Longitudinal modeling of a mechanism-based biomarker informs selection of golcadomide doses and dosing schedules for optimization in patients with relapsed or refractory non-Hodgkin lymphoma
Authors: Zheng Xirong 
Published: February 2025

Objectives: Golcadomide (CC-99282/BMS-986369) is a novel, oral CELMoD® agent that interacts with cereblon to induce degradation of target proteins including Ikaros and Aiolos, which are transcription factors critical for the development of B-cell malignancies and normal hematopoiesis. Golcadomide has demonstrated promising efficacy in patients with relapsed or refractory non-Hodgkin lymphoma (R/R NHL) in Study CC-99282-NHL-001 (Study NHL-001, NCT03930953)[1]. Neutropenia is an on-target adverse event of golcadomide, resulting from Ikaros degradation causing reversible neutrophil maturation arrest. It is thus important to optimize the clinical dose and schedule of golcadomide that lead to desired efficacy while allow sufficient Ikaros recovery to mitigate neutropenia risk. The aim of these analyses was to develop a population pharmacokinetic-pharmacodynamic (PPK-PD) model to characterize golcadomide plasma concentration and Ikaros profiles in R/R NHL patients in support of further dose optimization of golcadomide.Methods: An indirect PD response model was integrated with the previously developed population PK model of golcadomide[2] to simultaneously characterize golcadomide clinical PK and drug-induced Ikaros degradation. The PD parameters include ksyn, kdeg, Emax, and EC50. Plasma concentration of golcadomide and golcadomide-induced Ikaros degradation data were obtained from 52 patients in Study NHL-001, where patients received oral daily doses of golcadomide (0.2 mg, 0.4 mg, 0.6 mg, or 0.8 mg) in 3 different intermittent dosing schedules (5/7 days, 7/14 days, or 14/28 days) within 28-day cycles. The PPK-PD model was implemented in Monolix® (version 2020R1, Lixoft), and population parameters were estimated using the software-supplied stochastic approximation expectation-maximization algorithm.Results: The longitudinal PD model adequately captured golcadomide concentration-dependent Ikaros degradation in R/R NHL patients. The model parameters were estimated with reasonable precision ( < 50%). The modeling analyses indicate no significant covariate effects of age, body weight, ethnicity, race, sex, and tumor type on these parameters. The model simulation suggests that both 0.2 and 0.4 mg of golcadomide lead to rapid and deep Ikaros degradation following the 14/28-day schedule, with good recovery of Ikaros achieved at the end of drug holidays. Based on the model simulations, 0.2 mg and 0.4 mg were selected for further exploration in the expansion phase (Part B) of this study, with the aim to identify the optimal dose that results in deep and sustained Ikaros degradation while allowing sufficient Ikaros recovery during drug holidays for neutropenia mitigation.Conclusions: The longitudinal PD model adequately characterized the time-course of golcadomide-induced Ikaros degradation, and was successfully used to support dose selection/optimization of golcadomide in further clinical trials [3].Citations: [1] Michot, J. M., Chavez, J., Carpio, C., Bachy, E., Ferrari, S., Morschhauser, F., ... & Nastoupil, L. (2023). Open‐label phase 1/2 study of CC‐99282, a cereblon E3 ligase modulator (CELMoD) agent ± rituximab, in patients with relapsed/refractory (R/R) non‐Hodgkin lymphoma (NHL). Hematological Oncology, 41, 134-136.[2] Wu, F., Zheng, X., Patah P., Li, S., Buchholz, T., Pourdehnad, M., Lamba, M. (2022). Population pharmacokinetic modeling for CC-99282, a novel cereblon E3 ligase modulator (CELMoD) agent, in patients with relapsed or refractory non-Hodgkin lymphoma [Poster presentation]. American Conference on Pharmacometrics, Aurora, Colorado[3] Chavez, J. C., Nastoupil, L. J., Morschhauser, F., Cartron, G., Joergensen, J. M., Bachy, E., ... & Michot, J. M. (2023). Efficacy and safety of golcadomide, a novel cereblon E3 ligase modulator (CELMoD) agent, combined with rituximab in a phase 1/2 open-label study of patients with relapsed/refractory non-Hodgkin lymphoma. Blood, 142, 4496.