Phase 1 and Pharmacokinetic Study of Lexatumumab in Patients with Advanced Cancers

• Published in: Clinical cancer research 2007-10, Vol.13 (20), p.6187-6194
• Main Authors: PLUMMER, Ruth, ATTARD, Gerhardt, HALPERN, Wendy, COREY, Alfred, CALVERT, Hilary, DE BONO, Johann, PACEY, Simon, LOUISE LI, RAZAK, Albiruni, PERRETT, Rebecca, BARRETT, Mary, JUDSON, Ian, KAYE, Stan, FOX, Norma Lynn
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antineoplastic agents; Apoptosis; Area Under Curve; Biological and medical sciences; DR5; Drug Administration Schedule; Female; HGS-ETR2; Humans; Immunohistochemistry; Lexatumumab; Male; Maximum Tolerated Dose; Medical sciences; Middle Aged; Neoplasms - drug therapy; Neoplasms - pathology; Pharmacokinetics; Pharmacology. Drug treatments; Phase 1; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism; TRAIL-R2; Treatment Outcome; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-0950

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 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 ≥33%. The maximum tolerated dose was defined as the highest dose at which 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.