Phase 1b Trial of Cereblon-Modulating Agents Iberdomide and CC-99282 Plus R-CHOP in Previously Untreated Aggressive B-Cell Lymphoma

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive B-cell lymphoma (a-BCL). The standard of care for patients (pts) with DLBCL is chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); however, up to 45%-50% of pts relapse after first-line (1L) R-CHOP. While pts who relapse have poor outcomes and limited treatment options, there is an opportunity to improve 1L response rates by building on the R-CHOP backbone. Lenalidomide (LEN) modulates cereblon E3 ligase, leading to antitumor effects and degradation of target proteins. The randomized, phase (ph) 3, ROBUST study evaluating LEN plus R-CHOP (R2-CHOP) in pts with activated B-cell like (ABC) DLBCL failed to demonstrate significant outcome improvements over R-CHOP alone (Nowakowski et al. J Clin Oncol 2021;39:1317-1328). A subsequent randomized ph 2 study showed significantly improved progression-free survival with R2-CHOP in all pts with untreated DLBCL, regardless of cell of origin (COO) (HR, 0.66; 95% CI, 0.43-1.01; one-sided P = 0.03) including those with ABC subtype (Nowakowski et al. J Clin Oncol 2021;39:1329-1338). These results reflect heterogeneity within COO subtypes, suggesting that COO alone does not support a precision medicine approach in DLBCL.

Iberdomide (IBER, CC-220) and CC-99282 are novel cereblon E3 ligase modulating (CELMoD) agents designed to optimize degradation of target proteins Ikaros and Aiolos, and improve tissue distribution for lymphoma-specific needs. In preclinical studies, compared with LEN, IBER showed enhanced affinity for cereblon, with significantly faster and deeper degradation of target substrates and increased tumoricidal activity (Matyskiela et al. J Med Chem 2018). IBER and CC-99282 demonstrated rapid and extensive tumor killing in vitro and in mouse models independent of COO, and enhanced T and NK cell immunostimulatory activity (Lopez-Girona et al. Hematol Oncol 2021, Carrancio et al. Blood 2021, Nakayama et al. ASH 2021). Initial results from a ph 1 study of CC-99282 monotherapy in relapsed/refractory non-Hodgkin lymphoma (R/R NHL) (Michot et al. Blood 2021) and a ph 1 study of IBER as a single agent and in combination with rituximab in R/R NHL (Thieblemont et al. ASH 2022) showed a predictable and manageable safety profile with promising clinical activity independent of COO, consistent with preclinical data. CC-220-DBLCL-001 (NCT04884035) is a dose-finding and safety trial in progress that will assess CELMoD agents in combination with R-CHOP for the treatment of previously untreated a-BCL.

Methods: CC-220-DLBCL-001 is a ph 1b, open-label, global, multicenter, dose-escalation (part 1), dose-expansion (part 2) study. Eligible pts aged ≥ 18 years must have untreated a-BCL with measurable disease per Lugano 2014 classification, with ECOG performance status ≤ 2. Part 1 includes pts with international prognostic index (IPI) scores 0-5; for part 2, pts must have IPI scores of 2-5. Primary objectives are to define the maximum tolerated dose and recommended ph 2 dose (RP2D) for IBER in combination with R-CHOP administered in 21-day cycles (R-CHOP-21), and CC-99282 in combination with R-CHOP-21, for pts with untreated a-BCL (part 1) and to evaluate safety and tolerability of these treatment combinations further at RP2D in pts with untreated a-BCL (part 2). Key secondary objectives include preliminary efficacy, pharmacokinetics, safety, and tolerability of the treatment combinations. In part 1, an estimated total of 36 pts will be enrolled who will receive escalating CELMoD dose levels guided by a modified toxicity probability interval design. Part 2 will enroll 40-80 pts who will be randomized to receive IBER or CC-99282 in combination with R-CHOP-21; further randomization may be introduced for dose optimization between RP2D and the next lower dose (Figure). Treatment will continue for 6 cycles or until disease progression, unacceptable toxicity, or study withdrawal. All pts will be followed for 28 days after the final dose for adverse event reporting. Pts who complete treatment will be assessed every 3 months during the first year and every 6 months for up to 2 years, with imaging at 9, 12, 18, and 24 months. The study opened on September 15, 2021 and is currently recruiting.

Study support: This study is supported by Bristol Myers Squibb.

Westin:Novartis: Consultancy, Research Funding; MorphoSys/Incyte Corporation: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Calithera: Consultancy, Research Funding; Iksuda: Consultancy; ADC Therapeutics: Consultancy, Research Funding; MonteRosa: Consultancy; AstraZeneca: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Merck: Consultancy; Abbvie/GenMab: Consultancy; SeaGen: Consultancy. Martín García-Sancho:Clinigen: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Eusa Pharma: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Lilly: Consultancy, Other: Support for attending meetings and/or travel; Takeda: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; ADC Therapeutics America: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Servier: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Incyte: Consultancy, Other: Support for attending meetings and/or travel; Gilead/Kite: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Roche: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Kyowa Kirin: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Kern: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Miltenyi: Consultancy, Honoraria, Other: Support for attending meetings and/or travel. Hoffmann:TG Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Beigene: Consultancy, Honoraria. Vassilakopoulos: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; Genesis Pharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Glaxo: Honoraria; AbbVie: Honoraria; Integris: Honoraria; AstraZeneca: Honoraria. Yeh:Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda Oncology: Membership on an entity's Board of Directors or advisory committees. Gkasiamis:Bristol Myers Squibb: Current Employment. Patah:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Patel:Bristol Myers Squibb: Current Employment. Li:Bristol Myers Squibb: Current Employment, Current holder of stock options in a privately-held company. Nowakowski:Bantam Pharmaceutical: Consultancy; Blueprint Medicines Corporation: Consultancy; Celgene Corporation/Bristol Myers Squibb: Consultancy, Research Funding; Curis, Inc.: Consultancy; Daiichi Sankyo Inc: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Genentech, Inc: Consultancy, Research Funding; Incyte: Consultancy; Karyopharm: Consultancy; Kite Pharma Inc.: Consultancy; Kymera Therapeutics: Consultancy; MorphoSys US Inc: Consultancy; NanoString: Research Funding; Ryvu Therapeutics: Consultancy; Selvita: Consultancy; TG Therapeutics: Consultancy; Zai Lab: Consultancy.