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Phase I Pharmacokinetic and Biologic Correlative Study of Mapatumumab, a Fully Human Monoclonal Antibody With Agonist Activity to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Receptor-1

Anthony W. Tolcher, Monica Mita, Neal J. Meropol, Margaret von Mehren, Amita Patnaik, Kristin Padavic, Monique Hill, Theresa Mays, Therese McCoy, Norma Lynn Fox, Wendy Halpern, Alfred Corey, Roger B. Cohen

From the Institute for Drug Development, Cancer Therapy and Research Center; The University of Texas Health Science Center at San Antonio, San Antonio, TX; Fox Chase Cancer Center, Philadelphia, PA; and Human Genome Sciences, Rockville, MD

Address reprint requests to Anthony W. Tolcher MD, FRCP (C), Institute for Drug Development, Cancer Therapy and Research Center, 7979 Wurzbach, Suite 414, San Antonio, TX 78229; e-mail: atolcher{at}idd.org

Purpose To assess the safety, pharmacokinetics, and preliminary evidence of antitumor activity of mapatumumab (HGS-ETR1, TRM-1), a fully human agonist monoclonal antibody directed to the tumor necrosis factor–related apoptosis-inducing ligand receptor-1 (TRAIL-R1).

Patients and Methods Patients with advanced solid malignancies were treated with escalating doses of mapatumumab intravenously (IV) administered over 30 to 120 minutes, initially as a single dose and then repetitively. Plasma mapatumumab concentrations were measured and serum was assayed to detect human antimapatumumab antibody formation. Archival tumor specimens were collected to detect the presence of TRAIL-R1 by immunohistochemistry.

Results Forty-nine patients received 158 courses at doses ranging from 0.01 to 10 mg/kg IV. Initially, patients received mapatumumab as a single dose, then every 28 days repetitively, and then 10 mg/kg every 14 days. Mild (grade 1 or 2) fatigue, fever, and myalgia were the most frequently reported nonhematologic adverse events related to mapatumumab, whereas hematologic toxicity was not clinically significant. The mean (± standard deviation) clearance and terminal elimination half-life values for mapatumumab at 10 mg/kg every 14 days were 3.7 mL/d/kg (± 1.5 mL/d/kg) and 18.8 days (± 10.1 days), respectively. TRAIL-R1 was documented in 68% of patients' tumors assayed. Nineteen patients had stable disease, with two lasting 9 months.

Conclusion Mapatumumab can be administered safely and feasibly at 10 mg/kg IV every 14 days. The absence of severe toxicities and the attainment of plasma mapatumumab concentrations that are active in preclinical models warrant further disease-directed studies of this agent alone and in combination with chemotherapy in a broad array of tumors.

Supported by Human Genome Sciences Inc.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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