Petel, Adrien

Abstract Background and Significance Diffuse large B-cell lymphoma (DLBCL) and other LBCLs account for 35–40% of non-Hodgkin lymphoma cases in North America, Europe, and East Asia. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard first-line treatment for DLBCL, achieving cure rates in approximately 60–70% of patients. However, 30–40% of patients will relapse or become refractory (R/R) to treatment, facing poor prognosis. Patients with high International Prognostic Index (IPI) scores (3–5) and those with IPI 1–2 who have bulky disease and/or very high lactate dehydrogenase (LDH) are recognized as high-risk (HR) subsets with suboptimal outcomes (Maurer et al, ASH 2023, #4512). Novel combination strategies are an area of focus for improving efficacy in this population. GOLCA 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. GOLCA 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 [COO]) and immunomodulatory activity. In the Phase 1b study CC-220-DLBCL-001, GOLCA in combination with R-CHOP demonstrated a predictable and manageable safety profile with high rates of durable responses, irrespective of COO, in previously untreated aggressive B-cell lymphomas (BCL), including promising activity in HR patients (Amzallag et al, ASH 2024, #579). The median relative dose intensity for GOLCA and CHO components was high (97–99%), indicating uncompromised delivery of curative standard-of-care treatment and combinability. GOLCA ± rituximab has also shown encouraging efficacy and safety in patients with R/R DLBCL (Bachy et al, ICML, #148). These findings support the further study of GOLCA + R-CHOP combination in the Phase 3 setting. Study Design and Methods GOLSEEK-1 (NCT06356129) is a randomized, double-blind, placebo-controlled, Phase 3 study evaluating GOLCA + R-CHOP versus placebo + R-CHOP in patients with previously untreated HR LBCL. Approximately 850 patients with previously untreated LBCL will be randomized 1:1 to either GOLCA + R-CHOP or placebo + R-CHOP. Eligible patients include those with histologically confirmed LBCL per WHO 2022 criteria—including DLBCL (not otherwise specified [NOS], ABC/GCB), high-grade BCL with MYC and BCL2 rearrangements or NOS, T-cell/histiocyte–rich LBCL, or Epstein Barr Virus-positive DLBCL. HR status is defined by IPI ≥3, or IPI 1–2 with HR features: LDH >1.3× upper limit of normal and/or bulky disease (≥7 cm lesion). All patients must have measurable disease as defined by Lugano criteria. Key exclusion criteria are other lymphoma subtypes such as primary mediastinal LBCL; primary cutaneous DLBCL-leg type, grade 3b follicular lymphoma (FL); transformed indolent lymphoma; anaplastic lymphoma kinase (ALK) positive LBCL; primary effusion lymphoma; and Burkitt lymphoma and known or suspected central nervous system involvement. Randomization will be stratified by IPI score (HR 1–2 and 3 vs 4–5) and bulky disease status (≥7 cm vs <7 cm). After a screening period of ≤4 weeks, patients will receive either GOLCA (0.4 mg) or placebo orally once daily for 7 consecutive days in each of 6 cycles, combined with R-CHOP every 21 days. The primary endpoint is progression-free survival (PFS) by investigator assessment per Lugano Response Criteria. Key secondary endpoints include PFS in non–high-grade BCL, event-free survival, independently assessed complete metabolic response, undetectable minimal residual disease by PhasED-Seq (defined as undetectable circulating tumor DNA levels at end of treatment), and overall survival. Patients will be followed up for up to approximately 67 months after beginning treatment. This study is currently recruiting at 309 sites in 36 countries , across the United States, Europe, Latin America, and East Asia. Acknowledgement BMS Artificial Intelligence was used to revise existing text with human author oversight.

Background and Significance Diffuse large B-cell lymphoma (DLBCL) and other LBCLs account for 35-40% of non-Hodgkin lymphoma cases in North America, Europe, and East Asia. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), typically administered for 6 cycles, is the standard therapy for DLBCL and is curative in ~60-70% of patients (pts). However, 30-40% of pts have relapsed/refractory (RR) DLBCL following treatment with R-CHOP, with poor clinical outcomes. International Prognostic Index (IPI) scores of 3-5 are used to identify high-risk (HR) pts who are more likely to be RR following treatment. Additionally, pts with IPI scores of 1-2 who also have bulky disease and/or very high lactate dehydrogenase levels (LDH), have been identified as a HR subset with similar outcomes to pts with an IPI score of 3 (Maurer et al. ASH 2023, #4512). First-line therapy represents the greatest opportunity to address the unmet need for these pts. Golcadomide (GOLCA) is a potential first-in-class oral cereblon E3 ligase modulator (CELMoD™) agent purposefully designed for the treatment of lymphoma. GOLCA co-opts cereblon to induce targeted degradation of the transcription factors Ikaros/Aiolos, inducing deep, rapid, and extensive tumor killing, independent of cell of origin, and enhanced immunostimulatory activity. In the phase 1b study CC-220-DLBCL-001, GOLCA combined with R-CHOP was well tolerated, showing promising activity and combinability with high rates of durable responses irrespective of cell of origin in pts with previously untreated aggressive BCL, including those with HR disease (Hoffmann et al. EHA 2024, S235). Additionally, GOLCA has shown encouraging efficacy and safety profiles in pts with RR DLBCL, both as a monotherapy (Michot et al. ICML 2023, P90) and in combination with rituximab (Chavez et al. ASH 2023, P4496). The efficacy and safety data observed in early-phase studies suggest promising activity and a manageable safety profile. This supports further investigation of the GOLCA + R-CHOP combination in the phase 3 setting. Here, we present the study design of GOLSEEK-1, a multicenter, randomized, double-blind, placebo-controlled phase 3 study (NCT06356129) comparing the efficacy and safety of GOLCA + R-CHOP vs placebo + R-CHOP in pts with previously untreated HR LBCL. Study Design and Methods Approximately 850 pts with previously untreated LBCL will be randomized 1:1 to either GOLCA + R-CHOP or placebo + R-CHOP. Pts must have a histologically confirmed diagnosis of LBCL according to WHO 2022 classification, including: DLBCL, not otherwise specified (NOS) including ABC and GCB subtypes; high-grade B-cell lymphoma with MYC and BCL2 rearrangements, or NOS; T-cell/histiocyte-rich LBCL; Epstein-Barr Virus-Positive DLBCL. Other key inclusion criteria include an IPI score of 1 or 2 considered HR (LDH > 1.3 × upper limit of normal and/or bulky disease, defined as a single lesion of ≥ 7 cm [Maurer et al. ASH 2023, #4512]), or IPI score ≥ 3; and measurable disease as defined by the Lugano classification. Key exclusion criteria include other lymphoma subtypes such as primary mediastinal LBCL; primary cutaneous DLBCL-leg type, grade 3b follicular lymphoma (FL); transformed indolent lymphoma; anaplastic lymphoma kinase (ALK)-positive LBCL; primary effusion lymphoma; and Burkitt lymphoma, as well as documented or suspected central nervous system involvement. Randomization will be stratified by IPI score (1-2 with risk factors and 3 vs 4-5) and bulky disease (> 7 cm vs ≤ 7 cm). After a screening period of ≤ 4 weeks, pts will receive GOLCA (0.4 mg) or placebo orally once daily for 7 consecutive days in each of 6 cycles in combination with R-CHOP in 21-day cycles. The primary endpoint of this study is progression-free survival (PFS) in untreated HR LBCL, assessed by investigator based on the Lugano Response Criteria. Key secondary endpoints include PFS in untreated non-high-grade BCL, event-free survival in pts with untreated HR LBCL, independently assessed complete metabolic response rate, undetectable minimal residual disease by PhasED-Seq (defined as undetectable circulating tumor DNA levels at treatment end), and overall survival. Patient follow-up will occur for up to approximately 67 months after beginning treatment. This study is recruiting at 293 sites in 37 countries, across the United States, Europe, Latin America, and East Asia.