Golseek-4: A Phase 3, randomized study of golcadomide, a potential, first-in-class, oral CELMoD™ agent, plus rituximab versus Investigator's choice in patients with Relapsed/Refractory follicular lymphoma who have received ≥1 line of systemic therapy

Abstract

Abstract Background and Significance Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma (NHL), primarily manifesting as advanced-stage disease at diagnosis. Although frontline therapies can induce long remissions in many FL patients, the disease remains incurable, and subsequent relapses are associated with significantly shorter remissions. Current regimens for relapsed/refractory (R/R) FL, including non-cross-resistant chemoimmunotherapy and rituximab-lenalidomide, are associated with suboptimal long-term outcomes. Emerging T-cell-redirecting therapies have demonstrated improved efficacy in the third line and later settings, but limitations regarding tolerability and logistical challenges persist. An unmet need remains for effective, well-tolerated, and more convenient therapies for patients with R/R FL who have received ≥ 1 line of systemic therapy. Golcadomide is a potential, first-in-class, oral CELMoD agent designed for the treatment of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. Golcadomide drives the closed, active conformation of cereblon to induce rapid and deep degradation of Ikaros and Aiolos, leading to direct cell killing (agnostic of cell of origin) and immunomodulatory activity. In the Phase 1/2 CC-99282-NHL-001 study, golcadomide 0.4 mg in combination with rituximab demonstrated encouraging efficacy (objective response rate 94%; complete response rate 63%) and a tolerable safety profile among heavily pre-treated R/R FL patients, including those with prior exposure to lenalidomide and T-cell-redirecting therapies (Cordoba et al., EHA 2025, #1879). Study Design and Methods GOLSEEK-4 (NCT06911502) is a global, randomized, Phase 3 trial evaluating the efficacy and safety of golcadomide + rituximab versus investigator's choice (IC) in patients with R/R FL who have received ≥1 line of systemic therapy. Eligible adults (≥18 years) include patients with histologically confirmed grade 1-3A R/R FL and positron emission tomography (PET)-positive disease with at least one PET-positive lesion and measurable disease by computed tomography per the Lugano criteria, Eastern Cooperative Oncology Group (ECOG) 0–2 (ECOG 3 if due to lymphoma), requiring treatment according to modified Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria, and at least 1 prior line of therapy. Patients who had prior exposure to T-cell-redirecting therapies are also eligible for the study. Key exclusion criteria include composite diffuse large B-cell lymphoma and FL or of transformed NHL or any other indolent lymphoma, CNS involvement, and history of another primary malignancy that has not been in remission for ≥ 3 years except for non-invasive malignancies. Approximately 400 patients will be randomized 1:1 to golcadomide + rituximab or IC. Patients randomized to the golcadomide + rituximab arm will receive golcadomide (0.4 mg orally once daily on Days 1–14 of each 28-day cycle) with rituximab for 5 cycles, followed by golcadomide monotherapy for 7 cycles (total of 12 cycles). Patients randomized to IC will receive rituximab-lenalidomide (lenalidomide 20 mg Days 1–21 every 28 days plus rituximab) for 5 cycles followed by lenalidomide monotherapy for 7 cycles (total of 12 cycles) or rituximab-chemotherapy (R-CHOP or R-Bendamustine) for 6 cycles. Randomization will be stratified by progression of disease within 24 months vs >24 months from initial therapy, number of prior systemic regimens (2L vs 3L+), and comparator IC regimen. The primary endpoint is progression-free survival by independent review adjudication committee (IRAC). Key secondary endpoints include overall response rate by IRAC and overall survival. Additional secondary endpoints include investigator-assessed complete metabolic response, minimal residual disease via ctDNA at end of treatment, time to next treatment, and duration of response. Safety is an exploratory endpoint. Patients will be followed for up to five years from the last patient's first visit. GOLSEEK-4 will evaluate the safety and efficacy of golcadomide + rituximab as a fixed-duration, chemotherapy-free, outpatient treatment for patients with R/R FL, who have received ≥1 line of systemic therapy as compared to Investigator's choice of R-chemo or R-len. Recruitment started July 2025. AcknowledgementBMS Artificial Intelligence was used to revise existing text with human author oversight.