First Results of a Phase 1, First-in-Human, Dose Escalation Study of ISB 2001, a BCMAxCD38xCD3 Targeting Trispecific Antibody in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Abstract

Background: Despite advances, MM remains an incurable disease and resistance mechanisms are emerging. ISB 2001 has been designed to overcome tumor escape mechanisms inherent to current MM therapies, such as tumor associated antigen (TAA) downregulation. ISB 2001 is a arst in class trispeciic T cell engager using Ichnos' Bispeciic Engagement by Antibodies based on the T cell receptor (BEAT®) heavy chain heterodimerization technology that redirects cytotoxic T cells to BCMA and/or CD38 expressing myeloma cells. Simultaneous targeting of two TAA by ISB 2001 increases avidity binding to tumor cells with low expression of BCMA or CD38 (Carretero-Iglesia at al., AACR 2024, abstract #1238). We report here erst-time data from the early dose-escalation portion of an ongoing, multi-center, single-agent Phase 1 study of ISB 2001. Study design: This study assesses the safety, tolerability, effcacy, pharmacokinetics (PK), and pharmacodynamics (PD) of ISB 2001 in RRMM patients(pts). This study is enrolling pts who have received immunomodulatory drugs, proteasome inhibitors, and anti-CD38 therapies either in combination or as a single agent, and are refractory to, or intolerant of, established therapies known to provide clinical beneet in MM. Prior BCMA targeted and/or T-cell directed therapies were allowed. ISB 2001 is administered weekly by subcutaneous (SC) injection in 28-day cycles, with two step-up doses on cycle 1 day 1 (C1D1) and C1D4 before administering the full target dose on C1D8. To enable early exposure to the expected effcacious dose, an accelerated dose escalation strategy for the initial 3 cohorts was followed by a conventional 3+3 dose escalation design. The primary outcome measure is the number of dose-limiting toxicities (DLTs) during the erst 28 days after the erst study treatment. After completion of Part 1 (dose escalation) the study will continue with Part 2 (dose expansion) (FDA Project Optimus) to connrm safety and to select the recommended Phase 2 dose (RP2D). Results: Based on data extracted on 29-Jul-2024, 14 pts were treated with ISB 2001 in dose escalation: target dose 5 µg/kg (n =1); 15 µg/kg (n =1); 50 µg/kg (n =1); 150 µg/kg (n =4); 300 µg/kg (n =3); 600 µg/kg (n =4)and received at least one cycle of ISB 2001. Median age was 66y; 57.1% male, 92.9% white. Pts had median of 4 prior regimens (range: 2 to 10). All 14 pts were triple-exposed, 9/14 penta-exposed (3/9 penta-refractory). Median follow-up was 2.2 months (range, 1.0 to 6.6). No DLT was observed. AEs of special interest were : injection site reaction Grade (Gr) 1 in 7 pts; lower and upper respiratory tract infection in the same patient (Gr2 and Gr1, respectively) and one Gr3 urinary tract infection; no ICANS were reported; CRS occurred