A phase 1 study of mapatumumab (fully human monoclonal antibody to TRAIL-R1) in patients with advanced solid malignancies.

Abstract

PURPOSE:

Mapatumumab (TRM-1, HGS-ETR1) is a fully human agonistic monoclonal antibody that targets and activates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 1 (death receptor 4). Mapatumumab functions like the natural receptor ligand, TRAIL, a tumor necrosis factor superfamily member that is an important mediator of apoptosis in cancer cell lines. Promising preclinical activity with mapatumumab has been observed.

EXPERIMENTAL DESIGN:

This phase I, open-label, dose-escalation study assessed the tolerability and toxicity profile of > or =2 doses of mapatumumab administered i.v. in patients with advanced solid tumors. Patients received mapatumumab every 28 days until progression or dose-limiting toxicity.

RESULTS:

There were escalation levels from 0.01 to 20.0 mg/kg. Forty-one patients, 27 female, with a median age of 55 years (range, 23-81) were entered into the study and received 143 courses. The most common diagnoses were colorectal (10 patients) and ovarian cancer (9 patients). Patients received a median of two cycles (range, 1-33). Mapatumumab was well tolerated. Adverse events considered at least possibly related to mapatumumab that occurred most frequently included fatigue (36.2%), hypotension (34.1%), nausea (29.3%), and pyrexia (12.2%). The majority of adverse events were grade 1 or 2. The maximum tolerated dose was not reached. Linear pharmacokinetics was observed for doses up to 0.3 mg/kg and for the 20 mg/kg level, whereas exposure at 3 and 10 mg/kg increased less than proportionally. No objective responses were observed, but 12 patients had stable disease for 1.9 to 29.4 months.

CONCLUSIONS:

Mapatumumab is well tolerated and further evaluation of this TRAIL-R1 targeting agent is warranted.

• Authors: Sébastien J Hotte, Hal W Hirte, Eric X Chen, Lillian L Siu, Lyly H Le, Alfred Corey, Anne Iacobucci, Martha MacLean, Larry Lo, Norma Lynn Fox, Amit M Oza
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 11 Pg. 3450-5 (Jun 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18519776 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• mapatumumab

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (administration & dosage, adverse effects, pharmacokinetics)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Drug Administration Schedule
• Female
• Half-Life
• Humans
• Male
• Middle Aged
• Neoplasms (drug therapy)