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)

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 first in class trispecific T cell engager using Ichnos' Bispecific 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 first-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, efficacy, 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 benefit 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 efficacious 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 first 28 days after the first study treatment. After completion of Part 1 (dose escalation) the study will continue with Part 2 (dose expansion) (FDA Project Optimus) to confirm 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 in 71.4% (10 out of 14) of the pts. All were Gr1, except one Gr2. CRS was most common after the first priming dose (64.3% of pts), 14.3% post C1D4, 7.1% post C1D8. Median time to CRS was 2 days with a median duration of 1.5 days (range: 1 to 4). Tocilizumab was used in 3 patients. No patient discontinued the treatment due to a TEAE and no treatment-related death was reported. During the dose escalation, Overall Response Rate (ORR) was 75% (9 of 12 efficacy-evaluable pts) across all doses, stringent CR (sCR), MRD negative was 8.3%, VGPR 16.7% and PR 50.0%. Objective response was observed with dose level as low as 50μg/kg and ORR in doses ≥50μg/kg was 90%. Median time to response was 36 days (range: 29 to 57) with responses deepening over time. 100% (9/9) of responses were still on treatment at data extract. ISB 2001 was slowly absorbed into the circulation after weekly dosing with Tmax generally occurring 7 days post dosing. PK data up to 150 µg/kg indicate general dose linear increase in serum exposures and available data imply a tentative half-life of 12 days . Transient increases in T-cell activation, proliferation and functional markers were observed following ISB 2001 administration, consistent with the T-cell dependent mechanism of action. Conclusion: ISB 2001, a novel, FIH, BCMAxCD38xCD3 trispecific antibody is well tolerated with low grade CRS and manageable safety profile up to 600 μg/kg. Sustained objective responses were demonstrated from 50μg/kg (MRD neg, sCR) in pts with heavily pre-treated RRMM, with a high ORR of 75% across dose levels. Dose-escalation continues with no DLT observed thus far (NCT05862012).