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)
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).