Clinical Activity of CC-99282, a Novel, Oral Small Molecule Cereblon E3 Ligase Modulator (CELMoD) Agent, in Patients (Pts) with Relapsed or Refractory Non-Hodgkin Lymphoma (R/R NHL) - First Results from a Phase 1, Open-Label Study
Authors: Michot Jean-Marie , Chavez Julio C. , Carpio Cecilia , Ferrari Silvia , Feldman Tatyana A. , Morillo Daniel , Kuruvilla John , Pinto Antonio , Ribrag Vincent , Bachy Emmanuel , Buchholz Tonia J , Carrancio Soraya , Guarinos Carla , Wu Fan , Li Shaoyi , Patah Poliana , Pourdehnad Michael , Nastoupil Loretta 
Published: November 2021

Abstract
CC-99282 is a novel, small molecule CELMoD ® agent that co-opts cereblon to induce targeted degradation of Ikaros/Aiolos, transcription factors critical for development of B-cell malignancies. Lopez-Girona et al. reported that in preclinical models, compared with lenalidomide and other immunomodulatory agents, CC-99282 showed similar immunostimulatory effects and stronger antitumor activity along with robust distribution across multiple tissues. In addition, CC-99282 was shown to exhibit 10- to 100-fold enhanced antiproliferative and apoptotic activity in a range of diffuse large B-cell lymphoma (DLBCL) cell lines, independent of subtype or chemotherapy-resistant status (Lopez-Girona, et al. Hematol Oncol. 2021). Here, we present results from CC-99282-NHL-001, a phase 1, open-label, dose-finding, first-in-human study evaluating CC-99282 in pts with R/R NHL (NCT03930953).
This multicenter study consists of 2 parts, dose escalation of CC-99282 monotherapy (part A) and expansion with or without combination partners (part B). Part A includes pts with R/R DLBCL or follicular lymphoma (FL) who have progressed after ≥ 2 lines of therapy, including prior CELMoD agent and chimeric antigen receptor T cell therapy (CAR T), or pts with R/R DLBCL who received ≥ 1 lines of standard therapy and are unfit for transplant. Pts receive oral CC-99282 (0.2 mg, 0.4 mg, 0.6 mg, or 0.8 mg) once daily following 3 different intermittent dosing schedules of 28-day cycles, with ≥ 3 pts in each dosing cohort. Primary objectives are to determine the safety, tolerability, maximum tolerated dose (MTD), and/or the recommended phase 2 dose (RP2D); secondary objectives include pharmacokinetics (PK) and preliminary efficacy of CC-99282 monotherapy in pts with R/R NHL. The pharmacodynamics (PD) of CC-99282 in R/R NHL is an exploratory endpoint.
As of April 9, 2021, 35 eligible pts were treated in part A (30 DLBCL and 5 FL). Median age was 66 (range 35-81) years and 57% were male. Median number of prior anticancer therapies was 3 (range 1-8); 7 (20%) pts had received CAR T, 7 (20%) had received prior stem cell transplants, and 20 (57%) were refractory to last treatment.
Median treatment duration was 8 (range 4-72) weeks, and at time of analysis 8 (23%) pts were still on treatment and 22 (63%) had discontinued treatment because of progressive disease. Twenty-one (60%) pts had a treatment-emergent adverse event (TEAE) of grade 3/4 related to CC-99282, the most common being neutropenia (19 pts [54%]), thrombocytopenia (3 pts [9%]), and febrile neutropenia (2 pts [6%]). Dose-limiting toxicities observed have been hematologic TEAEs and the MTD has not been reached. Management of neutropenia included dose reductions and/or interruptions, and prophylaxis or treatment with colony-stimulating factors.
At the tolerated schedules of dose levels ≥ 0.4 mg, CC-99282 monotherapy demonstrated an overall response rate of 40% (10/25 pts with objective responses including 3 FL, 1 FL grade IIIB, and 6 DLBCL), including complete responses in 3 pts and partial responses in 7 pts. Responses appeared durable with an observed range of 9-407 days, as of the cutoff date. Objective responses were observed in patients treated with prior CAR T or lenalidomide. Selection of the RP2D is pending and updated data for optimal dose regimen will be presented at ASH 2021.
Interim PK analysis showed that CC-99282 was absorbed rapidly with a prolonged terminal half-life (median of ~ 50 hours at doses ≥ 0.4 mg) and excellent distribution into the peripheral compartment. Increase in plasma CC-99282 and degradation of Ikaros/Aiolos in peripheral T cells occurred in a dose-dependent manner where maximum degradation (&gt; 90%) occurred by day 4 of treatment at doses ≥ 0.4 mg. Immunophenotyping of peripheral blood mononuclear cells showed immunostimulatory activity with increases in both T cell and natural killer cell compartments. The circulating tumor DNA analysis showed a reduction in the single nucleotide variants of tumor DNA as early as cycle 1 day 15 that correlated with response to CC-99282 treatment and suggested fast tumor cell-intrinsic activity.
CC-99282 monotherapy showed a predictable and manageable safety profile and demonstrated promising efficacy in heavily pretreated pts with R/R NHL with PK/PD data consistent with robust CC-99282-mediated antitumor activity. This study is ongoing and actively enrolling additional cohorts.

Disclosures
Michot: ASTEX: Research Funding, Speakers Bureau; Astra Zeneca: Honoraria, Research Funding; Roche: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Abbvie: Research Funding; Aduro: Research Funding; Agios: Research Funding; Amgen: Research Funding; Argen-x: Research Funding; Bayer: Research Funding; Beigene: Research Funding; Blueprint: Research Funding; Celgene: Research Funding; Boeringer Ingelheim: Research Funding; Chugai: Research Funding; Clovis: Research Funding; Daiichi Sankyo,: Research Funding; Debiopharm: Research Funding; Eisai: Research Funding; Eos: Research Funding; Exelixis: Research Funding; Forma: Research Funding; Gamamabs: Research Funding; Genentech: Research Funding; GSK: Consultancy, Honoraria, Research Funding; H3 biomedecine: Research Funding; Incyte: Research Funding; Innate Pharma: Research Funding; Celgene: Honoraria; MSD: Consultancy, Honoraria; GSK: Honoraria. Chavez: MorphoSys: Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Speakers Bureau; Merck: Research Funding; Abbvie: Consultancy; Adaptive: Research Funding; AstraZeneca: Research Funding; BeiGene: Speakers Bureau; Epizyme: Speakers Bureau; Novartis: Consultancy; Karyopharm Therapeutics: Consultancy; Kite/Gilead: Consultancy. Carpio: Regeneron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Takeda: Consultancy; Celgene: Other: Travels and accommodations . Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Morillo: Abbvie: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Kuruvilla: Incyte: Honoraria; Gilead: Honoraria; Amgen: Honoraria; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karyopharm: Honoraria, Other: Data and Safety Monitoring Board; Medison Ventures: Honoraria; AbbVie: Honoraria; Seattle Genetics: Honoraria; TG Therapeutics: Honoraria; BMS: Honoraria; AstraZeneca: Honoraria, Research Funding; Novartis: Honoraria; Merck: Honoraria; Antengene: Honoraria; Pfizer: Honoraria. Pinto: Roche: Honoraria, Speakers Bureau; Bristol Myers Squibb-CELGENE: Honoraria; MSD: Honoraria; Incyte: Honoraria; Takeda: Consultancy. Ribrag: Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Bachy: Kite, a Gilead Company: Honoraria; Roche: Consultancy; Takeda: Consultancy; Novartis: Honoraria; Daiishi: Research Funding; Incyte: Consultancy. Buchholz: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Carrancio: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Guarinos: Bristol Myers Squibb: Current Employment. Wu: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Li: Bristol Myers Squibb: Current Employment. Patah: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Pourdehnad: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: No royalty. Nastoupil: Gilead/Kite: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Denovo Pharma: Other: DSMC; Genentech: Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; IGM Biosciences: Research Funding; Janssen: Honoraria, Research Funding; Caribou Biosciences: Research Funding; MorphoSys: Honoraria; ADC Therapeutics: Honoraria; Bayer: Honoraria.