A phase I/II, multicenter, open-label study of REGN5668 (mucin [MUC]16 x CD28 bispecific antibody [bsAb]) with cemiplimab (programmed death [PD]-1 Ab) or REGN4018 (MUC16 x CD3 bsAb) in recurrent ovarian cancer (rOVCA).
Authors: Winer Ira Seth , Shields Anthony Frank , Yeku Oladapo O. , Liu Joyce F. , Peterman Mary Jane , Yoo Suk Young , Lowy Israel , Yama-Dang N. Alice , Goncalves Priscila Hermont , Kroog Glenn 
Published: June 2021

TPS5602 Background: There is a high unmet need in rOVCA treatment, with 14,000 deaths/year in the US and a 30%‒40% 5-year overall survival rate in patients (pts) with advanced disease. REGN5668 and REGN4018 are human IgG4-based bsAbs that bridge ovarian MUC16+ tumor cells to CD28 and CD3, respectively, on T-cells to stimulate cytotoxicity. Cemiplimab is a human monoclonal Ab that blocks PD-1 binding to PD-ligand(L)1 and PD-L2. REGN5668 demonstrated increased preclinical anti-tumor activity with PD-1 inhibition or REGN4018 relative to each monotherapy. A Phase I/II study of REGN4018 alone or with cemiplimab is ongoing. Methods: This first-in-human study (NCT04590326) will assess safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of REGN5668 with cemiplimab (Module 1) or REGN4018 (Module 2) in pts with rOVCA. Key inclusion criteria include histologically confirmed diagnosis of advanced epithelial ovarian (except carcinosarcoma), fallopian tube, or primary peritoneal cancer; serum CA-125 level ≥2x upper normal limit; ≥1 prior-line of platinum-based therapy; prior treatment with or intolerance to available standard-of-care therapy. Exclusion criteria include recent biologic therapy ( < 5 half-lives or 28 days, whichever is longer, except < 3 half-lives for bevacizumab or other nonimmunomodulatory Abs with half-lives > 7 days); approved conventional therapy (except biologics or immunotherapy) < 3 weeks (wks) or investigational agents < 4 wks prior to first study dose; and anti–PD-L1 therapy < 5 half-lives prior to first study dose. This two-phase study includes dose escalation (a 4+3 design modified from 3+3) and expansion phases. In Module 1, ≤84 pts will receive 3–4 wks of REGN5668 monotherapy lead-in at assigned intravenous (IV) weekly (QW) dose levels, followed by REGN5668 QW combined with cemiplimab IV every 3 wks. In Module 2, ≤106 pts will receive 4–5 wks of REGN4018 QW IV lead-in, followed by REGN4018 full QW dose combined with REGN5668 at initial and full assigned QW doses. In expansion, REGN5668+cemiplimab and REGN5668+REGN4018 combination regimens will each recruit 20 pts in stage 1 and 30 pts in stage 2 using a Simon two-stage design. In escalation, primary endpoints are dose-limiting toxicities, serious and treatment-emergent adverse events (TEAEs), deaths, laboratory abnormalities (Grade ≥3), concentrations of REGN5668 in serum alone and in each combination regimen; key secondary endpoint is objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. In expansion, primary endpoint is ORR by RECIST 1.1 for each combination; key secondary endpoints are TEAEs, serious AEs, deaths. Key exploratory endpoints are correlation between clinical efficacy endpoints and baseline protein expression levels of MUC16 and PD-L1. Clinical trial information: NCT04590326.