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Lookup NU author(s): Professor Ruth Plummer, Dr Louise Li, Rebecca Perrett, Professor Alan Calvert
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Purpose: 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. Experimental Design: In this phase1, 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 ≥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 (≥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. ©2007 American Association for Cancer Research.
Author(s): Plummer R, Attard G, Pacey S, Li L, Razak A, Perrett RH, Barrett M, Judson I, Kaye S, Fox NL, Halpern W, Corey A, Calvert AH, de Bono J
Publication type: Article
Publication status: Published
Journal: Clinical Cancer Research
Year: 2007
Volume: 13
Issue: 20
Pages: 6187-6194
Print publication date: 15/10/2007
ISSN (print): 1078-0432
ISSN (electronic): 1557-3265
URL: http://dx.doi.org/10.1158/1078-0432.CCR-07-0950
DOI: 10.1158/1078-0432.CCR-07-0950
PubMed id: 17947486
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