A phase I and pharmacokinetic study of HGS-ETR1(TRM-1), a human monoclonal agonist-antibody to TRAIL R1, in patients with advanced solid tumors

Abstract

3060 Background: HGS-ETR1 (TRM-1) is a fully-human high affinity monoclonal antibody directed and agonistic to the Tumor Necrosis Apoptosis Inducing Ligand (TRAIL) Receptor 1. TRAIL R1 is widely expressed on human tumor cells, is part of the tumor necrosis factor superfamily, and regulates the activation of caspases in the extrinsic pathway of apoptosis. TRM-1 mediates apoptosis via binding with TRAIL R1 and agonist induced activation of the extrinsic pathway of apoptosis. In preclinical studies TRM-1 induces apoptosis in sensitive human tumor cell lines in vitro at an IC50 of 3.3 nM and elicited both tumor growth inhibition and tumor regressions in a broad array of human tumor xenograft models at 10 mg/kg. Methods: Patients with advanced refractory solid tumors were treated with TRM-1 iv once every 28 days. Results: Currently 31 patients have received 56 courses of TRM-1 over 6 dose levels that ranged from 0.01 to 3.0 mg/kg. The median number of courses is 1 (1–6). One patient with pre-existing grade 2 peripheral neuropathy treated at the first dose-level had worsening of symptoms to grade 3, although no other patient has had drug-related toxicities ≥ grade 2. Pharmacokinetic parameters (Mean [±SD] ) at the 1 mg/kg dose level are characterized by a long elimination t1/2 of 14.4 [4.9] days, Vd that approximates plasma volume, Cl of 3.8 [1.4] mL/day/kg, Cmax of 23.6 [5.1] μg/mL, and an AUC of 290.4 [97.2] μg × days/mL. No evidence of human anti-human antibody formation has been detected. Accrual continues next at the10 mg/kg dose level. Conclusions: TRM-1 represents the first specific TRAIL R1 targeting agent and can be safely administered IV every 4 weeks at doses that reach plasma concentrations associated with activity in preclinical studies. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Human Genome Sciences Human Genome Sciences Human Genome Sciences Human Genome Sciences Human Genome Sciences