Initial Results of Dose Escalation of ISB 1342, a Novel CD3xCD38 Bispecific Antibody, in Patients with Relapsed / Refractory Multiple Myeloma (RRMM)

Introduction: ISB 1342 is a heterodimer based on the Ichnos proprietary Bispecific Engagement by Antibodies based on the TCR (BEAT^®) platform and is a humanized CD3xCD38 bispecific antibody designed to simultaneously engage the CD3 molecule on T cells and the CD38 antigen on multiple myeloma (MM) cells. By co-engaging CD3ε on T cells and CD38 on tumor cells, ISB 1342 redirects T cells to kill CD38-expressing tumor cells. This mechanism of action is differentiated from existing monospecific CD38 targeting therapies and was designed to overcome resistance to daratumumab in MM. We report here, findings from the dose-escalation portion of an ongoing, multi-center, open-label, single-agent phase 1 study (NCT03309111) of ISB 1342 in patients with RRMM.

Methods: Adult patients (≥18 years of age) with RRMM that relapsed after or were considered refractory to prior therapies, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody; received escalating, intravenous (IV) doses of ISB 1342 every two weeks (Q2W) or weekly (QW) with a priming dose administered on the first day. The focus of this report will be on patients enrolled in the QW schedule. Patients had measurable disease per the International Myeloma Working Group (IMWG) updated criteria 2016. Dose escalation began with 0.001mg/kg (prime) / 0.003 mg/kg in the Q2W schedule with single patient accelerated titration for the first four cohorts then a “3 + 3” design; dose escalation in the QW schedule began at 0.2/0.3 mg/kg and followed a “3 + 3” design. The primary study objectives are to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of ISB 1342. Secondary objectives included evaluation of anti-myeloma activity, pharmacokinetics (PK) and pharmacodynamics, and immunogenicity of ISB 1342.

Results: As of July 7, 2022, 24 patients had received a once weekly, IV infusion of ISB 1342 in 6 dose-escalation groups from 0.2/0.3 mg/kg dose level to 1.0 / 4.0 mg/kg dose level. The majority were males (63%) and white (67%); 21% were black or African American. The median age was 67 years (range, 54-76) and the median disease duration since onset was 6.7 years (range, 2.8-22.2). The median number of prior anti-myeloma lines of therapy was 6 (range 1-10); 8 (33%) patients had received prior B cell maturation antigen (BCMA)-targeted therapy including bi-specifics, antibody drug conjugates (ADCs) and/or cell therapies. Twenty-one (88%) patients were considered to be triple-refractory and 18 (75%) were considered to be penta-refractory. Twenty-two (92%) patients experienced treatment-related adverse events (TRAEs) of any grade. Most TRAEs were grade 1-2, including infusion related reactions (42%), anemia (21%), cytokine release syndrome (CRS, 17%), thrombocytopenia (17%), and diarrhoea (13%). Nine (38%) patients had grade 3 or higher TRAEs with only infusion related reactions occurring in more than 5% of patients (17%, all grade 3 events). No grade 5 TRAE was observed. One dose limiting toxicity (DLT), a Grade 3 delirium was observed in a 73-year-old patient treated at 0.3/0.55 dose level after the third dose of ISB 1342, and who also presented with Grade 4 pneumonia; three additional patients were enrolled at that dose level, no other DLT was observed, and dose escalation continued. The median duration of treatment was 2 months (range, 1-5). The ISB 1342 serum concentration-time profiles showed C_max near the end of infusion, followed by a biphasic decline. The serum exposures showed a dose-dependent increase following both Q2W and Q1W regimens. With the Q1W regimen, the serum C_trough was higher than that with the Q2W regimen at similar dose levels. Transient increases in serum cytokine levels were observed within 24 hours following ISB 1342 administration, including IFNg, TNFa, IL-2, IL-6 and IL-10.

Conclusions: Treatment with ISB 1342 was well tolerated at the dose levels evaluated. The observed CRS events were moderate. Dose escalation continues with additional dose cohorts accruing. The updated clinical, biomarker and PK data will be presented for this ongoing study.