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


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.
Wakelee
H A
HA
Department of Medicine-Oncology, Stanford University, Stanford, CA. Electronic address: hwakelee@stanford.edu.
Patnaik
A
A
Department of Clinical Research, Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX.
Sikic
B I
BI
Department of Medicine-Oncology, Stanford University, Stanford, CA.
Mita
M
M
Department of Clinical Research, Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX.
Fox
N L
NL
Human Genome Sciences, Rockville, MD, USA.
Miceli
R
R
Human Genome Sciences, Rockville, MD, USA.
Ullrich
S J
SJ
Human Genome Sciences, Rockville, MD, USA.
Fisher
G A
GA
Department of Medicine-Oncology, Stanford University, Stanford, CA.
Tolcher
A W
AW
Department of Clinical Research, Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX.
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C510234:lexatumumab