Originally published as JCO Early Release 10.1200/JCO.2009.23.7537 on January 4 2010

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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

From the University of Colorado at Denver, Aurora, CO; Fox Chase Cancer Center, Philadelphia, PA; Indiana University Simon Cancer Center, Indianapolis, IN; and ImClone Systems, New York, NY.

Corresponding author: Jennifer L. Spratlin, MD, FRCPC, Department of Medical Oncology, Cross Cancer Institute, 11560 University Ave, Edmonton, Alberta, Canada T5G 1Z2; e-mail: Jennifer.Spratlin{at}albertahealthservices.ca.

Purpose To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics, and preliminary anticancer activity of ramucirumab (IMC-1121B), a fully human immunoglobulin G₁ 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.

Supported in part by ImClone Systems, a wholly owned subsidiary of Eli Lilly, and by Grant No. P30 CA006927 from the National Cancer Institute to Fox Chase Cancer Center. J.L.S., a senior fellow mentored by S.G.E., received funding from the National Cancer Institute of Canada through the Terry Fox Foundation and the Alberta Heritage Foundation for Medical Research.

Presented in part at the 20th Annual European Organisation for Research and Treatment of Cancer–National Cancer Institute–American Association for Cancer Research (EORTC-NCI-AACR) Symposium on Molecular Targets and Cancer Therapeutics, October 21-24, 2008, Geneva, Switzerland; 19th Annual EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, October 22-26, 2007, San Francisco, CA; 18th Annual EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, November 7-10, 2006, Prague, Czech Republic; 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT00793975 [ClinicalTrials.gov] .

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