Carmod, an Open-Label, Multicenter, Proof of Concept, Phase II Trial, Investigating the Safety and Efficacy of Golcadomide in Post-CART for Patients with Relapsed/Refractory High-Risk Aggressive Large B-Cell Lymphoma

Background. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has emerged as curative option for patients with relapsed or refractory aggressive large B-cell lymphomas (LBCL) who have failed after at least one line of immunochemotherapy, with durable remissions observed in 30% to 40% of patients in the pivotal clinical trials. For patients who progress or relapse after CAR T-cells, most of the failures occur early within the first 3-4 months after infusion. Factors associated with relapse are multiple. Among them, we and others have identified that high tumor mass assessed on the measure of a total metabolic tumor volume (TMTV) > 80ml, was one of the key parameters to predict early progression or relapse after CAR T-cell infusion.

Golcadomide is a potential first-in-class oral cereblon E3 ligase modulator (CELMoD™) agent for non-Hodgkin lymphoma, purposefully designed to target Ikaros/Aiolos and have favorable PK, resulting in apoptotic and immunomodulatory activity with preferential distribution to lymphoid organs. Given the promising results of administering lenalidomide post CAR-T, we hypothesized that golcadomide administration post CAR-T could further improve clinical results. PK/PD modelling led us to hypothesize that weekly dosing of golcadomide could yield optimal CAR-T stimulation and migration to the tumor.

Methods. The objective of CARMOD (NCT06271057) is to improve clinical efficacy of CAR T-cells in patients with relapsed/refractory aggressive LBCL with high-risk of early relapse through the administration of golcadomide started at D5 after CAR T-cell infusion, with a weekly administration for 6 cycles (each cycle of 4 weeks, D1=D28). Patients with a TMTV > 80 ml at time of lymphodepletion will be selected for this trial. Calculation of TMTV will be centrally calculated by Pixilib, GaelO platform (SK). We expect to decrease the number of early progression/relapses occurring within the first 3 months by modulating CAR T-cell function during their expansion and by reprogramming the immunosuppressive tumor microenvironment using golcadomide. The ancillary studies will characterize the immunomodulatory abilities of golcadomide on both CAR T-cells themselves and the tumor microenvironment (TME).

The primary objective of the study is to estimate the efficacy of golcadomide administered post-anti-CD19 CAR T-cell infusion. The primary endpoint is the efficacy determined by complete metabolic response (CMR) rate at 3 months after infusion of anti-CD19 CAR T-cells as assessed by study investigator.

The secondary objectives include the objective response rate (ORR) defined as the incidence of either a complete (CMR) or a partial (PMR) metabolic response per the Lugano Classification (Cheson 2014) as determined by study investigators at 1 month, 3 months, 6 months, 1 year and 2 years, from CAR-T infusion; the ORR, CMR and PMR determined by imaging central review at 1 Month, 6 Months, 1 year, and 2 years; the Duration of response (DoR); and the Event-free survival (EFS) including earlier date of progression, start of subsequent new anti-lymphoma therapy including Stem Cells Transplant (SCT), or death from any cause; Progression-free survival (PFS) defined from CAR T-cells infusion date to the date of disease progression per the Lugano Classification (Cheson 2014) or death from any cause; the time to next anti-lymphoma therapy (TTNLT) including SCT (except SCT done as consolidation post-CART); the overall survival; the Incidence of adverse events and clinically significant changes in safety laboratory values; the incidence of cytokine released syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

Ancillary studies will analyze the impact of golcadomide on initial expansion and persistence of anti-CD19 CAR T-cells in peripheral blood; on the level of cytokines in serum, and circulating immune cells number and activation, and on TME in situ. Quantitative and qualitative analysis of Minimal Residual Disease by circulating tumor (Ct) DNA will also be assessed.

The sponsor of the trial is the Lymphoma Academic Research Organisation (LYSARC) with the support of Bristol Myers Squibb. The first patient has been included on 25 June 2024.

Thieblemont:BMS: Honoraria; Abbvie: Honoraria. Roulland:BMS: Research Funding. Lamy:BMS: Honoraria. Brisou:Kite-Gilead: Honoraria.