Phase I study of enavatuzumab, a first-in-class humanized monoclonal antibody targeting the TWEAK receptor, in patients with advanced solid tumors

Elaine T. Lam, S. Gail Eckhardt, Wells Messersmith, Antonio Jimeno, Cindy L. O'Bryant, Ramesk K Ramanathan, Glen J. Weiss, Manpreet Chadha, Abbie Oey, Han Ting Ding, Patricia A. Culp, Stephan F. Keller, Vivian Y. Zhao, L. Claire Tsao, Anil Singhal, Kyle D. Holen, Daniel Von Hoff

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

This phase I study evaluates the safety, MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary anticancer activity of enavatuzumab, a humanized IgG1 antibody to the TWEAK receptor, in patients with advanced solid malignancies. Patients received escalating doses of enavatuzumab given intravenously over 60 minutes every 2 weeks. Blood was obtained for PK and biomarker assessment. Three patients were enrolled per dose level in a standard 3 + 3 design with response assessment by RECIST version 1.0, every 8 weeks. Thirty patients were enrolled at 6 dose levels ranging from 0.1 to 1.5 mg/kg. Dose-limiting toxicities included grade 4 (G4) lipase, G3 bilirubin, and G4 amylase elevations. There was no apparent correlation of liver or pancreatic enzyme elevation with drug exposure or the presence of liver metastases. Enavatuzumab exhibited a two-compartment linear PK model. Estimated systemic clearance was 23 to 33 mL/h with an elimination half-life of 7 to 18 days. The predicted target efficacious peak and trough concentrations occurred at 1.0 mg/kg following the second dose. There were no objective responses; 4 patients had stable disease. The MTD of enavatuzumab is 1.0 mg/kg i.v. every 2 weeks. Higher doses were not tolerated due to hepatopancreatic lab abnormalities. Further evaluation of the mechanisms of the liver and pancreatic enzyme toxicities is needed before embarking on further single-agent or combination strategies.

Original languageEnglish (US)
Pages (from-to)215-221
Number of pages7
JournalMolecular Cancer Therapeutics
Volume17
Issue number1
DOIs
StatePublished - Jan 1 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Lam, E. T., Eckhardt, S. G., Messersmith, W., Jimeno, A., O'Bryant, C. L., Ramanathan, R. K., Weiss, G. J., Chadha, M., Oey, A., Ding, H. T., Culp, P. A., Keller, S. F., Zhao, V. Y., Tsao, L. C., Singhal, A., Holen, K. D., & Von Hoff, D. (2018). Phase I study of enavatuzumab, a first-in-class humanized monoclonal antibody targeting the TWEAK receptor, in patients with advanced solid tumors. Molecular Cancer Therapeutics, 17(1), 215-221. https://doi.org/10.1158/1535-7163.MCT-17-0330