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Currently, you can access the following clinical trials being conducted worldwide:

342,868 studies
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Clinical trial information and results are updated daily from ClinicalTrials.gov. The latest data update was conducted on 08/10/2020.
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Clinical trial information and results are updated daily from ClinicalTrials.gov. The latest data update was conducted on 08/10/2020.
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Our Science

    • Lenalidomide (IMiD® Agent)

    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.

    Proposed Mechanism of Action

    Lenalidomide is an oral, small-molecule immunomodulatory agent that directly induces tumor-cell killing and enhances immune function in preclinical studies.1,2

    Lymphoma

    Lenalidomide co-opts cereblon, a component of the E3 ubiquitin ligase complex, leading to direct tumoricidal and immunomodulatory effects.3-6 Preclinical studies have demonstrated increased activity of lenalidomide in combination with rituximab, an anti-CD20 monoclonal antibody that has been leveraged in the treatment of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia.7-12 Combinations of lenalidomide and rituximab are being investigated for the treatment of NHL subtypes, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma.13-15

    Myelodysplastic Syndromes

    Haploinsufficiency, caused when only 1 copy of a gene is present, is hypothesized to drive pathogenesis of del(5q) myelodysplastic syndromes (MDS)16-18 and may underlie the specific activity of lenalidomide.19 In myeloid cell lines, haploinsufficiency increases the sensitivity of del5q MDS cells to lenalidomide-mediated degradation of casein kinase 1A1 (CSNK1A1), a gene located in the deleted region of chromosome 5 in del(5q) MDS.20,21

    Preclinical and correlative studies in MDS cells suggest that in non-del(5q) MDS, the effects of lenalidomide on cellular progenitors and the microenvironment work together to promote normal erythropoiesis through expansion of progenitor populations,1,22 reduction in proinflammatory cytokines,22 and reduction of marrow microvessel density.22

    Multiple Myeloma

    In preclinical studies, lenalidomide has demonstrated direct tumoricidal and immunomodulatory effects, which are mediated in both myeloma and immune cells by co-opting cereblon, a component of the E3 ubiquitin ligase complex.2-6 This interaction triggers proteasome degredation of transcription factors Ikaros and Aiolos, resulting in downregulation of myeloma survival signals, IRF4 and c-Myc, and upregulation of immunoregulatory molecule IL-2.4,6,23

    Lenalidomide Hypothesized Mechanism of Action in Multiple Myeloma

    Lenalidomide is an IMiD agent shown in vitro to have direct tumoricidal and immunomodulatory effects in lymphoma, multiple myeloma, and myelodysplastic syndromes.

    Lenalidomide by Disease State

    Lenalidomide in Lymphoma

    Post Approval Research
    Mantle cell lymphoma: Relapsed/refractory

    Phase 3
    Diffuse large B-cell lymphoma (ABC-subtype): First-line

    Phase 3
    Follicular/marginal zone lymphoma: Relapsed/refractory

    View Trials Investigating Lenalidomide in Lymphoma
    View Rationale for Clinical Development

    Rationale for Clinical Development

    Follicular Lymphoma

    Lenalidomide exerts direct effects on FL tumors and their microenvironment in vitro.5,9,24,25 In preclinical studies, these effects on FL, T, and natural killer (NK) cells contribute to immune synapse repair and alter expression of costimulatory molecules.9,24 Immunomodulatory effects in vitro include enhanced T-cell proliferation and function and NK-cell function, including NK-cell–mediated antibody-dependent cellular cytotoxicity (ADCC) in conjunction with rituximab.5,10,25

    Proposed Mechanism of Action of Lenalidomide Plus Rituximab (R2) in Follicular Lymphoma

    R2 has demonstrated increased activity in preclinical studies of follicular lymphoma.

     

    Diffuse Large B-Cell Lymphoma

    Lenalidomide has direct effects in vitro on both DLBCL cells and the tumor microenvironment.5,10,25-28 In preclinical studies, direct effects using non–germinal center B cell-like (GCB) tumor cells are mediated by binding to the cereblon-containing E3 ubiquitin ligase and include inhibition of interferon regulatory factor 4 expression and nuclear factor κB activity, increased interferon-β production, inhibition of proliferation, and induction of apoptosis.26-28

    Proposed Mechanism of Action of R2-CHOP in Diffuse Large B-Cell Lymphoma

    The increased immunomodulatory activity of R2 compared with either agent alone combined with the cytotoxic activity of CHOP represent the rationale for investigating R2-CHOP in activated B-cell DLBCL.

    Mantle Cell Lymphoma

    In preclinical studies, lenalidomide increases mitochondrial release of cytochrome c and activates caspases, resulting in direct MCL tumor cell killing.11,29 In lymphoma cells, the combination of lenalidomide and rituximab increases both direct anti-tumor killing activities of lenalidomide and NK-cell–mediated killing observed with rituximab.10,11 Lenalidomide also increases rituximab-mediated activation of caspases 3, 8, and 911 and increases NK-cell killing capacity through ADCC in these cells.10

    Lenalidomide in Multiple Myeloma

    Post Approval Research
    Relapsed/refractory

    Post Approval Research
    Newly diagnosed

    Post Approval Research
    Maintenance

    View Trials Investigating Lenalidomide in Multiple Myeloma
    View Rationale for Clinical Development

    Rationale for Clinical Development

    Lenalidomide has shown direct anti-myeloma activity and direct stimulation of immune function in preclinical studies.2 Additional preclinical studies demonstrated increased anti-myeloma activity of lenalidomide in combination with dexamethasone and certain proteasome inhibitors and monoclonal antibodies.30-33 Celgene is currently investigating lenalidomide as a foundation for combination with other agents in multiple myeloma.

    View Related Pathways

    Cereblon/E3 Ligase Pathway
    Cereblon E3 Ligase Modulators (CELMoD® agents) in Targeted Protein Degradation

    References

    1. Komrokji RS, List AF. Semin Oncol. 2011;38:648-657. PMID: 21943671
    2. Borello I. Leuk Res. 2012;36:S3-S12. PMID: 23176722
    3. Revlimid (lenalidomide) capsules, for oral use [package insert]. Summit, NJ: Celgene Corporation; 2019.
    4. Lu G, et al. Science. 2014;343:305-309. PMID: 24292623
    5. Lopez-Girona A, et al. Leukemia. 2012;26:2326-2335. PMID: 22552008
    6. Bjorklund CC, et al. Blood Cancer J. 2015;5:e354. PMID: 26430725
    7. Lagrue K, et al. Blood. 2015;126:50-60. PMID: 26002964
    8. Gribben JG, et al. J Clin Oncol. 2015;33:2803-2811. PMID: 26195701
    9. Ramsay AG, et al. Blood. 2009;114:4713-4720. PMID: 19786615
    10. Reddy N, et al. Br J Haematol. 2008;140:36-46. PMID: 17995965
    11. Zhang L, et al. Am J Hematol. 2009;84:553-559. PMID: 19565649
    12. Rituxan (rituximab) [package insert]. South San Francisco, CA: Genentech, Inc; 2016.
    13. ClinicalTrials.gov. https://clinicaltrials.gov/show/NCT01996865.
    14. ClinicalTrials.gov. https://clinicaltrials.gov/show/NCT01938001.
    15. ClinicalTrials.gov. https://clinicaltrials.gov/show/NCT02285062.
    16. Boultwood J, et al. Blood. 2002;99:4638-4641. PMID: 12036901
    17. Horrigan SK, et al. Blood. 1996;88:2665-2670. PMID: 8839861
    18. Ebert BL, et al. Nature. 2008;451:335-339. PMID: 18202658
    19. Wei S, et al. Proc Natl Acad Sci U S A. 2009;106:12974-12979. PMID: 19470455
    20. Hollenbach P, et al. Blood. 2014;124 [abstract 3606].
    21. Fink EC, et al. Blood. 2014;124 [abstract 4].
    22. List AF, et al. Cancer Control. 2006;13(suppl):4-11. PMID: 17242661
    23. Krönke J, et al. Science. 2014;343:301-305. PMID: 24292625
    24. Rawal S, et al. Blood. 2012;120 [poster 2766].
    25. Haslett PAJ, et al. J Infect Dis. 2003;187:946-955. PMID: 12660941
    26. Zhang LH, et al. Br J Haematol. 2013;160:487-502. PMID: 23252516
    27. Yang Y, et al. Cancer Cell. 2012;21:723-737. PMID: 22698399
    28. Shaffer AL, et al. Clin Cancer Res. 2009;15:2954-2961. PMID: 19383829
    29. Qian Z, et al. Leuk Res. 2011;35:380-386. PMID: 21047686
    30. Gandhi AK, et al. Br J Haematol. 2014;164:811-821. PMID: 24328678
    31. Gandhi AK, et al. Curr Cancer Drug Targets. 2010;10:155-167. PMID: 20088798
    32. Chauhan D, et al. Blood. 2010;116:4906-4915. PMID: 20805366
    33. Das DS, et al. Br J Haematol. 2015;171:798-812. PMID: 26456076