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.

Hoffmann:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Munoz:Targeted Oncology: Honoraria; Alexion: Consultancy; Kyowa: Honoraria, Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Millennium: Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Verastem: Consultancy, Speakers Bureau; Physicians' Education Resource: Honoraria; Epizyme: Consultancy; Pfizer: Consultancy; Pharmacyclics/Abbvie: Consultancy, Research Funding; Beigene: Consultancy, Research Funding, Speakers Bureau; Lilly/Loxo: Consultancy; TG Therapeutics: Consultancy; Morphosys/Incyte: Consultancy; Genmab: Consultancy; Acrotech/Aurobindo: Consultancy, Speakers Bureau; Celgene/ Bristol-Myers Squibb: Consultancy, Speakers Bureau; Celgene: Research Funding; Merck: Research Funding; MEI: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Curio: Honoraria; Portola: Research Funding; Incyte: Research Funding; OncView: Honoraria; Pharmacyclics/ Janssen: Consultancy, Research Funding, Speakers Bureau; Karyopharm: Consultancy; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau. Westin:SeaGen: Consultancy; Genentech: Consultancy, Research Funding; Kymera: Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Kite/Gilead: Consultancy, Research Funding; Calithera: Research Funding; Nurix: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Morphosys/Incyte: Consultancy, Research Funding; MonteRosa: Consultancy; AstraZeneca: Consultancy, Research Funding; Abbvie: Consultancy. Vassilakopoulos:Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; AstraZeneca: Honoraria; Integris: Honoraria; GlaxoSmithKline: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Martin Garcia-Sancho:F. Hoffmann-La Roche Ltd, BMS / Celgene, Kyowa Kirin, Novartis, Gilead / Kite, Incyte, Lilly, ADC Therapeutics America, Miltenyi, Ideogen, Abbvie, Sobi: Consultancy; AbbVie: Consultancy, Honoraria; Ideogen: Consultancy, Honoraria; Miltenyi: Consultancy, Honoraria; ADC Therapeutics America: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; Gilead / Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Clinigen: Consultancy; Eusa Pharma: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd, BMS/Celgene, Janssen, Gilead/Kite, Takeda, Eusa Pharma, Abbvie: Honoraria; Kyowa Kirin: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Rueda Dominguez:Roche: Speakers Bureau. Jurczak:AstraZeneca: Consultancy; AbbVie: Consultancy; BeiGene: Consultancy; Eli Lilly: Consultancy; Pfizer: Consultancy; Roche: Consultancy; SOBI: Consultancy; Takeda: Consultancy; AbbVie: Research Funding; AstraZeneca: Research Funding; Bayer: Research Funding; BeiGene: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Eli Lilly: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Roche: Research Funding; SOBI: Research Funding; Takeda: Research Funding. Yeh:AbbVie: Other: investigator for AbbVie sponsored trials. Gkasiamis:Bristol Myers Squibb: Current Employment. Kaplan:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Patel:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Boucaud:Bristol Myers Squibb: Current Employment. Li:Bristol Myers Squibb: Current Employment. Nowakowski:Curis: Consultancy; Karyopharm Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Ryvu Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bantam Pharmaceutical LLC: Consultancy; Seagen: Consultancy; MEI Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy; Debiopharm: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; F Hoffmann-La Roche Limited: Consultancy; Zai Lab Limited: Consultancy; Celgene Corporation: Consultancy; Abbvie: Consultancy; Kymera Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Selvita Inc: Consultancy; ADC Therapeutics: Consultancy.

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2023
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