OPEN‐LABEL PHASE 1/2 STUDY OF CC‐99282, A CEREBLON E3 LIGASE MODULATOR (CELMOD) AGENT ± RITUXIMAB, IN PATIENTS WITH RELAPSED/REFRACTORY (R/R) NON‐HODGKIN LYMPHOMA (NHL)

Abstract

Introduction: CC-99282 is a novel, oral, small molecule CELMoD® agent that co-opts cereblon to induce targeted degradation of Ikaros/Aiolos, transcription factors critical for B-cell malignancy development. Compared with immunomodulatory drugs (IMiD), CC-99282 had 10- to 100-fold enhanced antiproliferative and apoptotic activity in preclinical models of diffuse large B-cell lymphoma (DLBCL), while maintaining immunostimulatory effects. We previously reported promising efficacy and a predictable and manageable safety profile of CC-99282 in patients (pts) with R/R NHL (Michot et al. EHA, 2022). Methods: CC-99282-NHL-001 (NCT03930953) is a 2-part, multicentre, first-in-human study with dose escalation of CC-99282 monotherapy (part A) and expansion ± combination partners (part B) in pts with R/R DLBCL or follicular lymphoma (FL) who progressed after ≥2 lines of therapy, or pts with R/R DLBCL with ≥1 line of standard therapy and transplant-ineligible. Part A dosing is CC-99282 0.2–0.8 mg QD on 3 intermittent schedules of 28 d cycles. Part B dosing is CC-99282 0.2 or 0.4 mg alone on 2 intermittent schedules or with rituximab (RTX). Here, we report updated efficacy results for CC-99282 monotherapy (part A) and new safety data for CC-99282 + RTX (part B). Results: For part A, as of Sep 14, 2022, 50 pts were treated (38 DLBCL, 12 FL; median age 66 y); 3 pts (6%) completed, 7 (14%) were ongoing and 40 (80%) discontinued, most commonly due to progressive disease (n = 33, 66%). Median # of prior systemic anticancer therapies was 3 (range 1–8). For doses ≥0.4 mg on 7/14 or 14/28 d schedules, the overall response rate was 43% (17/40 evaluable pts; 10/30 DLBCL, 7/10 FL), with complete response in 7 and partial response in 10 pts. Responders included pts previously treated with CAR T cell therapy and/or IMiD/CELMoD agents. Responses were durable (Figure), with median duration of response (mDOR) of 299 d (range 48–898; median follow-up [mFU] 293) in pts with DLBCL and mDOR of 448 d (135–930; mFU 572) in pts with FL. For part B, as part of the safety run-in, 12 pts were treated with CC-99282 + RTX (9 DLBCL, 3 FL; median age 61y). With mFU of 6 wks (range 4–28), neutropenia was the most common any-grade treatment-emergent adverse event (AE), occurring in 5/12 (42%) pts, including 25% (3/12) grade 3/4 neutropenia. No febrile neutropenia occurred. There were no dose reductions, discontinuations, or dose-limiting toxicities (DLTs). Severe AEs included fever (n = 2), and dyspnoea and fatigue (n = 1 each). Similar safety profiles were observed at both CC-99282 dose levels, 0.2 and 0.4 mg, combined with RTX. The research was funded by: Celgene, a Bristol-Myers Squibb Company Keywords: aggressive B-cell non-Hodgkin lymphoma, combination therapies, indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract J. M. Michot Honoraria: Ideogen Educational grants: Amgen J. Chavez Consultant or advisory role: Advisory board of Kite and Novartis C. Carpio Consultant or advisory role: Consultancy: Takeda, Regeneron, Novartis Educational grants: Celgene E. Bachy Consultant or advisory role: Consultancy: Roche, Takeda, Incyte Honoraria: Kite/Gilead, Novartis Research funding: Daiishi F. Morschhauser Consultant or advisory role: Consultancy: Roche, Gilead, Genmab, Novartis, Abbvie J. M. Jørgensen Consultant or advisory role: Advisory board: Roche, Gilead, Novartis, BMS R. Cordoba Consultant or advisory role: Advisory role: BMS, Janssen, Abbvie, Astra Zeneca, Eli Lilly, Beigene, Kite P. Bories Consultant or advisory role: Consultancy: Abbvie; Advisory role: Kite/Gilead Research funding: BMS Educational grants: Kite/Giliead P. Patah Employment or leadership position: Employment: BMS Other remuneration: Equity ownership: BMS B. de Moucheron Employment or leadership position: Employment: BMS Stock ownership: BMS S. Carrancio Employment or leadership position: Employment: BMS Stock ownership: BMS C. Guarinos Employment or leadership position: Employment: BMS X. Zheng Employment or leadership position: Employment: BMS C. Mei Employment or leadership position: Employment: BMS M. Pourdehnad Employment or leadership position: BMS Stock ownership: BMS L. Nastoupil Honoraria: DC Therapeutics, Abbvie, BMS/Celgene, Incyte, Caribou Biosciences, Epizyme, Genentech, Gilead/Kite, Janssen, Novartis, Pfizer, Takeda Research funding: BMS/Celgene, Caribou Biosciences, Epizyme, Genentech, Gilead/Kite, IGM Biosciences, Janssen, Novartis, Pfizer, Takeda