termination of Clinical Trials; D005240:Feasibility Studies; D005260:Female; D060831:Hand-Foot Syndrome / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology; D007700:Kinetics; D008297:Male; D008545:Melanoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000097:blood / Q000737:chemistry; D012720:Severity of Illness Index; D000077157:Sorafenib; D042442:Vascular Endothelial Growth Factors / Q000097:blood / Q000737:chemistry
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D042442:Vascular Endothelial Growth Factors; D009536:Niacinamide; D000068258:Bevacizumab; D000077157:Sorafenib; D040262:Receptors, Vascular Endothelial Growth Factor