avadomide (CC-122)

P1, N=15, Terminated, Celgene | Completed --> Terminated; Replaced it with another clinical trial.

P1, N=174, Terminated, Celgene | Active, not recruiting --> Terminated; Replaced with another clinical trial.

P1, N=12, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

P1, N=271, Completed, Celgene | Active, not recruiting --> Completed | Phase classification: P1a/1b --> P1

P1, N=174, Active, not recruiting, Celgene | Phase classification: P1b --> P1 | Trial completion date: Oct 2023 --> Jan 2024 | Trial primary completion date: Oct 2023 --> Jan 2024

Methods Data used in this study included RNA (n=143) and whole exome (n=126) sequencing data from available FFPE tumor samples at the time of a relapse (any line of treatment, r1-r10 relapse timepoints included in analysis, one per patient), consented to the Molecular Epidemiology Resource (n=61), banked in the Mayo Lymphoma Biobank (n=50), or consented to the CC-122-ST-001 clinical trial (n=32, NCT01421524). In summary, we show for the first time that rrDLBCL patients can be classified into four gene expression clusters that are associated with distinct pathway, TME, and genetic programs. These clusters should now be tested to learn if they can help select patients for newer therapies for rrDLBCL such as CAR-T and bispecific antibodies.

P1b, N=75, Completed, Celgene | Active, not recruiting --> Completed

Our findings suggest that avadomide could be a novel therapeutic option to overcome gemcitabine resistance in patients with PDAC.

P1b, N=75, Active, not recruiting, Celgene | Trial completion date: Feb 2023 --> Aug 2023 | Trial primary completion date: Feb 2023 --> Aug 2023

P1a/1b, N=271, Active, not recruiting, Celgene | Trial completion date: Apr 2023 --> Jul 2023 | Trial primary completion date: Apr 2023 --> Jul 2023

P1b, N=174, Active, not recruiting, Celgene | Trial completion date: Apr 2023 --> Jul 2023 | Trial primary completion date: Apr 2023 --> Jul 2023

P1, N=12, Recruiting, Bristol-Myers Squibb | Not yet recruiting --> Recruiting

P1/2, N=62, Completed, Celgene | Active, not recruiting --> Completed

P1/2, N=62, Active, not recruiting, Celgene | Trial completion date: Jul 2025 --> Jan 2023 | Trial primary completion date: Jul 2025 --> Jan 2023

P1/2, N=62, Active, not recruiting, Celgene | Recruiting --> Active, not recruiting | N=108 --> 62

Our results provide a novel role for lineage factors Aiolos and Ikaros in DLBCL as well as further insight into the mechanism(s) of Aiolos and Ikaros mediated transcriptional repression and unique therapeutic combination strategies.

A total of 68 patients were enrolled (DLBCL [n = 27], FL [n = 41; 31 lenalidomide-naïve, 10 lenalidomide-treated]). Avadomide plus rituximab was well tolerated, and preliminary antitumor activity was observed in patients with R/R DLBCL and FL, including subgroups with typically poor outcomes. These results support further investigation of novel CELMoD agents in combination with rituximab in R/R DLBCL and FL.

CC-122 plus rituximab was well tolerated, with preliminary antitumor activity in patients with R/R DLBCL. This innovative study demonstrates the feasibility of assessing the tolerability and preliminary efficacy of novel combinations utilizing a multi-arm dose-finding design.

P1/2, N=108, Recruiting, Celgene | N=77 --> 108

P1/2, N=77, Recruiting, Celgene | Trial completion date: Oct 2024 --> Aug 2025 | Trial primary completion date: Oct 2024 --> Aug 2025

Compared with existing agents targeting Ikaros/Aiolos that show activity in hematologic malignancies, such as lenalidomide, avadomide, and iberdomide (CC-220), CC-99282 induced a more rapid, deep, and sustained degradation of Ikaros/Aiolos, causing derepression of cyclin-dependent kinase (CDK) inhibitors and interferon-stimulated genes ( IRF7 , IFIT3 , and DDX58 ), and the reduction of the highly critical oncogenic factors c-Myc and IRF4...In addition, CC-99282 acts synergistically in combination with anti-CD20 monoclonal antibody treatment. Collectively, these data support the clinical investigation of CC-99282 as monotherapy and in combination with rituximab in patients with R/R NHL.

P1b, N=174, Active, not recruiting, Celgene | Trial completion date: Nov 2021 --> Nov 2022 | Trial primary completion date: Nov 2021 --> Nov 2022

P1b, N=75, Active, not recruiting, Celgene | Trial completion date: Dec 2021 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Dec 2022

Additionally, we generated a disease-specific virtual patient population to represent the variability in patient characteristics and response to treatment observed for a diffuse large B-cell lymphoma trial cohort. Model utility was demonstrated by simulating the avadomide effect in the virtual population for various dosing schedules and determining the incidence of high-grade neutropenia, its duration, and the probability of recovery to low-grade neutropenia.

Furthermore, knockout of AMBRA1 renders resistance to CC-122 in SU-DHL-4 and U-2932, whereas knockout of RFX7 leads to resistance specifically in SU-DHL-4. The ubiquitous and cell line-specific mechanisms of CC-122 resistance in DLBCL cell lines revealed in this work pinpoint genetic alternations that are potentially associated with clinical resistance in patients and facilitate the development of biomarker strategies for patient stratification, which may improve clinical outcomes of patients with R/R DLBCL.

While patients with R/R NHL tend to have poor prognoses, agents mediating Ikaros/Aiolos degradation, such as lenalidomide (LEN) and avadomide (AVA), have shown promise in the R/R NHL setting... CC-99282 demonstrated potent autonomous cell killing and apoptosis in DLBCL cells, independent of the origin subtype, presence of high-risk chromosomal translocations, or acquired resistance to doxorubicin... CC-99282 is a novel CELMoD that, compared with LEN and other immunomodulatory agents, shows enhanced antiproliferative, apoptotic, and immune-stimulatory activity in a range of DLBCL models, including those with acquired chemoresistance. These data support the clinical investigation of CC-99282 in patients with R/R NHL.

P1/2, N=77, Recruiting, Celgene | Trial completion date: Aug 2023 --> Oct 2024 | Trial primary completion date: Aug 2023 --> Oct 2024

P1/2, N=35, Completed, Celgene | Active, not recruiting --> Completed

P1b, N=75, Active, not recruiting, Celgene | Trial completion date: Dec 2020 --> Dec 2021 | Trial primary completion date: Dec 2020 --> Dec 2021

While the results of early phase investigations involving ibrutinib and the IMiD agents, lenalidomide, pomalidomide, as well as avadomide, strongly support the hypothesis that the B-cell receptor (BCR) pathway, involving MYD88 and CD79B and NF-kB activation, is critical to the pathogenesis of PCNSL, much work is needed to elucidate mechanisms of resistance. Similarly, development of strategies to overcome immunosuppressive mechanisms that are upregulated in the tumor microenvironment is a high priority. Finally, ongoing evidence supports the hypothesis that the blood-brain barrier represents a significant impediment to efficient brain tumor penetration of novel therapeutic agents and innovative strategies of drug delivery remain essential to further improve outcomes.

Pts with early relapse (ER) (progressive disease <2 y after initial diagnosis) and those who are double-refractory (DR) to both rituximab and chemotherapy, have particularly poor outcomes. Conclusions : Long-term follow-up results demonstrate that avadomide plus obinutuzumab has a manageable safety profile and durable responses in patients with R/R FL. The antitumor activity of cereblon modulators plus next-generation anti-CD20 antibodies in heavily pretreated R/R NHL warrants further investigation as a novel chemotherapy-free option.

Avadomide (CC-122) is a novel cereblon-binding agent that exhibits antilymphoma and immune-modulation activities with a biological profile distinct from similar agents, such as lenalidomide. Avadomide dose intensity was consistent across cohorts and the 3-mg dose given 5 consecutive days/week was established as the RP2D. This phase I study identified a tolerable dose of avadomide, with an acceptable toxicity profile and clinically meaningful efficacy in Japanese patients with previously treated NHL.

Notably, clinical analyses showed increased PD-L1 expression on T cells, as well as intratumoral expression of chemokine signaling genes in B cell malignancy patients receiving avadomide-based therapy. These data illustrate the importance of overcoming a low inflammatory T cell state to successfully sensitize CLL to checkpoint blockade-based combination therapy.

P1b, N=174, Active, not recruiting, Celgene | Trial completion date: Nov 2020 --> Nov 2021 | Trial primary completion date: Nov 2020 --> Nov 2021

P1/2, N=47, Completed, Celgene | Active, not recruiting --> Completed

Avadomide plus obinutuzumab has a manageable toxicity, being a tolerable treatment option for most patients. Although the prespecified threshold for activity was not met in the trial, we believe that the preliminary antitumour activity of cereblon modulators plus next-generation anti-CD20 antibodies in heavily pretreated relapsed or refractory non-Hodgkin lymphoma warrants further investigation as a chemotherapy-free option in this setting.

P1/2, N=100, Recruiting, Celgene | Trial completion date: Apr 2023 --> Aug 2023 | Trial primary completion date: Apr 2023 --> Aug 2023

P1/2, N=100, Recruiting, Celgene | Trial completion date: Aug 2023 --> Apr 2023 | Trial primary completion date: Aug 2023 --> Apr 2023

P1/2, N=100, Recruiting, Celgene | Trial completion date: Apr 2023 --> Aug 2023| Trial primary completion date: Apr 2023 --> Aug 2023

P1/2, N=100, Recruiting, Celgene | Trial completion date: Mar 2022 --> Apr 2023 | Trial primary completion date: Mar 2022 --> Apr 2023