Phase 1, first-in-human study of ISB 2001: A BCMAxCD38xCD3-targeting trispecific antibody for patients with relapsed/refractory multiple myeloma (RRMM)—Dose escalation (DE) results.

Abstract

7514 Background: MM remains an incurable disease and resistance mechanisms are emerging. ISB 2001, a first-in-class trispecific T cell engager, redirects cytotoxic T cells to BCMA and/or CD38-expressing myeloma cells. By simultaneously targeting two TAA, ISB 2001 enhances avidity binding to tumor cells in vitro, hence potency, while the distal positioning of the CD38 vs CD3 binders minimizes CD38-related off-tumor adverse events. Methods: We report data from the DE portion of a Phase 1 study of ISB 2001, assessing safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) in RRMM patients (pts) exposed to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 therapies and refractory or intolerant to established therapies. Prior BCMA-targeted and/or T-cell directed therapies were allowed. ISB 2001 was administered weekly subcutaneously (SC) in 28-day cycles, with initial step-up doses on Days 1 (15µg/kg) and 4 (variable). DE utilized an accelerated titration design (initial 3 cohorts with single-patient dosing) followed by a standard 3+3 design. DLTs were evaluated in the first 28 days. After DE, the study will proceed with Part 2 (dose expansion) to confirm safety and select the recommended Ph2 dose under FDA Project Optimus. Results: As of January 13, 2025, 24 pts were treated with ISB 2001 across 8 dose levels (5–1800 μg/kg) with a median follow-up of 6 months (range: 2–12). DL9 (2700 µg/kg) is last dose level and currently enrolling. Among 24 pts, median age was 66 years; 58% male, 83% white with a median of 6 prior lines of therapy (range: 3-11). All pts were triple-exposed, 17/24 (71%) penta-exposed, and 3/17 penta-refractory (18 %). No DLT, adverse events (AE) leading to treatment discontinuation or deaths occurred. Serious AEs were reported in 8 (33%) patients. Drug related Grade (Gr) 3-4 AEs were seen in 13 (54%) pts. CRS was reported in 17 (70.8%) patients, primarily Grade 1–2, with a median onset of 3 days and a median duration of 2 days. No neurologic AEs or ICANs. The Overall Response Rate (ORR) was 75% across all 8 doses, including stringent CR (sCR) 13%, CR 13%, VGPR 38%, PR 13%. Responses were observed from dose level as low as 50 µg/kg (MRD-neg, sCR) with an ORR of 82% at doses ≥50 µg/kg. Median time to response was 36 days. ISB 2001 showed near dose-proportional PK, a half-life >10 days, and consistent T-cell activation, supporting its mechanism of action. Conclusions: ISB 2001 was well tolerated with manageable CRS, no ICANS and demonstrated robust anti-myeloma activity in heavily pretreated RRMM pts (NCT05862012). Full clinical data, including PK and PD results from the dose-escalation portion of the study, will be presented at the conference. Clinical trial information: NCT05862012 .