Concomitant use of pembrolizumab and entinostat in adult patients with metastatic uveal melanoma (PEMDAC study): protocol for a multicenter phase II open label study

Henrik Jespersen, Roger Olofsson Bagge, Gustav Ullenhag, Ana Carneiro, Hildur Helgadottir, Ingrid Ljuslinder, Max Levin, Charlotta All-Eriksson, Bengt Andersson, Ulrika Stierner, Lisa M Nilsson, Jonas A Nilsson, Lars Ny, Henrik Jespersen, Roger Olofsson Bagge, Gustav Ullenhag, Ana Carneiro, Hildur Helgadottir, Ingrid Ljuslinder, Max Levin, Charlotta All-Eriksson, Bengt Andersson, Ulrika Stierner, Lisa M Nilsson, Jonas A Nilsson, Lars Ny

Abstract

Background: While recent years have seen a revolution in the treatment of metastatic cutaneous melanoma, no treatment has yet been able to demonstrate any prolonged survival in metastatic uveal melanoma. Thus, metastatic uveal melanoma remains a disease with an urgent unmet medical need. Reports of treatment with immune checkpoint inhibitors have thus far been disappointing. Based on animal experiments, it is reasonable to hypothesize that the effect of immunotherapy may be augmented by epigenetic therapy. Proposed mechanisms include enhanced expression of HLA class I and cancer antigens on cancer cells, as well as suppression of myeloid suppressor cells.

Methods: The PEMDAC study is a multicenter, open label phase II study assessing the efficacy of concomitant use of the PD1 inhibitor pembrolizumab and the class I HDAC inhibitor entinostat in adult patients with metastatic uveal melanoma. Primary endpoint is objective response rate. Eligible patients have histologically confirmed metastatic uveal melanoma, ECOG performance status 0-1, measurable disease as per RECIST 1.1 and may have received any number of prior therapies, with the exception of anticancer immunotherapy. Twenty nine patients will be enrolled. Patients receive pembrolizumab 200 mg intravenously every third week in combination with entinostat 5 mg orally once weekly. Treatment will continue until progression of disease or intolerable toxicity or for a maximum of 24 months.

Discussion: The PEMDAC study is the first trial to assess whether the addition of an HDAC inhibitor to anti-PD1 therapy can yield objective anti-tumoral responses in metastatic UM.

Trial registration: ClinicalTrials.gov registration number: NCT02697630 . (Registered 3 March 2016). EudraCT registration number: 2016-002114-50.

Keywords: Entinostat; Epigenetics; Histone deacetylase inhibitors; Immunotherapy; Metastatic; Pembrolizumab; Programmed cell death 1 receptor; Uveal melanoma.

Conflict of interest statement

ROB, GU, IL, US, ML and LN have had a paid consulting or advisory role with MSD, Sweden. All other authors declare that they have no competing interests.

Figures

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Fig. 1
Schedule of enrolment, interventions and assessments

References

    1. Damato B. Treatment of primary intraocular melanoma. Expert Rev Anticancer Ther. 2006;6:493–506. doi: 10.1586/14737140.6.4.493.
    1. Bergman L, Seregard S, Nilsson B, Ringborg U, Lundell G, Ragnarsson-Olding B. Incidence of uveal melanoma in Sweden from 1960 to 1998. Invest Ophthalmol Vis Sci. 2002;43:2579–2583.
    1. Virgili G, Gatta G, Ciccolallo L, Capocaccia R, Biggeri A, Crocetti E, Lutz J-MM, Paci E, group E Incidence of uveal melanoma in Europe. Ophthalmology. 2007;114:2309–2315. doi: 10.1016/j.ophtha.2007.01.032.
    1. Eskelin S. Mode of presentation and time to treatment of uveal melanoma in Finland. British Journal of Ophthalmology. 2002;86(3):333–338. doi: 10.1136/bjo.86.3.333.
    1. Kujala E, Makitie T, Kivela T. Very long-term prognosis of patients with malignant uveal melanoma. Invest Ophthalmol Vis Sci. 2003;44:4651–4659. doi: 10.1167/iovs.03-0538.
    1. Diener-West M, Reynolds SM, Agugliaro DJ, Caldwell R, Cumming K, Earle JD, Hawkins BS, Hayman JA, Jaiyesimi I, Jampol LM. Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: collaborative ocular melanoma study group report no. 26. Arch Ophthalmol. 2005;123:1639–1643. doi: 10.1001/archopht.123.12.1639.
    1. Kath R, Hayungs J, Bornfeld N, Sauerwein W, Höffken K, Seeber S. Prognosis and treatment of disseminated uveal melanoma. Cancer. 1993;72:2219–2223. doi: 10.1002/1097-0142(19931001)72:7<2219::AID-CNCR2820720725>;2-J.
    1. Olofsson R, Ny L, Eilard MS, Rizell M, Cahlin C, Stierner U, Lonn U, Hansson J, Ljuslinder I, Lundgren L, et al. Isolated hepatic perfusion as a treatment for uveal melanoma liver metastases (the SCANDIUM trial): study protocol for a randomized controlled trial. Trials. 2014;15:317. doi: 10.1186/1745-6215-15-317.
    1. Moore AR, Ceraudo E, Sher JJ, Guan Y, Shoushtari AN, Chang MT, Zhang JQ, Walczak EG, Kazmi MA, Taylor BS, et al. Recurrent activating mutations of G-protein-coupled receptor CYSLTR2 in uveal melanoma. Nat Genet. 2016;48:675–680. doi: 10.1038/ng.3549.
    1. Johansson P, Aoude LG, Wadt K, Glasson WJ, Warrier SK, Hewitt AW, Kiilgaard JF, Heegaard S, Isaacs T, Franchina M, et al. Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4. Oncotarget. 2016;7:4624–4631.
    1. Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O’Brien JM, Simpson EM, Barsh GS, Bastian BC. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457:599–602. doi: 10.1038/nature07586.
    1. Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T, Obenauf AC, Wackernagel W, Green G, Bouvier N, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010;363:2191–2199. doi: 10.1056/NEJMoa1000584.
    1. Carvajal RD, Piperno-Neumann S, Kapiteijn E, Chapman PB, Frank S, Joshua AM, Piulats JM, Wolter P, Cocquyt V, Chmielowski B, et al. Selumetinib in combination with Dacarbazine in patients with metastatic uveal melanoma: a phase III, multicenter, randomized trial (SUMIT) J Clin Oncol. 2018;36:1232–1239. doi: 10.1200/JCO.2017.74.1090.
    1. Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, Council ML. Matatall KA, Helms C, Bowcock AM. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 2010;330:1410–1413. doi: 10.1126/science.1194472.
    1. Algazi AP, Tsai KK, Shoushtari AN, Munhoz RR, Eroglu Z, Piulats JM, Ott PA, Johnson DB, Hwang J, Daud AI, et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-1L antibodies. Cancer. 2016;122:3344–3353. doi: 10.1002/cncr.30258.
    1. Ericsson C, Seregard S, Bartolazzi A, Levitskaya E, Ferrone S, Kiessling R, Larsson O. Association of HLA class I and class II antigen expression and mortality in uveal melanoma. Invest Ophthalmol Vis Sci. 2001;42:2153–2156.
    1. Sato Takami, Nathan Paul D., Hernandez-Aya Leonel Fernando, Sacco Joseph J, Orloff Marlana M., Truscello Jessica, McAlpine Cheryl, Hulstine Ann-Marie, Lanasa Mark C., Coughlin Christina Marie, Carvajal Richard D. Intra-patient escalation dosing strategy with IMCgp100 results in mitigation of T-cell based toxicity and preliminary efficacy in advanced uveal melanoma. Journal of Clinical Oncology. 2017;35(15_suppl):9531–9531. doi: 10.1200/JCO.2017.35.15_suppl.9531.
    1. Chandran SS, Somerville RP, Yang JC, Sherry RM, Klebanoff CA, Goff SL, Wunderlich JR, Danforth DN, Zlott D, Paria BC, et al. Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: a single-Centre, two-stage, single-arm, phase 2 study. Lancet Oncol. 2017;18:792–802. doi: 10.1016/S1470-2045(17)30251-6.
    1. Yang J, Manson DK, Marr BP, Carvajal RD. Treatment of uveal melanoma: where are we now? Ther adv med oncol. 2018;10:1–17.
    1. Weintraub K. Take two: combining immunotherapy with epigenetic drugs to tackle cancer. Nat Med. 2016;22:8–10. doi: 10.1038/nm0116-8.
    1. Campoli M, Ferrone S. HLA antigen changes in malignant cells: epigenetic mechanisms and biologic significance. Oncogene. 2008;27:5869–5885. doi: 10.1038/onc.2008.273.
    1. Landreville S, Agapova OA, Matatall KA, Kneass ZT, Onken MD, Lee RS, Bowcock AM, Harbour WJ. Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma. Clin Cancer Res. 2012;18:408–416. doi: 10.1158/1078-0432.CCR-11-0946.
    1. Lee JH, Choy ML, Ngo L, Foster SS, Marks PA. Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair. Proc Natl Acad Sci U S A. 2010;107:14639–14644. doi: 10.1073/pnas.1008522107.
    1. Kim K, Skora AD, Li Z, Liu Q, Tam AJ, Blosser RL, Diaz LA, Papadopoulos N, Kinzler KW, Vogelstein B, Zhou S. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci. 2014;111:11774–11779. doi: 10.1073/pnas.1410626111.
    1. Maio M, Coral S, Fratta E, Altomonte M, Sigalotti L. Epigenetic targets for immune intervention in human malignancies. Oncogene. 2003;22:6484–6488. doi: 10.1038/sj.onc.1206956.
    1. Woods DM, Sodre AL, Villagra A, Sarnaik A, Sotomayor EM, Weber J. HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade. Cancer Immunol Res. 2015;3:1375–1385. doi: 10.1158/2326-6066.CIR-15-0077-T.
    1. Booth L, Roberts JL, Poklepovic A, Kirkwood J, Dent P. HDAC inhibitors enhance the immunotherapy response of melanoma cells. Oncotarget. 2017;8:83155–83170.
    1. Hauschild A, Trefzer U, Garbe C, Kaehler K, Ugurel S, Kiecker F, Eigentler T, Krissel H, Schadendorf D. A phase II multicenter study on the histone deacetylase (HDAC) inhibitor MS-275, comparing two dosage schedules in metastatic melanoma. J Clin Oncol. 2006;24 (abstr 8044).
    1. Agarwala Sanjiv S., Moschos Stergios J., Johnson Melissa Lynne, Opyrchal Mateusz, Gabrilovich Dmitry, Danaher Patrick, Wang Fang, Brouwer Susan, Ordentlich Peter, Sankoh Serap, Schmidt Emmett V., Meyers Michael L., Sullivan Ryan J. Efficacy and safety of entinostat (ENT) and pembrolizumab (PEMBRO) in patients with melanoma progressing on or after a PD-1/L1 blocking antibody. Journal of Clinical Oncology. 2018;36(15_suppl):9530–9530. doi: 10.1200/JCO.2018.36.15_suppl.9530.
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026.
    1. Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements. Clin Cancer Res. 2013;19:3936–3943. doi: 10.1158/1078-0432.CCR-13-0895.
    1. Simon R. Optimal two-stage designs for phase II clinical trials. Controlled clin trials. 1989;10:1–10. doi: 10.1016/0197-2456(89)90015-9.
    1. Ritchie G, Gasper H, Man J, Lord S, Marschner I, Friedlander M, Lee CK. Defining the Most appropriate primary end point in phase 2 trials of immune checkpoint inhibitors for advanced solid cancers: a systematic review and meta-analysis. JAMA oncol. 2018;4:522–528. doi: 10.1001/jamaoncol.2017.5236.

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