title: Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2.
abstract: PURPOSE To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics, and preliminary anticancer activity of ramucirumab (IMC-1121B), a fully human immunoglobulin G(1) monoclonal antibody targeting the vascular endothelial growth factor receptor (VEGFR)-2. PATIENTS AND METHODS Patients with advanced solid malignancies were treated once weekly with escalating doses of ramucirumab. Blood was sampled for PK studies throughout treatment. The effects of ramucirumab on circulating vascular endothelial growth factor-A (VEGF-A), soluble VEGFR-1 and VEGFR-2, tumor perfusion, and vascularity using dynamic contrast-enhanced magnetic resonance imaging were assessed. Results Thirty-seven patients were treated with 2 to 16 mg/kg of ramucirumab. After one patient each developed dose-limiting hypertension and deep venous thrombosis at 16 mg/kg, the next lower dose (13 mg/kg) was considered the MTD. Nausea, vomiting, headache, fatigue, and proteinuria were also noted. Four (15%) of 27 patients with measurable disease had a partial response (PR), and 11 (30%) of 37 patients had either a PR or stable disease lasting at least 6 months. PKs were characterized by dose-dependent elimination and nonlinear exposure consistent with saturable clearance. Mean trough concentrations exceeded biologically relevant target levels throughout treatment at all dose levels. Serum VEGF-A increased 1.5 to 3.5 times above pretreatment values and remained in this range throughout treatment at all dose levels. Tumor perfusion and vascularity decreased in 69% of evaluable patients. CONCLUSION Objective antitumor activity and antiangiogenic effects were observed over a wide range of dose levels, suggesting that ramucirumab may have a favorable therapeutic index in treating malignancies amenable to VEGFR-2 inhibition.
authors.affiliation: FRCPC, Department of Medical Oncology, Cross Cancer Institute, 11560 University Ave, Edmonton, Alberta, Canada T5G 1Z2. Jennifer.Spratlin@albertahealthservices.ca
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Spratlin
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
authors.forename: Matthew
authors.initials: M
authors.lastname: Eadens
authors.forename: Lia
authors.initials: L
authors.lastname: Gore
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
authors.forename: Sami
authors.initials: S
authors.lastname: Diab
authors.forename: Stephen
authors.initials: S
authors.lastname: Leong
authors.forename: Cindy
authors.initials: C
authors.lastname: O'Bryant
authors.forename: Laura Q M
authors.initials: LQ
authors.lastname: Chow
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Serkova
authors.forename: Neal J
authors.initials: NJ
authors.lastname: Meropol
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Lewis
authors.forename: E Gabriela
authors.initials: EG
authors.lastname: Chiorean
authors.forename: Floyd
authors.initials: F
authors.lastname: Fox
authors.forename: Hagop
authors.initials: H
authors.lastname: Youssoufian
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor / Q000097:blood; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008279:Magnetic Resonance Imaging; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; 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* / Q000378:metabolism; D000096662:Ramucirumab
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; 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; C501162:FLT1 protein, human