Proposed Mechanism of Action
Avadomide is a non-phthalimide analogue and pleiotropic pathway modifier.1-5 Preclinical studies have shown that avadomide targets cereblon, a substrate receptor of the CUL4-RING E3 ubiquitin ligase complex.3,5,6 Avadomide has been shown to exert multiple biological activities in vitro, including anti-proliferative activity, anti-angiogenic activity, and immunomodulatory effects.3,4
- The immunomodulatory effects of avadomide on T cells in vitro have been shown to be mediated by increased ubiquitination and subsequent proteasome-mediated degradation of the lymphoid transcription factor Aiolos as a result of avadomide binding to cereblon1,3,5
- Aiolos has been shown to repress interleukin-2 production in T cells and interferon-stimulated genes in lymphoma cells1,2,6
- Avadomide–induced degradation of Aiolos resulted in T-cell activation and lymphoma cell apoptosis1-3
- Exposure to avadomide in vitro resulted in cereblon- and Aiolos-dependent increases in expression of interferon-stimulated genes and apoptosis of lymphoma cell lines2
- Exposure of T cells and natural killer cells to avadomide in vitro resulted in increased cytokine and chemokine production and T- and NK-cell activation1,3
- Avadomide has demonstrated anti-angiogenic effects in an in vitro umbilical artery growth assay3
DDX58, DEAD (Asp-Glu-Ala-Asp) box polypeptide 58; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFIT3, interferon-induced protein with tetratricopeptide
repeats 3; IFN, interferon; IL, interleukin; IRF7, interferon regulatory factor 7; NK, natural killer; RANTES, regulated on activation, normal T cell expressed and secreted.
CRBN, cereblon; IFN, interferon; NK, natural killer.
Avadomide (CC-122) by Disease State
Avadomide (CC-122) in Lymphoma
- Phase 1 Lymphoma Diffuse large B-cell lymphoma
- Phase 1 Lymphoma Indolent lymphoma: Relapsed/refractory
View Trials Investigating avadomide (CC-122) in Lymphoma.Avadomide (CC-122) in Lymphoma
Rationale for clinical development
Preclinical studies demonstrated that avadomide elicits substantial immunomodulatory, anti-proliferative, and anti-angiogenic activity.3,4
In correlative studies of diffuse large B-cell lymphoma (DLBCL), avadomide showed anti-tumor activity, including decreased expression of Aiolos protein, and increased T-cell activation and interleukin-2 production.5 Clinical studies exploring drug combinations with avadomide are ongoing in patients with DLBCL.7,8
Avadomide (CC-122) in Solid Tumors
- Phase 1 Solid Tumors Hepatocellular carcinoma
View Trials Investigating avadomide (CC-122) in Solid Tumors.Avadomide (CC-122) in Solid Tumors
Rationale for clinical development
Avadomide has been shown to exert multiple biological activities in vitro, including anti-proliferative activity, anti-angiogenic activity, and immunomodulatory effects.3,4
Avadomide demonstrated activity in a dose-escalation study that included patients with advanced solid tumors.1 Based on this activity, avadomide is currently being explored in a phase I trial of patients with solid tumors or hematologic malignancies, including multiple myeloma and lymphoma.7
The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated.
- Rasco DW, et al. Blood. 2013;122 [abstract 2905].
- Hagner P, et al. Blood. 2014;124 [abstract 3035].
- Gandhi AK, et al. Clin Lymphoma Myeloma Leuk. 2013;13:S179 [abstract P-287].
- Gandhi A, et al. Blood. 2012;120 [abstract 2963].
- Ribrag V, et al. Blood. 2014;124 [abstract 3500].
- Gandhi AK, et al. Br J Haematol. 2014;164:811-821. PMID: 24328678
- ClinicalTrials.gov. https://clinicaltrials.gov/show/NCT01421524.
- ClinicalTrials.gov. https://clinicaltrials.gov/show/NCT02031419.