Phase I study of a fully human monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand death receptor 4 (TRAIL-R1) in subjects with advanced solid malignancies or non-Hodgkin's lymphoma (NHL)

Abstract

2533 Background: TRAIL is a member of the TNF ligand superfamily. There is strong evidence for its ability to induce apoptosis in cancer cell lines. TRAIL causes apoptosis via 2 death receptors [DR4 (TRAIL-R1) & DR5 (TRAIL-R2)] which are upregulated in different cancer cell types. TRM-1 (HGS-ETR1) is a fully human monoclonal antibody agonistic to TRAIL-R1 with preclinical evidence of anti-tumor activity. Methods: Primary objective of this open-label, dose-escalation Phase I study is to evaluate the safety and tolerability of ≥2 doses of TRM-1 in patients (pts) with advanced solid tumors or NHL. Secondary objectives are to evaluate the immunogenicity and pharmacokinetics (PK) of repeated TRM-1 and to assess tumor response. In addition to standard Phase I eligibility criteria, pts who have had previous hematopoietic stem cell transplant or other potentially immunosuppressive therapy are ineligible. Pts are given TRM-1 IV once every 28 days until progression or unacceptable toxicity. Tumor measurements are done every second cycle. Blood samples are collected for PK and immunogenicity analysis. Results: To date, 15 pts have been enrolled into 3 cohorts: 0.01 (7 pts), 0.03 (4 pts), and 0.3 mg/kg (4 pts), with planned escalation to 1, 3, 10, and 20 mg/kg. Mean number of cycles delivered: 2.27 (range 1–5). Tumor types include: colorectal (5), ovary (5), cervix (2), breast (1), prostate (1) and salivary gland (1). TRM-1 has been well tolerated with no clearly attributable toxicities other than 1 case of grade 3 thrombocytopenia thought possibly related. Eight subjects were removed from the trial for progressive disease, 1 died of progressive disease during follow-up, 1 died suddenly during follow-up, and 1 died of progressive disease while on study and was replaced. This pt was in the 1st cohort which was expanded. Preliminary PK results are linear across a 30-fold dose range with CL=3.3 mL/kg/day, V1=35 mL/kg, Vss=62 mL/kg, t1/2β=16days. Conclusions: TRM-1 is well tolerated and the maximum tolerated dose has not been reached. Accrual to this study continues. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Human Genome Sciences, Inc. Human Genome Sciences, Inc. Human Genome Sciences, Inc. Human Genome Sciences, Inc.