PWII-003 - TRANSLATIONAL FINDINGS FROM THE ONGOING FIRST-IN-HUMAN (FIH) STUDY OF UBAMATAMAB (REGN4018, MUC16XCD3 BISPECIFIC ANTIBODY [BSAB]) IN PATIENTS (PTS) WITH RECURRENT OVARIAN CANCER (OC): REGIMEN SELECTION.

M. Zhu, A. Crawford, M. Retter, M. Khaksar Toroghi, D. Conrado, J. Brouwer-Visser, P. Krueger, X. Meng, J. Davis, M. Peterman, T. Uldrick, E. Miller; Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.

Background: Ubamatamab is a MUC16xCD3 bsAb that promotes T cell–mediated cytotoxicity by binding MUC16-expressing OC cells and CD3+ T cells. Translational analysis was performed to support FIH regimen selection in dose escalation and expansion (NCT03564340).

Methods: Ubamatamab was administered intravenously to pts with OC as monotherapy (78 pts) or in combination with anti–PD-1 cemiplimab (27 pts). The first dose in Week (W) 1 was selected based on in vitro cytokine assay results. Mouse tumor regression models suggested effective concentrations to suppress tumor growth. Pharmacokinetic (PK) data in monkeys were scaled to predict drug exposures in pts. Modeling of CD3 bsAb + cemiplimab was used to set dosing sequence of cemiplimab plus ubamatamab. Preclinical and clinical PK, cytokine, and efficacy data from dose escalation were integrated to determine regimens in dose expansion. Population PK modeling simulated regimens of interest.

Results: In vitro data showed min and max cytokine release at concentrations of 0.01 mg/L and ≥0.1 mg/L. Data supported W1 step-up doses in the range of 0.1–1 mg in pts, leading to observed Cmax of 0.02–0.3 mg/L. Cmax values at W1 in all cohorts of pts were well predicted (within ±30%) from the scaling. PK data from mouse tumor regression model indicated efficacious concentrations (0.5–50 mg/L) that aligned with Cmin >4 mg/L at effective doses of ≥20 mg. PK simulation supported testing ≥250 mg Q3W in expansion. As the model predicted, no significant cytokine release occurred when combining cemiplimab with ubamatamab following an ubamatamab monotherapy lead-in.

Conclusion: Cytokine assay, mouse model, and monkey PK data had translational value for FIH dose selection. Using clinical data from escalation, rationale for regimen selection in expansion was established.