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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.

Publication ,  Journal Article
Chiorean, EG; Hurwitz, HI; Cohen, RB; Schwartz, JD; Dalal, RP; Fox, FE; Gao, L; Sweeney, CJ
Published in: Ann Oncol
June 2015

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. PATIENTS AND 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. CONCLUSION: 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. CLINICALTRIALSGOV: NCT00786383.

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Published In

Ann Oncol

DOI

EISSN

1569-8041

Publication Date

June 2015

Volume

26

Issue

6

Start / End Page

1230 / 1237

Location

England

Related Subject Headings

  • Vascular Endothelial Growth Factor Receptor-2
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factor A
  • United States
  • Treatment Outcome
  • Ramucirumab
  • Oncology & Carcinogenesis
  • Neoplasms
  • Middle Aged
  • Maximum Tolerated Dose
 

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Chiorean, E. G., Hurwitz, H. I., Cohen, R. B., Schwartz, J. D., Dalal, R. P., Fox, F. E., … Sweeney, C. J. (2015). 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. Ann Oncol, 26(6), 1230–1237. https://doi.org/10.1093/annonc/mdv144
Chiorean, E. G., H. I. Hurwitz, R. B. Cohen, J. D. Schwartz, R. P. Dalal, F. E. Fox, L. Gao, and C. J. Sweeney. “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.Ann Oncol 26, no. 6 (June 2015): 1230–37. https://doi.org/10.1093/annonc/mdv144.
Journal cover image

Published In

Ann Oncol

DOI

EISSN

1569-8041

Publication Date

June 2015

Volume

26

Issue

6

Start / End Page

1230 / 1237

Location

England

Related Subject Headings

  • Vascular Endothelial Growth Factor Receptor-2
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factor A
  • United States
  • Treatment Outcome
  • Ramucirumab
  • Oncology & Carcinogenesis
  • Neoplasms
  • Middle Aged
  • Maximum Tolerated Dose