Apo2L/TRAIL pharmacokinetics in a phase 1a trial in advanced cancer and lymphoma

Abstract

3047 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. [Table: see text] [Table: see text]

Development of a radioiodinated apoptosis–inducing ligand, rhTRAIL, and a radiolabelled agonist TRAIL receptor antibody for clinical imaging studies

“…Considering the rapid half-life in humans and animals (Ling et al, 2006), the small amount of aggregates present after storage of radiolabelled rhTRAIL at 37°C was not a matter for concern, as was confirmed in the in vivo biodistribution study. The liver uptake rapidly decreased in time, indicating non-specific and blood-pool-related uptake.…”

“…Upon storage in human serum at 37°C, high molecular weight impurities were seen after 4 h (8%), but no free iodine could be detected. Given the short serum elimination half-life of less than 30 min in vivo (Xiang et al, 2004;Ling et al, 2006), this was considered acceptable for (pre)clinical evaluation of 125 I-rhTRAIL.…”

Conatumumab, a fully human agonist antibody to death receptor 5, induces apoptosis via caspase activation in multiple tumor types

“…Several studies on the clinical validation of M30 and M65 (which measures intact CK18) assays in human subjects have been reported. 40,41 A transient increase in other cellular components, such as circulating DNA, immediately after antitumor agent treatment in xenograft-bearing mice has also been reported. 39 In addition, a transient increase in serum M30 or M65 levels in cancer patients has been linked to efficacy in certain chemotherapeutic treatments in prostate, breast, and non-small-cell lung cancer.…”

Mesenchymal stem cells expressing TRAIL lead to tumour growth inhibition in an experimental lung cancer model

“…Though the ability of Ad.TR to overcome TRAIL resistance in a range of cell lines has been explored no clear mechanism has been elucidated [36][37][38]. While administration of TRAIL protein or TRAIL receptor agonistic antibody may have potential for cancer therapy [26,27], it lacks many of the potential benefits that may be gained by using a gene therapy strategy for the production of the protein. Nakamizo et al [8] demonstrated the increased efficacy of IFN-␤ expression from MSCs over intravenous injection of IFN-␤ protein.…”