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


METHODS
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.
Hotte
Sébastien J
SJ
Juravinski Cancer Centre at Hamilton Health Sciences, 699 Concession Street, Hamilton, Ontario, Canada L8V 5C2. sebastien.hotte@hrcc.on.ca
Hirte
Hal W
HW
Chen
Eric X
EX
Siu
Lillian L
LL
Le
Lyly H
LH
Corey
Alfred
A
Iacobucci
Anne
A
MacLean
Martha
M
Lo
Larry
L
Fox
Norma Lynn
NL
Oza
Amit M
AM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C507357:mapatumumab