CC‐99282 plus R‐CHOP in patients (pts) with previously untreated aggressive B‐cell lymphoma (a‐BCL): early safety and efficacy results from a phase 1b study

Introduction: Up to 30–40% of pts with diffuse large BCL relapse/become refractory after first-line chemo-immunotherapy with R-CHOP. CELMoD agent CC-99282 builds on the efficacy of immunomodulatory agents by optimizing degradation of target proteins Ikaros/Aiolos, enhancing antiproliferative and apoptotic activity; it showed a manageable safety profile with promising clinical activity as monotherapy in relapsed/refractory non-Hodgkin lymphoma in a phase 1 study (Michot et al. Blood 2021). CC-220-DLBCL-001 (NCT04884035) is an open-label, multicenter, dose-escalation and expansion trial to assess safety and preliminary efficacy of CC-99282 or CC-220 plus R-CHOP for untreated a-BCL. We report initial results from the CC-99282 escalation phase. Methods: Pts aged ≥18 y had untreated a-BCL with measurable disease (Lugano 2014), with ECOG performance status ≤2 and International Prognostic Index (IPI) score 0–5. Pts received R-CHOP in 21-d cycles (C) plus CC-99282 at 3 dose levels (DLs): DL-1 (0.2 mg, d1–7), DL1 (0.4 mg, d1–7), and DL2 (0.4 mg, d1–10). Treatment (tx) continued for 6 C or until disease progression/unacceptable toxicity/study withdrawal. Primary endpoints: maximum tolerated dose and recommended phase 2 dose based on dose-limiting toxicity (DLT). Results: Of 25 pts enrolled and treated (DL-1, n = 9; DL1, n = 10; DL2, n = 6), median (range) age was 64.0 (31–81) y; 60.0% were male; most had IPI score 3–5 at diagnosis (60.0%), Ann Arbor stage III–IV disease (68.0%), and germinal center B-cell (GCB) as cell of origin (COO) (52.0%; 12.0% activated B-cell; 24.0% non-GCB). Four pts discontinued tx, 17 remain on tx, and 4 completed tx. In total, 22 (88.0%) pts experienced a grade (Gr) 3/4 tx-emergent adverse event (TEAE), most commonly neutropenia (88.0%); 12.0% had infections. Gr 3/4 febrile neutropenia occurred in 2 (8.0%) pts; neutrophil recovery was prompt, 24 (96%) pts reaching absolute neutrophil count >1000 by d15. Gr 3/4 thrombocytopenia occurred in 9 (36.0%) pts. Seven (28.0%) pts had a serious TEAE. Overall, 28.0% of pts had CC-99282 reduction and 1 pt permanently discontinued tx at DL2. R-CHOP was delayed in 3 (12.0%) pts, and vincristine dose was reduced due to AE in 2 (8.0%) pts. Median relative dose intensity for CC-99282 and CHOP components was >90%. DLTs occurred in 1/9, 1/10, and 2/4 pts at DL-1, DL1, and DL2, respectively. DL2 exceeded the predefined threshold for toxicity. In the efficacy evaluable population, complete response and complete metabolic response rates were highest at DL1 (100.0%, 95% CI: 59.0–100.0; 71.4%, 95% CI: 29.0–96.3, respectively). Overall response rate was 100.0% at all DLs. Conclusions: CC-99282 showed a manageable safety profile with timely delivery and uncompromised R-CHOP dose intensity. Preliminary efficacy data indicated early and robust response to DL1 irrespective of COO. Low DLTs were observed at DL1 and DL-1; these DLs will be used in the expansion phase. The research was funded by: Bristol Myers Squibb Keywords: Aggressive B-cell non-Hodgkin lymphoma, Combination Therapies, Immunotherapy Conflicts of interests pertinent to the abstract. J. Munoz Consultant or advisory role: Pharmacyclics/AbbVie, Bayer, Gilead/Kite Pharma, Pfizer, Janssen, Juno/Celgene, BMS, Kyowa, Alexion, Fosunkite, Innovent, Seattle Genetics, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, Beigene, Servier, Novartis, Morphosys/Incyte, Secura Bio, TG Therapeutics, MEI, Lilly/Loxo Honoraria: Targeted Oncology, OncView, Curio, Kyowa, Physicians' Education Resource, and Seattle Genetics Research funding: Bayer, Gilead/Kite Pharma, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, Millennium Other remuneration: Speaker’s bureau – Gilead/Kite Pharma, Kyowa, Bayer, Pharmacyclics/Janssen, Seattle Genetics, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche M. Hoffmann Consultant or advisory role: Janssen, Pharmacyclics, BeiGene, Novartis, AstraZeneca, AbbVie, Eli Lilly, Kite, TG Honoraria: Janssen, Pharmacyclics, BeiGene, Novartis, AstraZeneca, AbbVie, Eli Lilly, Kite, TG J. Westin Consultant or advisory role: Kite/Gilead, BMS, Novartis, Genentech, AstraZeneca, Morphosys/Incyte, ADC Therapeutics, Janssen, AbbVie, SeaGen, MonteRosa, Calithera, Foresight Research funding: Kite/Gilead, BMS, Novartis, Genentech, AstraZeneca, Morphosys/Incyte, ADC Therapeutics, Janssen T. P. Vassilakopoulos Consultant or advisory role: Genesis, Gilead, Novartis, Roche, Takeda Honoraria: AbbVie, Amgen, AstraZeneca, Genesis, Gilead, GlaxoSmithKline, Integris, Merck, Novartis, Roche, Takeda Research funding: AbbVie, Amgen, Bristol Myers Squibb, Dr. Reddy’s, Karyopharm, Mei, Merck, Pfizer, Roche, Takeda, A. M. García-Sancho Consultant or advisory role: Roche, BMS, Kyowa Kirin, Clinigen, Eusa Pharma, Novartis, Gilead/Kite, Incyte, Lilly, Takeda, ADC Therapeutics America, Miltenyi, Ideogen, AbbVie Honoraria: BMS, Janssen, Gilead/Kite, Takeda, Eusa Pharma, Novartis Educational grants: Gilead/Kite, Janssen, Roche, BMS A. Rueda-Domínguez Consultant or advisory role: BMS, Roche, MSD, Merck, Takeda Honoraria: BMS, Roche, MSD, Gilead, Merck, Takeda W. Jurczak Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, Lilly, Roche, Takeda Research funding: AbbVie, AstraZeneca, BeiGene, Janssen, Lilly, Merck, Morphosys, Roche, Takeda M. Bouzani Consultant or advisory role: AbbVie, Gilead, Genesis Honoraria: Janssen, AbbVie, Roche, Gilead, Integris, Genesis, AstraZeneca Educational grants: Takeda, AstraZeneca, Gilead A. Gkasiamis Employment or leadership position: Bristol Myers Squibb A. Patel Employment or leadership position: Bristol Myers Squibb F. Boucaud Employment or leadership position: Bristol Myers Squibb J. Li Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb G. S. Nowakowski Consultant or advisory role: Celgene, MorphoSys AG, Genentech, Selvita, Debiopharm Group, Kite/Gilead Research funding: Celgene, MorphoSys AG, NanoString Technologies