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Spratlin JL , Cohen RB , Eadens M , Gore L , Camidge DR , Diab S , Leong S , O'Bryant C , Chow LQM , Serkova NJ , Meropol NJ , Lewis NL , Chiorean EG , Fox F , Youssoufian H , Rowinsky EK , Eckhardt SG
Phase I Pharmacologic and Biologic Study of Ramucirumab (IMC-1121B), a Fully Human Immunoglobulin G(1) Monoclonal Antibody Targeting the Vascular Endothelial Growth Factor Receptor-2
Journal of Clinical Oncology. 2010 Feb;28(5) :780-787
PMID: ISI:000274368300014    PMCID: PMC2834394   
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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.
Notes
Spratlin, Jennifer L. Cohen, Roger B. Eadens, Matthew Gore, Lia Camidge, D. Ross Diab, Sami Leong, Stephen O'Bryant, Cindy Chow, Laura Q. M. Serkova, Natalie J. Meropol, Neal J. Lewis, Nancy L. Chiorean, E. Gabriela Fox, Floyd Youssoufian, Hagop Rowinsky, Eric K. Eckhardt, S. Gail ImClone Systems, Eli Lilly ; National Cancer Institute [P30 CA006927]; National Cancer Institute of Canada ; Terry Fox Foundation ; Alberta Heritage Foundation for Medical Research 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. 44 Amer soc clinical oncology; 2318 mill road, ste 800, alexandria, va 22314 usa 553ln