Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers.
OBJECTIVE
To assess the safety and tolerability, pharmacokinetics, and early evidence of antitumor activity of escalating doses of lexatumumab (HGS-ETR2), a fully human agonistic monoclonal antibody which targets and activates the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) in patients with advanced solid malignancies.


METHODS
In this phase 1, open label study, patients with advanced solid malignancies were treated with escalating doses of lexatumumab administered i.v. over 30 to 120 min every 21 days. A cohort of four patients, which could be expanded to six patients, was studied at each dose level. The dose-limiting toxicity (DLT) dose was defined as the dose at which the incidence of DLT in the first two cycles was >or=33%. The maximum tolerated dose was defined as the highest dose at which <33% of subjects experienced DLT. The pharmacokinetics and immunogenicity of lexatumumab were also characterized. Tumor specimens from historical or current biopsies, when available, were stained for TRAIL-R2 using immunohistochemistry techniques.


RESULTS
Thirty-seven patients received 120 cycles of lexatumumab at doses ranging from 0.1 to 20 mg/kg every 21 days as of May 2006. The 20 mg/kg dose was identified as the DLT dose based on DLTs in three of seven patients treated with this dose; DLTs included asymptomatic elevations of serum amylase, transaminases, and bilirubin. The 10 mg/kg dose cohort was expanded to 12 patients and the 10 mg/kg dose was identified as the maximum tolerated dose. The mean (+/-SD) clearance and apparent terminal half-life values at the 10 mg/kg dose averaged 6.0 (2.9) mL/d/kg and 16.4 (10.9) days, respectively. Twelve patients had durable stable disease that lasted a median of 4.5 months, including three patients with sarcoma having prolonged stable disease (>or=6.7 months). Immunohistochemistry for TRAIL-R2 showed specific staining in >10% of tumor cells for 16 of the 20 evaluable specimens submitted (80%).


CONCLUSIONS
Lexatumumab was safe and well tolerated at doses up to and including 10 mg/kg every 21 days. Lexatumumab was associated with sustained stable disease in several patients. Pharmacokinetics were linear over the dose range studied, and consistent with a two-compartment model with first-order elimination from the central compartment. Additional evaluation of this novel apoptosis-inducing agent, particularly in combination with chemotherapy agents, is warranted and ongoing.
Plummer
Ruth
R
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom. Ruth.Plummer@newcastle.ac.uk
Attard
Gerhardt
G
Pacey
Simon
S
Li
Louise
L
Razak
Albiruni
A
Perrett
Rebecca
R
Barrett
Mary
M
Judson
Ian
I
Kaye
Stan
S
Fox
Norma Lynn
NL
Halpern
Wendy
W
Corey
Alfred
A
Calvert
Hilary
H
de Bono
Johann
J
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D019540:Area Under Curve; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000911:Antibodies, Monoclonal; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; C510234:lexatumumab