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


METHODS
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.
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland. ldiaz1@jhmi.edu.
Luis A
LA
Diaz
Morphotek, Inc., Exton, Pennsylvania.
Christina M
CM
Coughlin
Morphotek, Inc., Exton, Pennsylvania.
Susan C
SC
Weil
Morphotek, Inc., Exton, Pennsylvania.
Jean
J
Fishel
Memorial Sloan Kettering Cancer Center, New York, New York.
Mrinal M
MM
Gounder
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
Susan
S
Lawrence
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
Nilofer
N
Azad
Morphotek, Inc., Exton, Pennsylvania.
Daniel J
DJ
O'Shannessy
Morphotek, Inc., Exton, Pennsylvania.
Luigi
L
Grasso
Morphotek, Inc., Exton, Pennsylvania.
Jason
J
Wustner
Morphotek, Inc., Exton, Pennsylvania.
Wolfgang
W
Ebel
Memorial Sloan Kettering Cancer Center, New York, New York.
Richard D
RD
Carvajal
D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C078203:CD248 protein, human; C000604563:ontuxizumab