title: Phase I study of every 2- or 3-week dosing of ramucirumab, a human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2 in patients with advanced solid tumors.
abstract: BACKGROUND
  Ramucirumab is a fully human immunoglobulin G1 monoclonal antibody receptor antagonist designed to block the ligand-binding site of vascular endothelial growth factor receptor-2 (VEGFR-2). An initial phase I study evaluated ramucirumab administered weekly in advanced cancer patients. This phase I study of ramucirumab [administered every 2 or 3 weeks (Q2W or Q3W)] examined safety, maximum tolerated dose, pharmacokinetics, immunogenicity, antitumor activity, and pharmacodynamics.
  
  
  METHODS
  Patients with advanced solid malignancies were treated with escalating doses of ramucirumab i.v. over 1 h. Blood was sampled for pharmacokinetics studies throughout treatment; levels of circulating vascular endothelial growth factor-A (VEGF-A) and soluble VEGF receptors (R)-1 and -2 were assessed.
  
  
  RESULTS
  Twenty-five patients were treated with ramucirumab: 13 with 6, 8, or 10 mg/kg Q2W, and 12 with 15 or 20 mg/kg Q3W. The median treatment duration was 12 weeks (range 2-81). No dose-limiting toxicities were observed. The most frequently reported adverse events (AEs) included proteinuria and hypertension (n = 6 each), and diarrhea, fatigue and headache (n = 4 each). Treatment-related grade 3/4 AEs were: two grade 3 hypertension (10 and 20 mg/kg), one each grade 3 vomiting, fatigue (20 mg/kg), atrial flutter (15 mg/kg), and one each grade 4 duodenal ulcer hemorrhage (6 mg/kg) and grade 4 pneumothorax (20 mg/kg). Pharmacokinetic analysis revealed low clearance and half-life of ∼110-160 h. Analysis of serum biomarkers indicated considerable patient-to-patient variability, but trends toward elevated VEGF-A and a transient decline in soluble VEGFR-2. Fifteen patients (60%) had best response of stable disease, with a median duration of 13 months (range 2-18 months) in tumor types including colorectal, renal, liver, and neuroendocrine cancers.
  
  
  CONCLUSIONS
  Ramucirumab was well tolerated. Study results led to recommended phase II doses of 8 mg/kg Q2W and 10 mg/kg Q3W. Prolonged stable disease was observed, suggesting ramucirumab efficacy in various solid tumors.
  
  
  BACKGROUND
  NCT00786383.
authors: Division of Medical Oncology, Department of Medicine, University of Washington and Fred Hutchinson Cancer Research Center, Seattle. Electronic address: gchiorea@uw.edu.
authors: E G
authors: EG
authors: Chiorean
authors: GI Oncology Unit, Duke University School of Medicine, Durham.
authors: H I
authors: HI
authors: Hurwitz
authors: Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia.
authors: R B
authors: RB
authors: Cohen
authors: Clinical Development, Eli Lilly and Company, Bridgewater.
authors: J D
authors: JD
authors: Schwartz
authors: Clinical Development, Eli Lilly and Company, Bridgewater.
authors: R P
authors: RP
authors: Dalal
authors: Clinical Development, Eli Lilly and Company, Bridgewater.
authors: F E
authors: FE
authors: Fox
authors: Clinical Development, Eli Lilly and Company, Bridgewater.
authors: L
authors: L
authors: Gao
authors: Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA.
authors: C J
authors: CJ
authors: Sweeney
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor / Q000097:blood; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D016896:Treatment Outcome; D014481:United States; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000097:blood / Q000276:immunology; D000096662:Ramucirumab
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000096662:Ramucirumab; C467484:VEGFA protein, human; C000588866:KDR protein, human
keywords: VEGFR-2; phase I study; ramucirumab; solid tumors; vascular endothelial growth factor