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

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 identified 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.

SUBMITTER: Diaz LA

PROVIDER: S-EPMC4612616 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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

Diaz Luis A LA Coughlin Christina M CM Weil Susan C SC Fishel Jean J Gounder Mrinal M MM Lawrence Susan S Azad Nilofer N O'Shannessy Daniel J DJ Grasso Luigi L Wustner Jason J Ebel Wolfgang W Carvajal Richard D RD

Clinical cancer research : an official journal of the American Association for Cancer Research 20141114 6

<h4>Purpose</h4>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.<h4>Experimental design</h4>This first-in-human, open-label, phase I study recruited patients with treatment- ...[more]

PMID: 25398449

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Dataset Information

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

Publications

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

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