Phase I and pharmacokinetic study of HGS-ETR2, a human monoclonal antibody to TRAIL R2, in patients with advanced solid malignancies

Abstract

3055 Background: HGS-ETR2 is a fully-human high affinity monoclonal antibody specific and agonistic to the Tumor Necrosis Apoptosis Inducing Ligand (TRAIL) Receptor 2. HGS-ETR2 mediates apoptosis by binding to TRAIL-R2, leading to activation of the extrinsic apoptosis pathway. Human tumor xenograft models show tumor regression in response to HGS-ETR2 at doses of 2.5 mg/kg or lower. Methods: Patients with advanced solid tumors were treated with HGS-ETR2 IV once every 21 days. Results: Currently 22 patients have received 73 courses of HGS-ETR2 over 5 dose levels ranging from 0.1 to 10 mg/kg. The majority (20/22) received at least 2 courses (range 1 - 13). One patient experienced an asymptomatic grade 3 elevation of serum amylase at 1 mg/kg detected at course 1 day 15 with a peak amylase of 423 u/L (3.4 x ULN) while receiving concomitant ciprofloxacin; no other patients have experienced dose-limiting toxicity. One subject with hepatocellular carcinoma and extensive hepatic metastases experienced grade 3 transient transaminitis at 3 mg/kg during Cycle 5 which resolved by Cycle 6, and went on to receive a further course with no enzyme changes. To date, stable disease (= 2 cycles) has been observed in seven subjects (range 2–13). HGS-ETR2 pharmacokinetics are linear across a 100-fold dose range, from 0.1 to 10 mg/kg, and at the 10 mg/kg dose are characterized by a mean (SD) t1/2,z of 15 (4) days, CL of 4.79 (2.30) mL/day/kg, and V1 of 51 (5) mL/kg, which is slightly larger than the plasma volume. The 1.7-fold larger Vss of 87 (7) mL/kg indicates that HGS-ETR2 distributes outside the plasma volume. Human anti-human antibody formation has not been detected. Conclusions: HGS-ETR2, a specific TRAIL R2 targeting agent, can be safely administered IV every 3 weeks at doses that reach plasma concentrations associated with activity in preclinical models. Further evaluation in Phase II trials is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Human Genome Sciences Human Genome Sciences Human Genome Sciences Human Genome Sciences