EWSR1 Immunotherapy in Ewing Sarcoma and DSRCT

Official title

Precision Analysis of Fusion Genes in Ewing Sarcoma (ES) and Desmoplastic Small Round Cell Tumor (DSRCT), Then EWSR1 (Ewing Sarcoma Gene Breakpoint Region 1 Gene) Immunotherapy Without or With Anti-CTLA-4 (Botensilimab) and Anti-PD1 (Balstilimab)

Overview

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.

Detailed description

Ewing sarcoma (ES) is an aggressive type of cancer that has a high risk of spreading to other parts of the body. Even though it often responds well to chemotherapy and radiation at first, it still carries the risk of coming back and/or spreading. Children and young adults whose cancer is limited to one area generally have a better outlook with overall survival at about 75%. However, outcomes are much worse for adults and for people whose cancer has already spread, returned after treatment, or relapsed. In these groups, overall survival is only about 15-25%. People with relapsed or metastatic ES, who make up nearly half of all cases, still need better treatments than the current standard of care. More effective therapies are needed to achieve longer-lasting results.

Desmoplastic small round cell tumor (DSRCT) is a rare cancer that belongs to the Ewing family of tumors. It often spreads widely throughout the abdomen. Like Ewing sarcoma, DSRCT often responds to chemotherapy and radiation at first. However, even with standard of care treatment, long-term outcomes remain poor. Overall survival is only about 10-15%, and the cancer frequently returns in additional, outside areas. Because current treatments have had limited success, there is an urgent need to develop new targeted therapies that can more effectively treat these cancers.

Both ES and DSRCT are driven by recurrent, highly conserved gene fusion events that create neoantigens. Conventional therapies are often unable to target these gene events, and thus are unable to effectively treat the cause of the cancer. However, because these fusion events create proteins that are required for tumor survival and generate unique tumor-specific neoantigens that are absent from normal tissues, they represent highly attractive targets for immunotherapeutic approaches. Recent advances in immuno-oncology have highlighted the promise of tumor-specific neoantigens, particularly those arising from gene fusions, as targets for precision immunotherapy. Our group has been at the forefront of defining the importance of tumor mutations and neoantigens in cancer therapy.

The overall goal of this study in using EWSR1 immunotherapy without or with dual checkpoint inhibition is to develop cancer-specific long-lasting immunity against EWSR1 neoantigens. Adding anti-CTLA-4 plus anti-PD1 will be done because of concern that monotherapy may not overcome tumor inhibitory microenvironment (TIME) and T-cell exhaustion. Therefore, it is hypothesized that this combination will be safe because of the known safety profiles of other immunotherapy interventions with dual checkpoint inhibition.

Interventions

• Drug EWSR1 immunotherapy
  Participants will receive EWSR1 immunotherapy at 50 micrograms (mcg) (or 25 mcg for children 12 years and younger) through an intramuscular injection on Weeks 0, 4, 12 and 24.
• Drug Botensilimab
  Participants will receive Botensilimab (anti-CTLA-4) at 1 milligram per kilogram (mg/kg) intravenously (through an IV) on Weeks 0, 4, 12, and 24.
• Drug Balstilimab
  Participants will receive Balstilimab (anti-PD1) at 3 milligram per kilogram (mg/kg) intravenously (through an IV) on Week 0 and then every 2 weeks for 6 months.

Primary outcome measures

• Safety of EWSR1 immunotherapy, measured by number of participants with grade 4 immunotherapy-related adverse events [Time frame: Up to 6 months]
• Safety of combination therapy (EWSR1 immunotherapy + botensilimab + balstilimab), measured by number of participants with grade 3 drug related adverse events lasting greater than 1 week [Time frame: Up to 6 months]
• Feasibility of EWSR1 immunotherapy monotherapy, measured by proportion of participants who receive doses [Time frame: Up to 6 months]
• Feasibility of combination therapy (EWSR1 immunotherapy + botensilimab + balstilimab), measured by number of participants who receive at least 3 months of therapy [Time frame: Up to 6 months]

Secondary outcome measures (3)

• Progression free survival (PFS) [Time frame: Up to 1.5 years]
• Overall survival (OS) [Time frame: Up to 1.5 years]
• Tumor response, as measured by change in tumor volume [Time frame: Baseline, month 6]

Eligibility criteria

Inclusion criteria

• Participants must have histologically confirmed Ewing sarcoma (ES) or desmoplastic small round cell tumor (DSRCT) and confirmation of fusion gene rearrangement and breakpoint EWSR1-FLI1, EWSR1-ERG, EWSR1-WT1, who have completed standard of care vincristine + doxorubicin + cyclophosphamide alternating with ifosfamide + etoposide (VDC/IE) and have relapsed or had metastatic disease or are very high-risk disease (Bosma groups C, D, E, and/or very poor necrosis after VDC/IE) are eligible. All EWSR1 immunotherapy monotherapy participants are expected to have completed standard of care VDC/IE chemotherapy with local control and have had end of therapy follow-up for > 3 months.
• Participants must have demonstrated HLA (human leukocyte antigens) fit with an EWSR1 gene fusion peptide contained in the EWSR1 immunotherapy, as determined by HLA-binding analysis of peptides that span the EWSR1 fusion gene breakpoint and analysis of HLA fit to one of the constructs included in EWSR1 immunotherapy.
• Participants may have no evidence of active disease, detectable disease (e.g., lung metastases < 1 cm or bone metastases), or measurable disease by iRECIST (Immune Response Evaluation Criteria in Solid Tumors) criteria. The presence of RECIST measurable disease is not required for study entry.
• At least 1 line of prior therapy (VDC/IE) is needed.
• Age. The first 3 EWSR1 immunotherapy monotherapy and combination therapy participants will be adults ≥ 18 years old. After safety analysis of EWSR1 immunotherapy monotherapy in adults and Institutional Review Board (IRB) approval, adolescents (13-17 years old and 40kg or more are eligible for EWSR1 immunotherapy monotherapy. After safety analysis of EWSR1 immunotherapy monotherapy in adolescents and IRB approval, adolescents will be eligible for combination therapy and children ages 12 years old or younger will be eligible for EWSR1 immunotherapy monotherapy. Only after safety analysis of EWSR1 immunotherapy monotherapy will any group become eligible for combination therapy.
• Participants must have adequate organ and marrow function as defined below:

• absolute neutrophil count ≥ 1000/microliter (mcL)
• platelets ≥ 100,000/mcL
• hemoglobin ≥ 8 g/dL (transfusion allowed)
• total bilirubin ≤ 1.5 x ULN (upper normal limits)
• AST(aspartate aminotransferase) / ALT (alanine aminotransferase) ≤ 2.5 x ULN
• creatinine ≤ 60 mL/min/1.73 m2 or ≤ 1.5 mg/mcL if < 18 yrs
• Participants on inhaled corticosteroids or maintenance doses of hydrocortisone are allowed (e.g., 20 mg in morning, 10 mg in evening in adult participants on chronic corticosteroids or history of adrenal insufficiency).
• Participants with treated brain metastases are eligible after central nervous system (CNS)-directed therapy (surgery or radiotherapy). If on corticosteroids these participants should be weaned to hydrocortisone (20 mg am/10 mg pm if ≥ 40 kg or if < 40 kg (20-39.9 kg) hydrocortisone 10 mg am/5 mg pm).
• Participants with leptomeningeal disease are eligible. If on corticosteroids these participants should be weaned to hydrocortisone (20 mg am/10mg pm if ≥ 40 kg or if < 40 kg hydrocortisone 10 mg am/5 mg pm).
• Performance Karnofsky or Lansky Scale ≥ 60%
• Participants with ES or DSRCT are eligible for planned radiotherapy before or during protocol therapy (e.g., to treat symptomatic lesions or bone metastases that are not "indicator lesions").
• A washout period of 2 weeks from chemotherapy and return of any chemotherapy related or radiation adverse events (AEs) to grade 1 or to baseline prior to cancer treatment except lymphopenia is required.
• The effects of EWSR1 immunotherapy on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control and/or abstinence for at least 90 days after last dose of EWSR1 immunotherapy. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Ability to understand and the willingness to sign a written informed consent document; minors must assent.
• Women of childbearing potential to have negative pregnancy test within 7 days of EWSR1 immunotherapy dosing.

Exclusion criteria

• Participants on concurrent chemotherapy or other immunotherapy.
• Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities ≥ Grade 2) with the exception of alopecia and lymphopenia, post-nadir neutropenia and thrombocytopenia, and decreased function that has achieved a "new and stable baseline" from cancer, surgery, or radiation.
• Participants who are receiving any other investigational agents.
• Participants on total parenteral nutrition.
• History of severe allergic reactions (anaphylaxis) attributed to compounds of similar chemical or biologic composition to EWSR1 immunotherapy.
• Participants with uncontrolled infection (e.g., on intravenous antibiotics or with symptoms of fever attributable to infection).
• Pregnant women are excluded from this study because of the unknown effects of EWS immunotherapy, botensilimab and balstilimab and their potential for teratogenic or abortifacient effects.
• Participants who are unwilling or unable to comply with required study visits are ineligible.
• Recent (< 2 weeks) vaccine use, active HIV/Hep B/C, or any current or prior medical condition or therapy that, in the opinion of the treating investigator, could confound the results of the trial or is not in the best interest of the participant to participate.
• Any participant with congestive heart failure (as defined by New York Heart Association Functional Classification III or IV), unstable angina, serious uncontrolled heart arrythmia, a myocardial infarction within 6 months prior to study entry, or a history of myocarditis.
• Inadequate pulmonary function as defined by baseline pulse oximetry 92% or less on room air.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Case Comprehensive Cancer Center, Cleveland Clinic Foundation Taussig Cancer Institute — Cleveland

Publications

• 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. PMID 23091096
• 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 PMID 28964585
• 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. PMID 31358784
• 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. PMID 27482030
• 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. PMID 33919988
• 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. PMID 40971749
• 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. PMID 39182183
• 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. PMID 40251761

Identifiers

NCT: NCT07695311 · CASE1723

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗