A first-in-human phase i study of MORAb-004, a monoclonal antibody to endosialin in patients with advanced solid tumors

Luis A. Diaz, Christina M. Coughlin, Susan C. Weil, Jean Fishel, Mrinal M. Gounder, Susan Lawrence, Nilofer Azad, Daniel J. O'Shannessy, Luigi Grasso, Jason Wustner, Wolfgang Ebel, Richard D. Carvajal

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Endosialin (TEM-1, CD248) is a protein expressed on the surface of activated mesenchymal cells, including certain subsets of tumors. Preclinical models suppressing endosialin function have shown antitumor activity. A humanized monoclonal antibody, MORAb-004, was engineered to target endosialin and is the first agent in clinical development for this mesenchymal cell target. Experimental Design: This first-in-human, open-label, phase I study recruited patients with treatment-refractory solid tumors. MORAb-004 was administered intravenously once weekly in 4-week cycles. Objectives included determination of the safety of multiple infusions of MORAb-004, identification of the maximum tolerated dose (MTD), pharmacokinetic modeling, detection of any anti-human antibody response, and assessment of objective radiographic response to therapy. Results: Thirty-six patients were treated at 10 dose levels of MORAb-004, ranging from 0.0625 to 16 mg/kg. Drug-related adverse events were primarily grade 1-2 infusion toxicities. Dose-limiting toxicity of grade 3 vomiting was observed at 16 mg/kg. Eighteen of 32 evaluable patients across all doses achieved disease stability, with minor radiographic responses observed in 4 patients (pancreatic neuroendocrine, hepatocellular, and sarcoma tumor types). Pharmacokinetics showed MORAb-004 accumulation beginning at 4 mg/kg and saturable elimination beginning at 0.25 mg/kg. Exposure increased in a greater-than-dose-proportional manner with terminal half-life increasing proportionally with dose. The MTD was identifi ed as 12 mg/kg. Conclusions: Preliminary antitumor activity was observed. Safety profile, pharmacokinetics, and early antitumor activity suggest that MORAb-004 is safe at doses up to 12 mg/kg and should be studied further for efficacy.

Original languageEnglish (US)
Pages (from-to)1281-1288
Number of pages8
JournalClinical Cancer Research
Volume21
Issue number6
DOIs
StatePublished - Mar 15 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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