Model-informed optimal dose selection of golcadomide in combination with R-CHOP in patients with previously untreated...

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.

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.

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.

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.