Ewing SarcomaPhase 1NCT07695311
EWSR1 Immunotherapy in Ewing Sarcoma and DSRCT
A Phase 1 study testing EWSR1 immunotherapy and Pembrolizumab in people with Ewing Sarcoma and Desmoplastic Small Round Cell Tumor, run by Rabi Hanna at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 2 years and older
- Conditions the study is for
- Ewing Sarcoma, Desmoplastic Small Round Cell Tumor
- What is being tested?
- EWSR1 immunotherapy and Pembrolizumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteUnited States
- Study dates
- Oct 2026to Jul 2030
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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:
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- 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.
Who cannot join
- 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).
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- Pregnant women are excluded from this study because of the unknown effects of EWS immunotherapy or anti-PD1and 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site
Case Comprehensive Cancer Center, Cleveland Clinic Foundation Taussig Cancer Institute
Cleveland, Ohio, 44195
Peter M Anderson, MD, PhD, 216-308-2706, ANDERSP@ccf.org
Rabi Hanna, MD
About this study
Official title: Precision Analysis of Fusion Genes in Ewing Sarcoma (ES) and Desmoplastic Small Round Cell Tumor (DSRCT), Then EWSR1 Immunotherapy Without or With Anti-PD1 (Pembrolizumab)
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 pembrolizumab (an infusion every 2 weeks), it is 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.
Read the 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 anti-PD1 is to develop cancer-specific long-lasting immunity against EWSR1 neoantigens. Adding 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 anti-PD1.
- Conditions
- Ewing Sarcoma, Desmoplastic Small Round Cell Tumor
- Being tested
- EWSR1 immunotherapy, Pembrolizumab
- Keywords
- EWSR1 immunotherapy, Pembrolizumab, EWSR1 Gene Fusion neoantigen with predicted immune responsiveness
- Medical subject headings
- Sarcoma, Ewing, Desmoplastic Small Round Cell Tumor
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EWSR1 immunotherapyDrug
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.
PembrolizumabDrug
Also called anti-PD1
Participants will receive Pembrolizumab (anti-PD1) at 3 milligram per kilogram (mg/kg) intravenously (through an IV) on Week 0 and Week 4.
| Study group | Role | What they receive |
|---|---|---|
| Monotherapy cohort | Experimental | First, a safety cohort of participants will be enrolled in the study. Participants will receive EWSR1 immunotherapy on Weeks 0, 4, 12 and 24. Receives: Drug: EWSR1 immunotherapy |
| Combination cohort | Experimental | After safety is established through the monotherapy cohort, participants will be enrolled in the combination cohort. Participants will receive EWSR1 immunotherapy on Weeks 0, 4, 12 and 24. Participants will also receive pembrolizumab (anti-PD1) on Week 0 and then every 2 weeks for 6 months. Receives: Drug: EWSR1 immunotherapy; Drug: Pembrolizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety of EWSR1 immunotherapy, measured by number of participants with grade 4 immunotherapy-related adverse events
Safety will be achieved in the EWSR1 immunotherapy monotherapy cohort if no participant has grade 4 EWSR1 immunotherapy-related toxicity
Measured: Up to 6 months
Safety of combination therapy (EWSR1 immunotherapy + pembrolizumab), measured by number of participants with grade 3 drug related adverse events lasting greater than 1 week
In the combination therapy cohort (EWSR1 immunotherapy + pembrolizumab) cohort, safety will be achieved if participants without progression at 6 months have no grade 3 drug related AE lasting > 1 week
Measured: Up to 6 months
Feasibility of EWSR1 immunotherapy monotherapy, measured by proportion of participants who receive doses
Feasibility will be achieved in the EWSR1 immunotherapy monotherapy cohort if participants receive at least 3 of 4 proposed doses.
Measured: Up to 6 months
Feasibility of combination therapy (EWSR1 immunotherapy + pembrolizumab), measured by number of participants who receive at least 3 months of therapy
In the combination therapy cohort (EWSR1 immunotherapy + pembrolizumab) cohort, feasibility will be achieved if 12 participants receive at least 3 months of combination therapy.
Measured: Up to 6 months
Secondary outcomes (3)
Progression free survival (PFS)
PFS will be assessed using iRECIST (Immunologic Response Evaluation Criteria in Solid Tumors) criteria and is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
Measured: Up to 1.5 years
Overall survival (OS)
OS is defined as the time from start of treatment until death from any cause.
Measured: Up to 1.5 years
Tumor response, as measured by change in tumor volume
Tumor responses will be determined comparing chest CT (Computed Tomography) and PET-CT (Positron Emission Tomography - Computed Tomography) scans. Trends of lesion size will be depicted using waterfall and "spaghetti" plots showing and tumor volume differences over time.
Measured: Baseline, month 6
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Jul 2026
- Study startOct 2026 (estimated)
- Primary completionOct 2029 (estimated)
- Study completionJul 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (37)Papers the sponsor has linked to this study.
- Other trials for Ewing SarcomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- An initial safety cohort of 12 participants will receive monotherapy. After safety analysis, a second cohort will of up to 12 participants will receive combination therapy.
- Masking
- None (open label)
- Enrolment
- 24 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Rabi Hanna
- Sponsor type
- University, hospital or other
- Collaborators
- The Little Warriors Foundation
- Responsible party
- Sponsor-investigator, Rabi Hanna, Case Comprehensive Cancer Center
- Investigators
- Rabi Hanna, MD, Principal investigator, Case Comprehensive Cancer Center, Cleveland Clinic Foundation Taussig Cancer InstitutePeter M Anderson, MD, PhD, Principal investigator, Case Comprehensive Cancer Center, Cleveland Clinic Foundation Taussig Cancer InstituteMatteo Trucco, MD, Principal investigator, Case Comprehensive Cancer Center, Cleveland Clinic Foundation Taussig Cancer InstituteTimothy A Chan, MD, PhD, Principal investigator, Case Comprehensive Cancer Center, Cleveland Clinic Center for Immunotherapy and Immuno-Oncology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07695311
- Sponsor's protocol ID
- CASE1723
- Status last verified
- Sep 2026
- First submitted
- 6 Jul 2026
- Last updated
- 17 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: All side effects of each participant are to be documented in Epic and available Cleveland Clinic monitoring and FDA audit, if needed. For patients getting vaccine + checkpoint inhibition safety and efficacy data (without patient identifiers) will be shared with Agenus, supplier of the antiPD1 antibodies.
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.
PubMed 23091096Ahmed 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.
PubMed 28964585Bosma 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.
PubMed 31358784Albergo 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.
PubMed 27482030Zollner 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.
PubMed 33919988Juan 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.
PubMed 40971749Gupta 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.
PubMed 39182183Shah 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.
PubMed 40251761Hayes-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.
PubMed 17706484Aguilera 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.
PubMed 18566684Hayes-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.
PubMed 20438942Hayes-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.
PubMed 21577112Pinnix 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.
PubMed 22104361Subbiah 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.
PubMed 23922674Hayes-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.
PubMed 24046124