An Innovative Approach to Optimize First‐In‐Human Minimal Anticipated Biological Effect Level Based Starting Dose in Oncology Trials for Bispecific T‐Cell Engagers: Experience from A Solid Tumor Bispecific T‐Cell Engager

Abstract

Bispecific T‐cell engagers (Bi‐TCEs) have revolutionized the treatment and management of both hematological and solid tumor indications with opportunities to become best‐in‐class therapeutics for cancer. However, defining the dose and dosing regimen for the first‐in‐human (FIH) studies of Bi‐TCEs can be challenging, as a high starting dose can expose subjects to serious toxicity while a low starting dose based on traditional minimal anticipated biological effect level (MABEL) approach could lead to lengthy dose escalations that exposes seriously ill patients to sub‐therapeutic dosing. Leveraging our in‐depth and broad clinical development experience across three generations of Bi‐TCEs across both liquid and solid tumor indications, we developed an innovative modified MABEL approach for starting dose selection that integrates knowledge based on the target biology, indication, toxicology, in vitro, in vivo pharmacological evaluations, and translational pharmacokinetic/pharmacodynamic (PK/PD) modeling, together with anticipated safety profile. Compared to the traditional MABEL approach in which high effector to target (E:T) cell ratios are typically used, our innovative approach utilized an optimized E:T cell ratio that better reflects the tumor microenvironment. This modified MABEL approach was successfully applied to FIH dose selection for a half‐life extended (HLE) Bi‐TCE for gastric cancer. This modified MABEL approach enabled a 10‐fold higher starting dose that was deemed safe and well tolerated and saved at least two dose‐escalation cohorts before reaching the projected efficacious dose. This approach was successfully accepted by global regulatory agencies and can be applied for Bi‐TCEs across both hematological and solid tumor indications for accelerating the clinical development for Bi‐TCEs.