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

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 immunomodulat...

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Veröffentlicht in:Blood 2021-11, Vol.138 (Supplement 1), p.3574-3574
Hauptverfasser: 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
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Sprache:eng
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Zusammenfassung: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 [5
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2021-147333