FIH dose selection beyond MABEL: Optimizing phase 1 clinical trial starting dose whilst protecting patient safety

Selecting first-in-human (FIH) doses for immunomodulators presents significant challenges. Conservative approaches, which rely on the minimal anticipated biological effect level (MABEL), emphasize safety but often result in sub-therapeutic starting doses. These doses limit patients' benefit in severe diseases and prolong dose escalation. To address these limitations, we previously introduced a refined integrative approach from an expert working group. This commentary highlights key enhancements of this refined framework for FIH dose selection, including a revised decision tree, industry case studies, and pharmacokinetic/pharmacodynamic (PK/PD) modeling. This approach allows for careful consideration of immunomodulator mechanisms of action and balances risk-benefit profiles. The case studies illustrate the utility of these strategies. Furthermore, the commentary discusses how emerging concepts of Model-Informed Drug Development (MIDD) including quantitative systems pharmacology (QSP) models can inform and potentially strengthen FIH starting dose selection, aiming to optimize the balance between patient safety and therapeutic efficacy in early-phase trials.