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

Authors: Diaz, L. A. Jr; Coughlin, C. M.; Weil, S. C.; Fishel, J.; Gounder, M. M.; Lawrence, S.; Azad, N.; O'Shannessy, D. J.; Grasso, L.; Wustner, J.; Ebel, W.; Carvajal, R. D.
Article Title: 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 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. ©2014 AACR.
Keywords: adult; clinical article; treatment response; aged; unclassified drug; fatigue; dose response; drug efficacy; drug safety; liver cell carcinoma; solid tumor; progression free survival; multiple cycle treatment; leukopenia; nausea; vomiting; monoclonal antibody; abdominal pain; backache; drug hypersensitivity; fever; hyperglycemia; sarcoma; confusion; hypokalemia; hyponatremia; drug accumulation; antibody response; urinary tract infection; radiography; open study; hyperbilirubinemia; bacteremia; maximum tolerated dose; phase 1 clinical trial; drug half life; somnolence; gastroesophageal reflux; diplopia; hematoma; pericardial effusion; urine retention; speech disorder; angioneurotic edema; sinus tachycardia; adult respiratory distress syndrome; hydronephrosis; drug elimination; cancer antibody; molecularly targeted therapy; disease activity; vagina bleeding; pancreatic neuroendocrine tumor; consciousness disorder; body weight disorder; infusion related reaction; human; male; female; priority journal; article; endosialin; morab 004
Journal Title: Clinical Cancer Research
Volume: 21
Issue: 6
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2015-03-15
Start Page: 1281
End Page: 1288
Language: English
DOI: 10.1158/1078-0432.ccr-14-1829
PROVIDER: scopus
PUBMED: 25398449
PMCID: PMC4612616
Notes: Export Date: 4 May 2015 -- Source: Scopus
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MSK Authors
  1. Richard D Carvajal
    133 Carvajal
  2. Mrinal M Gounder
    68 Gounder