Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors.

Abstract

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) t(1/2b) was 13.67 +/- 4.07 days, clearance was 4.95 +/- 1.93 ml/day/kg, V(1) was 45.55 ml/kg and V(ss) 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.

• Authors: H A Wakelee, A Patnaik, B I Sikic, M Mita, N L Fox, R Miceli, S J Ullrich, G A Fisher, A W Tolcher
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 21 Issue 2 Pg. 376-381 (Feb 2010) ISSN: 1569-8041 [Electronic] England
• PMID: 19633048 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• lexatumumab

Topics

• Adult
• Aged
• Antibodies, Monoclonal (administration & dosage, adverse effects, pharmacokinetics)
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Disease Progression
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Humans
• Injections, Intravenous
• Male
• Middle Aged
• Neoplasms (drug therapy, metabolism, pathology)
• Treatment Outcome