Model‐informed optimal dose selection of golcadomide in combination with R‐CHOP in patients with previously untreated aggressive B‐cell lymphoma

Vollständiger Abstract

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Aims Golcadomide is a potential first‐in‐class oral CELMoD™ agent for the treatment of lymphoma. This study aims to develop model‐informed drug development (MIDD) approaches to support optimal dose selection of golcadomide in combination with immunotherapy rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R‐CHOP) in alignment with the U.S. Food and Drug Administration (FDA) Project Optimus. Methods In the ongoing Phase 1b study CC‐220‐DLBCL‐001 (NCT04884035), clinical safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) data were collected across two dose levels (0.2 and 0.4 mg) of golcadomide in combination with R‐CHOP. Integrated analyses, including population PK (popPK), PK/PD and exposure–response (E–R) modelling analyses, were conducted to assess benefit–risk profiles and to inform dose selection in the combination setting. Results Compared with 0.2 mg, the 0.4 mg dose of golcadomide in combination with R‐CHOP was associated with higher exposure and more rapid, deeper degradation of targeted protein Ikaros. In addition, a positive relationship was observed between exposure and end‐of‐treatment complete metabolic response (CMR). Except for grade 4 thrombocytopenia, no obvious E–R trends were found for safety endpoints, including grade 3+ neutropenia, any grade febrile neutropenia and adverse events (AEs) leading to golcadomide dose modification. Conclusions The integrated MIDD evaluation conducted in this study provided a quantitative and mechanism‐based rationale for the optimal dose selection of golcadomide in previously untreated aggressive B‐cell lymphoma. The findings also highlight the value of a systematic MIDD framework for dose optimization in alignment with FDA's Project Optimus initiative and provide an example for oncology drug dose selection in combination therapy settings.