Boucaud, Floriane

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.

Introduction: GOLCA 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 pharmacokinetics, resulting in apoptotic and immunomodulatory activity with preferential distribution to lymphoid organs. CC-220-DLBCL-001 (NCT04884035) is an ongoing phase 1b, open-label, multicenter, dose-escalation/expansion trial to assess safety and preliminary 1L GOLCA + R-CHOP efficacy in a-BCL. Although longer follow-up is needed to assess durability of response, MRD negativity (MRD-) is an emerging endpoint in a-BCL. Achieving MRD- on and at end of treatment (EOT) can potentially predict clinical benefit. This study aimed to analyze circulating tumor DNA (ctDNA) kinetics of GOLCA + R-CHOP across the trial population and in defined patient (pt) segments-cell of origin (COO), high baseline ctDNA, and high-risk genomics-and to correlate MRD- with imaging and clinical outcomes. Methods: Eligible pts were ≥ 18 years of age with ECOG performance status ≤2, IPI 0-5 in Part 1 and 2-5 in Part 2, and untreated a-BCL with measurable disease. Pts were treated with GOLCA + R-CHOP for 6 x 21-day (D) cycles (C) or until disease progression/unacceptable toxicity/study withdrawal. Dose escalation phase GOLCA dose levels (DLs) were 0.2 mg D1-7 (DL-1), 0.4 mg D1-7 (DL1), or 0.4 mg D1-10 (DL2). During dose expansion, pts were randomized 1:1 to R-CHOP + GOLCA DL-1 or DL1. The primary endpoint was safety of GOLCA at DL1; efficacy was a secondary endpoint, ctDNA was an exploratory endpoint. ctDNA was analyzed using the PhasED-Seq assay (<10-6 sensitivity) at baseline, C2D1, C3D1, and EOT. MRD- was defined as the absence of detectable ctDNA on-treatment. Pretreatment biopsies were sequenced by whole genome sequencing (WGS) and whole transcriptome sequencing (WTS). Results: At data cutoff (June 3, 2024), the median follow-up was 14.3 months. One-year progression-free survival (PFS) was 85.3% at 0.4 mg and 77.3% at 0.2 mg. Rates of MRD- increased over time but were consistently higher at 0.4 vs 0.2 mg, with values of 44% (14/32) vs 29% (8/28) at C2D1; 63% (17/27) vs 54% (15/28) at C3D1, and 90% (26/29) vs 73% (19/26) at EOT, respectively. Interim MRD- at C3D1 strongly predicted EOT MRD-; all 0.4 mg pts and all but two 0.2 mg pts who were MRD- at C3D1 remained MRD- at EOT. In contrast, fold-changes from baseline ctDNA were similar between 0.4 mg and 0.2 mg. The early molecular response rate (≥102-fold drop from baseline at C2D1) was 81.2% (26/32) at 0.4 mg and 82.1% (23/28) at 0.2 mg. The major molecular response rate (≥102.5-fold drop from baseline at C3D1) was 88.9% (24/27) at 0.4 mg and 85.7% (24/28) at 0.2 mg. Across genetically defined pt segments, EOT MRD- at 0.4 mg was prevalent for both COO subtypes measured by the Hans algorithm: 94% (17/18) among germinal center B-cell (GCB) and 75% (6/8) among non-GCB pts. Of the 29 pts with baseline genomics, 13 were genomically high risk: p53 mutant (VAF >0.5), DZsig and/or A7 subtype. In these pts, EOT MRD- was 80% (4/5) at 0.4 mg but only 20% (1/5) at 0.2 mg. In high baseline ctDNA (>102.5 hGE/mL) pts who were high-risk for R-CHOP failure, EOT MRD- at 0.4 mg was 86.7% (13/15) vs 57.1% (8/14) at 0.2 mg. There was an association between high baseline ctDNA and lower PFS at 0.2 mg (HR, 4.56 [95% CI, 0.53-39.12]), but interestingly the association decreased at 0.4 mg (HR, 2.10 [95% CI, 0.19-23.5]). Combining both arms, MRD- at both C3D1 and EOT trends with improved PFS (C3D1: HR, 0.73 [95% CI, 0.2114-2.523]; EOT: HR, 0.53 [95% CI, 0.1103-2.592]); longer follow-up may be required to demonstrate significance. Conclusions: Interim and EOT levels of MRD- were higher at 0.4 mg vs 0.2 mg GOLCA, with a one-year PFS of 85.3% vs 77.3%, respectively. Although pt numbers were small, the data suggest that 0.4 mg is efficacious in high-risk ctDNA and high-genomic risk pts, independent of COO, and support the 0.4 mg GOLCA + R-CHOP regimen in the randomized phase 3 trial GOLSEEK-1. Interim MRD- may play a role in future adaptive trial designs.

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.

Introduction Up to 40% of pts with diffuse large B-cell lymphoma (DLBCL) relapse after first-line chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). CELMoD agents such as GOLCA potently degrade target proteins Ikaros/Aiolos, resulting in antiproliferative, apoptotic, and immunomodulatory activity. GOLCA preferentially distributes to tissues and lymphoid organs. In a phase 1 study, GOLCA demonstrated a manageable safety profile with promising clinical activity as monotherapy in relapsed/refractory non-Hodgkin lymphoma (Michot et al. Blood 2021). CC-220-DLBCL-001 (NCT04884035) is an ongoing open-label, multicenter, dose escalation and expansion trial to assess safety and preliminary efficacy of CELMoD agents + R-CHOP for untreated a-BCL. GOLCA demonstrated a manageable safety profile in the dose escalation phase (Munoz et al. ICML 2023 abstract 438); we report combined results from the GOLCA dose escalation and expansion phases. Methods Eligible pts were ≥ 18 years, had untreated a-BCL with measurable disease (Lugano 2014), ECOG performance status ≤ 2 and International Prognostic Index (IPI) score 0-5 (2-5 in dose expansion). Pts were treated with R-CHOP plus GOLCA in 21-day (D) cycles (C) for up to 6C, or until disease progression/unacceptable toxicity/study withdrawal/physician decision. During dose escalation, pts received GOLCA at dose levels (DL): 0.2 mg D1-7 (DL-1), 0.4 mg D1-7 (DL1), and 0.4 mg D1-10 (DL2). DL2 met the dose-limiting toxicity threshold and was not continued in the expansion phase. During dose expansion, pts were randomized 1:1 to R-CHOP plus GOLCA at DL-1 or DL1. The primary endpoint for the expansion phase was safety of GOLCA at the recommended phase 2 dose (DL1) (based on adverse events [AEs]); secondary endpoints included overall response rate (ORR) and complete metabolic response (CMR) rate (assessed at end of treatment [EoT] by PET-CT [Lugano 2014]). Circulating tumor DNA (ctDNA) was measured at C1D1, C2D1, C3D1, and EoT using the PhasED-Seq assay. Results Across escalation and expansion, 78 pts were treated (DL-1, n = 35; DL1, n = 37; DL2, n = 6). Median age was 63.0 years, 56.4% were male, most had high-intermediate/high IPI (3-5) score at diagnosis (64.1%), Ann Arbor stage III-IV disease (83.3%), and germinal center B cell as cell of origin (51.3%); 83.3% pts had DLBCL histology. At data extraction (May 25, 2023), across escalation and expansion, 38 pts had treatment ongoing, 31 completed treatment, and 35 continued to follow-up. A total of 3 pts discontinued due to AEs, 1 each at DL-1, DL1, and DL2. In the safety population (n = 78), median GOLCA relative dose intensity (RDI) was 99.4%; 82.1% of pts received RDI ≥ 85%. RDI for CHOP components was > 90%. A total of 73 (93.6%) pts had ≥ 1 treatment-emergent AE (TEAE); 70 (89.7%) pts had ≥ 1 TEAE considered related to GOLCA; 65 (83.3%) pts had ≥ 1 grade 3/4 TEAE, 62 (79.5%) pts had ≥ 1 grade 3/4 TEAE considered related to GOLCA. The most frequently occurring grade 3/4 TEAEs were neutropenia (76.9%) and thrombocytopenia (32.1%) ( Table). A total of 30 (38.5%) pts had serious TEAEs, most frequently febrile neutropenia (preferred term: 11 pts, 14.1%); 12 (15.4%) pts had serious TEAEs of infection or infestation (system organ class); 6 pts (7.7%) had venous thromboembolisms considered related to GOLCA (4 deep vein thrombosis, 1 superficial thrombosis, 1 pulmonary embolism). Treatment-related AEs leading to GOLCA dose reduction or discontinuation occurred in 11 (14.1%) pts and 6 (7.7%) pts, respectively. After a median follow-up time of 4.1 months (range 0.3-12.3) and among all treated pts with EoT response available, 21/25 had CMR; together, 14/14 pts who received GOLCA 0.4 mg (DL1 and DL2) achieved CMR at EoT ( Figure). Among efficacy-evaluable pts (n = 56), ORR was 91.1% (95% CI 80.4-97.0). Pts treated with GOLCA at DL-1 and DL1 who were ctDNA high-risk (≥ 2.5 log hGE/mL) responded to study treatment (CMR-PMR) and had early decreases in ctDNA (Kaplan et al. ASH 2023). Conclusions GOLCA demonstrated a manageable safety profile, showed good combinability with R-CHOP, and did not compromise delivery of curative treatment. Efficacy results and substantial ctDNA decrease indicate robust clinical activity in frontline DLBCL, with a high CMR rate at EoT, particularly among patients treated at DL1. Study support Bristol Myers Squibb.