Gkasiamis, Argyrios

7011 Background: Up to 40% of pts with diffuse large B-cell lymphoma (DLBCL) will relapse or have refractory disease following 1L treatment (Tx) with SOC chemoimmunotherapy regimens R-CHOP or Pola-RCHP. High risk (HR) populations include those with International Prognostic Index (IPI) score 3–5 and IPI 1–2 with either ≥1 lesion ≥7 cm or baseline LDH >1.3×ULN. GOLCA is a potential, first-in-class, oral CELMoD designed for the Tx of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. GOLCA induces rapid and deep degradation of Ikaros and Aiolos, leading to direct cell killing and immunomodulatory activity. GOLCA 0.4 mg + R-CHOP has shown promising safety, a ≥90% minimal residual disease (MRD) negativity rate, and durable efficacy (24-mo PFS, 79%) in 1L a-BCL (Nowakowski et al, ASH 2025, 476) and is being evaluated in the Phase (Ph) 3 study GOLSEEK-1 (NCT06356129). We report initial Ph1b results with GOLCA + Pola-RCHP in 1L a-BCL. Methods: Pts aged ≥18 y with ECOG PS ≤2, IPI 0–5 (Part 2A) or 2–5 (Part 2B), and newly diagnosed a-BCL with measurable tumorous disease were included. Pts were treated with GOLCA + Pola-RCHP for six 21-day (D) cycles or until disease progression/unacceptable toxicity/study withdrawal. In dose escalation, GOLCA was dosed at 0.2 and 0.4 mg D1–7. In dose expansion, pts were randomized 1:1 to Pola-RCHP + GOLCA 0.2 or 0.4 mg. Primary endpoint: safety; efficacy was a secondary endpoint. Results: At data cutoff, 57 pts were treated with GOLCA + Pola-RCHP (0.2 mg, n=28; 0.4 mg, n=29). Median age was 63 y. Most pts had HR disease (86%) and DLBCL not otherwise specified histology (84%). For known cell of origin (COO), 47% were germinal center B cell (GCB) and 39% non-GCB by Hans algorithm. Forty-seven pts (83%) completed Tx and 52 (91%) entered the follow-up (f/u) period. Grade 3/4 Tx-emergent adverse events occurred in 95% of pts, most frequently neutropenia (86%; an on-target side effect of GOLCA) and anemia (39%). Median relative dose intensity for GOLCA and Pola-RCHP components was >95%. At 15.5 mo median f/u, end of Tx (EOT) complete metabolic response (CMR) rate was 69% at 0.2 mg, 82% at 0.4 mg, and similar across COO subtypes. EOT CMR was consistent in HR pts (65% at 0.2 mg, 83% at 0.4 mg). The 12-mo DOR and PFS rates were 92% and 88% at 0.2 mg, and 96% and 96% at 0.4 mg. In pts with both pre-Tx and EOT ctDNA analysis, 65% and 83% at 0.2 and 0.4 mg achieved MRD negativity (PhasED-Seq) at EOT. Conclusions: GOLCA + Pola-RCHP demonstrated a predictable and manageable safety profile, and addition of GOLCA did not compromise median dose intensity of Pola-RCHP. GOLCA 0.4 mg + Pola-RCHP resulted in a high rate of durable CMRs, high rate of MRD negativity, and a promising 12-mo PFS rate. These data continue to show that GOLCA + SOC regimens R-CHOP and Pola-RCHP has potential to improve outcomes in 1L HR a-BCL. Clinical trial information: NCT04884035 .

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.