EWSR1 Immunotherapy in Ewing Sarcoma and DSRCT

Summary

This study is for people who have high-risk Ewing sarcoma (ES), or a related Ewing's family tumor, desmoplastic small round cell tumor (DSRCT). The purpose of this study is to see if a new EWSR1 immunotherapy (a lipid nanoparticle coated with EWSR1 mRNA) which is given as a shot is safe and whether it can help the body's immune system better recognize and fight cancer. This EWSR1 immunotherapy is designed to target a specific genetic change (EWSR1 fusion gene) that is found in cancer cells but not in normal, healthy cells. Because the EWSR1 gene is broken in cancer cells and the small protein it makes are only in the ES or DSRCT cancer cells, the goal of EWSR1 immunotherapy is to help the immune system identify and attack the cancer without harming normal cells. It is not yet approved by the Food and Drug Administration (FDA). EWSR1 immunotherapy will be given as a shot into the muscle of the arm, leg, or buttock. If participants also receive botensilimab (4 doses after each EWSR1 immunotherapy shot) and balstilimab (an infusion every 2 weeks), these are given intravenously (IV) by a needle in the arm over 30 minutes. Participants in this study will receive treatment for about 6 months or until their cancer gets worse. Participants will remain in the study for follow-up for an additional year, for a total time of about 1.5 years in the study.

Timeline

Start

2026-10

Primary completion

2029-10

Completion

2030-07

Publications

• Background Womer RB, West DC, Krailo MD, Dickman PS, Pawel BR, Grier HE, Marcus K, Sailer S, Healey JH, Dormans JP, Weiss AR. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol. 2012 Nov 20;30(33):4148-54. doi: 10.1200/JCO.2011.41.5703. Epub 2012 Oct 22.
• Background Ahmed SK, Randall RL, DuBois SG, Harmsen WS, Krailo M, Marcus KJ, Janeway KA, Geller DS, Sorger JI, Womer RB, Granowetter L, Grier HE, Gorlick RG, Laack NNI. Identification of Patients With Localized Ewing Sarcoma at Higher Risk for Local Failure: A Report From the Children's Oncology Group. Int J Radiat Oncol Biol Phys. 2017 Dec 1;99(5):1286-1294. doi: 10.1016/j.ijrobp.2017.08.020. Epub 2017 Aug 24.
• Background Bosma SE, Lancia C, Rueten-Budde AJ, Ranft A, Gelderblom H, Fiocco M, van de Sande MAJ, Dijkstra PDS, Dirksen U. Easy-to-use clinical tool for survival estimation in Ewing sarcoma at diagnosis and after surgery. Sci Rep. 2019 Jul 29;9(1):11000. doi: 10.1038/s41598-019-46721-8.
• Background Albergo JI, Gaston CL, Laitinen M, Darbyshire A, Jeys LM, Sumathi V, Parry M, Peake D, Carter SR, Tillman R, Abudu AT, Grimer RJ. Ewing's sarcoma: only patients with 100% of necrosis after chemotherapy should be classified as having a good response. Bone Joint J. 2016 Aug;98-B(8):1138-44. doi: 10.1302/0301-620X.98B8.37346.
• Background Zollner SK, Amatruda JF, Bauer S, Collaud S, de Alava E, DuBois SG, Hardes J, Hartmann W, Kovar H, Metzler M, Shulman DS, Streitburger A, Timmermann B, Toretsky JA, Uhlenbruch Y, Vieth V, Grunewald TGP, Dirksen U. Ewing Sarcoma-Diagnosis, Treatment, Clinical Challenges and Future Perspectives. J Clin Med. 2021 Apr 14;10(8):1685. doi: 10.3390/jcm10081685.
• Background Juan Ribelles A, Felix A, Benavent N, Escriva-Fernandez J, Brahmi M, Gaspar N, Gatz SA, Grunewald TG, Linder-Stragliotto C, Palmerini E, Pantziarka P, Strauss S, Surdez D, Berlanga P, McCabe MG. Recurrent and Refractory Ewing Sarcoma Phase I/II Trials: Current Perspective From the Euro-Ewing Consortium. JCO Precis Oncol. 2025 Sep;9:e2500377. doi: 10.1200/PO-25-00377. Epub 2025 Sep 19.
• Background Gupta A, Dietz MS, Riedel RF, Dhir A, Borinstein SC, Isakoff MS, Aye JM, Rainusso N, Armstrong AE, DuBois SG, Wagner LM, Rosenblum JM, Cohen-Gogo S, Albert CM, Zahler S, Chugh R, Trucco M. Consensus recommendations for systemic therapies in the management of relapsed Ewing sarcoma: A report from the National Ewing Sarcoma Tumor Board. Cancer. 2024 Dec 1;130(23):4028-4039. doi: 10.1002/cncr.35537. Epub 2024 Aug 25.
• Background Shah C, Campbell SR, Murphy E, Braunstein S, Dietz MS, Binitie O, Kastenberg ZJ, Yanagawa J, Halpern J, Kis B, Hunt S, Yazdanpanah F, Gupta A, Trucco M. Consensus recommendations regarding local and metastasis-directed therapies in the management of relapsed/recurrent Ewing sarcoma. Cancer. 2025 May 1;131(9):e35858. doi: 10.1002/cncr.35858.
• Background Hayes-Jordan A, Anderson P, Curley S, Herzog C, Lally KP, Green HL, Hunt K, Mansfield P. Continuous hyperthermic peritoneal perfusion for desmoplastic small round cell tumor. J Pediatr Surg. 2007 Aug;42(8):E29-32. doi: 10.1016/j.jpedsurg.2007.05.047.
• Background Aguilera D, Hayes-Jordan A, Anderson P, Woo S, Pearson M, Green H. Outpatient and home chemotherapy with novel local control strategies in desmoplastic small round cell tumor. Sarcoma. 2008;2008:261589. doi: 10.1155/2008/261589.
• Background Hayes-Jordan A, Green H, Fitzgerald N, Xiao L, Anderson P. Novel treatment for desmoplastic small round cell tumor: hyperthermic intraperitoneal perfusion. J Pediatr Surg. 2010 May;45(5):1000-6. doi: 10.1016/j.jpedsurg.2010.02.034.
• Background Hayes-Jordan A, Anderson PM. The diagnosis and management of desmoplastic small round cell tumor: a review. Curr Opin Oncol. 2011 Jul;23(4):385-9. doi: 10.1097/CCO.0b013e3283477aab.
• Background Pinnix CC, Fontanilla HP, Hayes-Jordan A, Subbiah V, Bilton SD, Chang EL, Grosshans DR, McAleer MF, Sulman EP, Woo SY, Anderson P, Green HL, Mahajan A. Whole abdominopelvic intensity-modulated radiation therapy for desmoplastic small round cell tumor after surgery. Int J Radiat Oncol Biol Phys. 2012 May 1;83(1):317-26. doi: 10.1016/j.ijrobp.2011.06.1985. Epub 2011 Nov 19.
• Background Subbiah V, Brown RE, Jiang Y, Buryanek J, Hayes-Jordan A, Kurzrock R, Anderson PM. Morphoproteomic profiling of the mammalian target of rapamycin (mTOR) signaling pathway in desmoplastic small round cell tumor (EWS/WT1), Ewing's sarcoma (EWS/FLI1) and Wilms' tumor(WT1). PLoS One. 2013 Jul 29;8(7):e68985. doi: 10.1371/journal.pone.0068985. Print 2013.
• Background Hayes-Jordan A, Green HL, Lin H, Owusu-Agyemang P, Fitzgerald N, Arunkumar R, Mejia R, Okhuysen-Cawley R, Mauricio R, Fournier K, Ludwig J, Anderson P. Complete cytoreduction and HIPEC improves survival in desmoplastic small round cell tumor. Ann Surg Oncol. 2014 Jan;21(1):220-4. doi: 10.1245/s10434-013-3269-y. Epub 2013 Sep 18.
• Background Hayes-Jordan A, LaQuaglia MP, Modak S. Management of desmoplastic small round cell tumor. Semin Pediatr Surg. 2016 Oct;25(5):299-304. doi: 10.1053/j.sempedsurg.2016.09.005. Epub 2016 Sep 14.
• Background Osborne EM, Briere TM, Hayes-Jordan A, Levy LB, Huh WW, Mahajan A, Anderson P, McAleer MF. Survival and toxicity following sequential multimodality treatment including whole abdominopelvic radiotherapy for patients with desmoplastic small round cell tumor. Radiother Oncol. 2016 Apr;119(1):40-4. doi: 10.1016/j.radonc.2015.10.016. Epub 2015 Oct 30.
• Background Bulbul A, Fahy BN, Xiu J, Rashad S, Mustafa A, Husain H, Hayes-Jordan A. Desmoplastic Small Round Blue Cell Tumor: A Review of Treatment and Potential Therapeutic Genomic Alterations. Sarcoma. 2017;2017:1278268. doi: 10.1155/2017/1278268. Epub 2017 Nov 1.
• Background Hayes-Jordan AA, Coakley BA, Green HL, Xiao L, Fournier KF, Herzog CE, Ludwig JA, McAleer MF, Anderson PM, Huh WW. Desmoplastic Small Round Cell Tumor Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Results of a Phase 2 Trial. Ann Surg Oncol. 2018 Apr;25(4):872-877. doi: 10.1245/s10434-018-6333-9. Epub 2018 Jan 30.
• Background Menegaz BA, Cuglievan B, Benson J, Camacho P, Lamhamedi-Cherradi SE, Leung CH, Warneke CL, Huh W, Subbiah V, Benjamin RS, Patel S, Daw N, Hayes-Jordan A, Ludwig JA. Clinical Activity of Pazopanib in Patients with Advanced Desmoplastic Small Round Cell Tumor. Oncologist. 2018 Mar;23(3):360-366. doi: 10.1634/theoncologist.2017-0408. Epub 2017 Dec 6.
• Background Subbiah V, Lamhamedi-Cherradi SE, Cuglievan B, Menegaz BA, Camacho P, Huh W, Ramamoorthy V, Anderson PM, Pollock RE, Lev DC, Qiao W, McAleer MF, Benjamin RS, Patel S, Herzog CE, Daw NC, Feig BW, Lazar AJ, Hayes-Jordan A, Ludwig JA. Multimodality Treatment of Desmoplastic Small Round Cell Tumor: Chemotherapy and Complete Cytoreductive Surgery Improve Patient Survival. Clin Cancer Res. 2018 Oct 1;24(19):4865-4873. doi: 10.1158/1078-0432.CCR-18-0202. Epub 2018 Jun 5.
• Background Tarek N, Hayes-Jordan A, Salvador L, McAleer MF, Herzog CE, Huh WW. Recurrent desmoplastic small round cell tumor responding to an mTOR inhibitor containing regimen. Pediatr Blood Cancer. 2018 Jan;65(1). doi: 10.1002/pbc.26768. Epub 2017 Sep 22.
• Background Morani AC, Bathala TK, Surabhi VR, Yedururi S, Jensen CT, Huh WW, Prasad S, Hayes-Jordan A. Desmoplastic Small Round Cell Tumor: Imaging Pattern of Disease at Presentation. AJR Am J Roentgenol. 2019 Mar;212(3):W45-W54. doi: 10.2214/AJR.18.20179. Epub 2019 Jan 23.
• Background Anderson P, Ghisoli M, Crompton BD, Klega KS, Wexler LH, Slotkin EK, Stanbery L, Manning L, Wallraven G, Manley M, Horvath S, Bognar E, Nemunaitis J. Pilot Study of Recurrent Ewing's Sarcoma Management with Vigil/Temozolomide/Irinotecan and Assessment of Circulating Tumor (ct) DNA. Clin Cancer Res. 2023 May 1;29(9):1689-1697. doi: 10.1158/1078-0432.CCR-22-2292.
• Background Anderson PM, Tu ZJ, Kilpatrick SE, Trucco M, Hanna R, Chan T. Routine EWS Fusion Analysis in the Oncology Clinic to Identify Cancer-Specific Peptide Sequence Patterns That Span Breakpoints in Ewing Sarcoma and DSRCT. Cancers (Basel). 2023 Mar 6;15(5):1623. doi: 10.3390/cancers15051623.
• Background Anderson, P.M., et al., Sarcoma gene fusion breakpoints: non-random event patterns in sarcoma with gene fusions including Ewing sarcoma, DSRCT, rhabdomyosarcoma, synovial sarcoma, CCNB3-BCOR, and CIC-DUX. Connective Tissue Oncology Society 2022 Vancouver , Canada, 2022.
• Background Minas TZ, Surdez D, Javaheri T, Tanaka M, Howarth M, Kang HJ, Han J, Han ZY, Sax B, Kream BE, Hong SH, Celik H, Tirode F, Tuckermann J, Toretsky JA, Kenner L, Kovar H, Lee S, Sweet-Cordero EA, Nakamura T, Moriggl R, Delattre O, Uren A. Combined experience of six independent laboratories attempting to create an Ewing sarcoma mouse model. Oncotarget. 2017 May 23;8(21):34141-34163. doi: 10.18632/oncotarget.9388.
• Background Bauer J, Kohler N, Maringer Y, Bucher P, Bilich T, Zwick M, Dicks S, Nelde A, Dubbelaar M, Scheid J, Wacker M, Heitmann JS, Schroeder S, Rieth J, Denk M, Richter M, Klein R, Bonzheim I, Luibrand J, Holzer U, Ebinger M, Brecht IB, Bitzer M, Boerries M, Feucht J, Salih HR, Rammensee HG, Hailfinger S, Walz JS. The oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma. Nat Commun. 2022 Oct 27;13(1):6401. doi: 10.1038/s41467-022-33746-3.
• Background Yang W, Lee KW, Srivastava RM, Kuo F, Krishna C, Chowell D, Makarov V, Hoen D, Dalin MG, Wexler L, Ghossein R, Katabi N, Nadeem Z, Cohen MA, Tian SK, Robine N, Arora K, Geiger H, Agius P, Bouvier N, Huberman K, Vanness K, Havel JJ, Sims JS, Samstein RM, Mandal R, Tepe J, Ganly I, Ho AL, Riaz N, Wong RJ, Shukla N, Chan TA, Morris LGT. Immunogenic neoantigens derived from gene fusions stimulate T cell responses. Nat Med. 2019 May;25(5):767-775. doi: 10.1038/s41591-019-0434-2. Epub 2019 Apr 22.
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• Background Ho AS, Kannan K, Roy DM, Morris LG, Ganly I, Katabi N, Ramaswami D, Walsh LA, Eng S, Huse JT, Zhang J, Dolgalev I, Huberman K, Heguy A, Viale A, Drobnjak M, Leversha MA, Rice CE, Singh B, Iyer NG, Leemans CR, Bloemena E, Ferris RL, Seethala RR, Gross BE, Liang Y, Sinha R, Peng L, Raphael BJ, Turcan S, Gong Y, Schultz N, Kim S, Chiosea S, Shah JP, Sander C, Lee W, Chan TA. The mutational landscape of adenoid cystic carcinoma. Nat Genet. 2013 Jul;45(7):791-8. doi: 10.1038/ng.2643. Epub 2013 May 19.
• Background Riaz N, Havel JJ, Kendall SM, Makarov V, Walsh LA, Desrichard A, Weinhold N, Chan TA. Recurrent SERPINB3 and SERPINB4 mutations in patients who respond to anti-CTLA4 immunotherapy. Nat Genet. 2016 Nov;48(11):1327-1329. doi: 10.1038/ng.3677. Epub 2016 Sep 26.
• Background Turcan S, Makarov V, Taranda J, Wang Y, Fabius AWM, Wu W, Zheng Y, El-Amine N, Haddock S, Nanjangud G, LeKaye HC, Brennan C, Cross J, Huse JT, Kelleher NL, Osten P, Thompson CB, Chan TA. Mutant-IDH1-dependent chromatin state reprogramming, reversibility, and persistence. Nat Genet. 2018 Jan;50(1):62-72. doi: 10.1038/s41588-017-0001-z. Epub 2017 Nov 27.
• Background Ma X, Riaz N, Samstein RM, Lee M, Makarov V, Valero C, Chowell D, Kuo F, Hoen D, Fitzgerald CWR, Jiang H, Alektiar J, Alban TJ, Juric I, Parthasarathy PB, Zhao Y, Sabio EY, Verma R, Srivastava RM, Vuong L, Yang W, Zhang X, Wang J, Chu LK, Wang SL, Kelly DW, Pei X, Chen J, Yaeger R, Zamarin D, Zehir A, Gonen M, Morris LGT, Chan TA. Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity. Nat Genet. 2022 Jul;54(7):996-1012. doi: 10.1038/s41588-022-01108-w. Epub 2022 Jul 11.
• Background Wilky BA, Schwartz GK, Gordon MS, El-Khoueiry AB, Bullock AJ, Henick B, Agulnik M, Singh A, Mahadevan D, Stebbing J, Delepine C, Chand D, Avagyan M, Wu W, Johnson B, Grossman JE, O'Day S, Trent JC, Jones RL, Tsimberidou AM. Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas. J Clin Oncol. 2025 Apr 10;43(11):1358-1368. doi: 10.1200/JCO-24-02524. Epub 2025 Jan 27.
• Background Palmer CD, Rappaport AR, Davis MJ, Hart MG, Scallan CD, Hong SJ, Gitlin L, Kraemer LD, Kounlavouth S, Yang A, Smith L, Schenk D, Skoberne M, Taquechel K, Marrali M, Jaroslavsky JR, Nganje CN, Maloney E, Zhou R, Navarro-Gomez D, Greene AC, Grotenbreg G, Greer R, Blair W, Cao MD, Chan S, Bae K, Spira AI, Roychowdhury S, Carbone DP, Henick BS, Drake CG, Solomon BJ, Ahn DH, Mahipal A, Maron SB, Johnson B, Rousseau R, Yelensky R, Liao CY, Catenacci DVT, Allen A, Ferguson AR, Jooss K. Individualized, heterologous chimpanzee adenovirus and self-amplifying mRNA neoantigen vaccine for advanced metastatic solid tumors: phase 1 trial interim results. Nat Med. 2022 Aug;28(8):1619-1629. doi: 10.1038/s41591-022-01937-6. Epub 2022 Aug 15.

Drugs

Indications