Patient-Centric First-in-Human Dose Selection: An Ex Vivo Minimal Anticipated Biological Effect Level Approach for...

The minimal anticipated biological effect level (MABEL) approach to first-in-human (FIH) dose calculation can lead to long dose-escalation periods before observing clinical activity. We used a novel ex vivo MABEL approach to calculate the FIH starting dose for forimtamig, a T-cell bispecific antibody under investigation for the treatment of relapsed/refractory multiple myeloma (RRMM). We used in vitro and ex vivo MABEL approaches to calculate the FIH dose for a Phase 1 trial (NCT04557150) in patients with RRMM. In vitro assays used the OPM-2 MM cell line and peripheral blood mononucleocytes from healthy donors and patients with MM. Ex vivo assays used fresh bone marrow aspirates from MM patient donors. Forimtamig increased tumor cell lysis, cytokine release, and T-cell activation in vitro and ex vivo. Tumor cell lysis was considered the most relevant assay for dose calculation. EC₅₀ for LDH release (in vitro: mean 0.6 pM; ex vivo: 9 pM for the most sensitive patient) led to calculated FIH starting doses of 0.4 and 6 μg, respectively. FIH starting dose was 6 μg. Clinical activity was observed in the second dosing cohort (18 and 54 μg). The third dosing cohort (54 and 162 μg) showed durable objective responses. Cytokine release syndrome was Grade 1 at the starting dose and absent in the second dosing cohort. Our ex vivo MABEL approach was accepted by regulatory authorities and yielded a tolerated forimtamig FIH starting dose which demonstrated clinical activity in the second dosing cohort. We encourage similar innovative patient-centric approaches to FIH dose calculation.