Abstract

<jats:p> 3047 </jats:p><jats:p> Background: Apo2L/TRAIL (Apo2L ligand/tumor necrosis factor-related apoptosis-inducing ligand) is the first recombinant human protein that selectively induces apoptosis or programmed cell death in cancer cells while sparing normal cells. The molecule used in this joint clinical development between Genentech, Inc. and Amgen, Inc., is an optimized recombinant human Apo2L/TRAIL protein produced in E. coli. It displays broad activity in preclinical models of a variety of solid and hematologic cancers. This is the first report of the pharmacokinetics of Apo2L/TRAIL in humans. Methods: Thirty-nine patients enrolled in a phase 1a study had PK assessments at dose levels ranging from 0.5–15 mg/kg in two cohorts, those with and those without liver metastases. Recombinant human Apo2L/TRAIL was administered as a 1-hr IV infusion for 5 consecutive days over a 21-day cycle. Serum concentrations were determined using a sensitive ELISA assay. PK calculations were performed using Non-compartmental analyses. Results: Currently Apo2L/TRAIL PK data are available for 27 patients, 15 in cohort 1 (no liver metastases) and 12 in cohort 2 (liver metastases). Mean (± SD) PK data for patients in cohort 1 and cohort 2 did not differ. PK data for cohort 1 are outlined in the table below. Apo2L/TRAIL clearance appeared proportional to dose and consistent with that predicted from nonclinical models. Cmax achieved at doses ≥ 4 mg/kg are equivalent to or greater than those displaying activity in preclinical models. There was no evidence of drug accumulation between day 1 and day 5 of treatment. Conclusions: Apo2L/TRAIL at doses which can be safely administered in humans produces serum concentrations consistent with those demonstrating efficacy in tumor xenograft models. Hepatic metastases with or without mild liver dysfunction do not appear to influence the PK of Apo2L/TRAIL. </jats:p><jats:p> [Table: see text] </jats:p><jats:p> [Table: see text] </jats:p>