EWSR1 Immunotherapy in Ewing Sarcoma and DSRCT

NCT07695311 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: CASE1723
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Ewing Sarcoma; Desmoplastic Small Round Cell Tumor

Keywords

EWSR1 immunotherapy; Botensilimab; Balstilimab; EWSR1 Gene Fusion neoantigen with predicted immune responsiveness

Outcome Measures

Primary Outcomes (4)

• 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

  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

  In the combination therapy cohort (EWSR1 immunotherapy + botensilimab + balstilimab) cohort, safety will be achieved if participants without progression at 6 months have no grade 3 drug related AE lasting \> 1 week

  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.

  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

  In the combination therapy cohort (EWSR1 immunotherapy + botensilimab + balstilimab) cohort, feasibility will be achieved if 12 participants receive at least 3 months of combination therapy.

  Up to 6 months

Secondary Outcomes (3)

• Progression free survival (PFS)

  Up to 1.5 years

• Overall survival (OS)

  Up to 1.5 years

• Tumor response, as measured by change in tumor volume

  Baseline, month 6

Study Arms (2)

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.

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 Botensilimab (anti-CTLA-4) at on Weeks 0, 4, 12, and 24. Participants will also receive Balstilimab (anti-PD1) on Week 0 and then every 2 weeks for 6 months.

Drug: EWSR1 immunotherapy; Drug: Botensilimab; Drug: Balstilimab

Interventions

EWSR1 immunotherapy DRUG

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.

Combination cohort; Monotherapy cohort

Botensilimab DRUG

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.

Also known as: anti-CTLA-4

Combination cohort

Balstilimab DRUG

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.

Also known as: anti-PD1

Combination cohort

Eligibility Criteria

• Age: 2 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Rabi Hanna: lead
• The Little Warriors Foundation: collaborator

Study Sites (1)

Case Comprehensive Cancer Center, Cleveland Clinic Foundation Taussig Cancer Institute

Cleveland, Ohio, 44195, United States

Location

Related Publications (37)

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MeSH Terms

Conditions

Sarcoma, Ewing; Desmoplastic Small Round Cell Tumor

Interventions

Ipilimumab; balstilimab; spartalizumab

Condition Hierarchy (Ancestors)

Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Rabi Hanna, MD

  Case Comprehensive Cancer Center, Cleveland Clinic Foundation Taussig Cancer Institute

  PRINCIPAL INVESTIGATOR

• Peter M Anderson, MD, PhD

  Case Comprehensive Cancer Center, Cleveland Clinic Foundation Taussig Cancer Institute

  PRINCIPAL INVESTIGATOR

• Matteo Trucco, MD

  Case Comprehensive Cancer Center, Cleveland Clinic Foundation Taussig Cancer Institute

  PRINCIPAL INVESTIGATOR

• Timothy A Chan, MD, PhD

  Case Comprehensive Cancer Center, Cleveland Clinic Center for Immunotherapy and Immuno-Oncology

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Peter M Anderson, MD, PhD

CONTACT

216-308-2706; andersp@ccf.org

Rabi Hanna, MD

CONTACT

216-407-8655; hannar2@ccf.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Model Details: 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.

Study Record Dates

• First Submitted: July 6, 2026
• First Posted: July 10, 2026
• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): October 1, 2029
• Study Completion (Estimated): July 1, 2030
• Last Updated: July 16, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, CSR
• Time Frame: Data will be available in in a timely, proactive manner to allow monthly Cleveland Clinic study monitoring and also to be ready for any potential FDA audit
• Access Criteria: on site for Cleveland Clinic Monitoring

Locations

US (1)