Annals of Oncology Advance Access published online on July 24, 2009
Annals of Oncology, doi:10.1093/annonc/mdp292
Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors
1 Department of Medicine-Oncology, Stanford University, Stanford, CA
2 Department of Clinical Research, Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX
3 Human Genome Sciences, Rockville, MD, USA
* Correspondence to: Dr H. A. Wakelee, Stanford Cancer Center, Stanford University, 875 Blake Wilbur Drive, Room 2233, Stanford, CA 94305-5826, USA. Tel: +1-650-736-7221; Fax: +1-650-724-3697; E-mail: hwakelee{at}stanford.edu
Background: Lexatumumab (HGS-ETR2) is a fully human agonistic mAb to the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 that activates the extrinsic apoptosis pathway and has potent preclinical antitumor activity.
Materials and methods: This phase 1, dose escalation study assessed the safety, tolerability, pharmacokinetics (PKs) and immunogenicity of lexatumumab administered i.v. every 14 days in patients with advanced solid tumors.
Results: Thirty-one patients received lexatumumab over five dose levels (0.1–10 mg/kg). Most (26 of 31) received four or more cycles of treatment. One patient at 10 mg/kg experienced a possibly related dose-limiting toxicity of grade 3 hyperamylasemia. Nine patients achieved stable disease. One patient with chemotherapy-refractive Hodgkin's disease experienced a mixed response. Lexatumumab PKs were linear up to 10 mg/kg. At the 10 mg/kg dose, the mean (±standard deviation) t1/2b was 13.67 ± 4.07 days, clearance was 4.95 ± 1.93 ml/day/kg, V1 was 45.55 ml/kg and Vss was 79.08 ml/kg, indicating that lexatumumab distributes outside the plasma compartment. No human antihuman antibodies were detected.
Conclusions: Lexatumumab can be safely administered every 14 days at 10 mg/kg. The PK profile supports this schedule. Further evaluation of lexatumumab at this dose schedule is warranted, including combination trials with other agents.
apoptosis, HGS-ETR2, lexatumumab, pharmacokinetics, phase I, TRAIL-R2
Present address: Department of Clinical Research, South Texas Accelerated Research Therapeutics, San Antonio, TX, USA. Received for publication February 4, 2009. Revision received March 21, 2009. Accepted for publication April 24, 2009.