Relapsed & Refractory Ewing Sarcoma
How To Use This Information
New possibilities continue to develop, but figuring out what’s right for you or your child is overwhelming. It feels like the world’s worst “choose your own adventure” book—where the stakes couldn’t be higher and the choices are rarely clear.
Think of this page as a starting point—a way to explore what’s out there, ask thoughtful questions, and move forward with as much clarity and confidence as possible.
Use this content in partnership with your medical team.
Because this landscape is changing quickly, we welcome your help in keeping this resource up to date. If you notice something that should be added, updated, or clarified, please let us know. This is not an exhaustive list, and inclusion here does not necessarily imply endorsement—just as exclusion does not mean an option isn’t worth considering.
Second Opinions
Remote consults, tumor boards, and more.
Trials that build on I/T or VIT.
Salvage Protocols
A summary of what is typically offered: I/T or VIT.
Salvage + Targeted Add On
Engaging the immune system to attack Ewing Sarcoma.
Beyond Standard Chemo Combos
Trials that are not built on the typical salvage protocols.
Cell & Immunotherapies
You’re not alone. Find answers from the Ewing’s community.
Community Support
NEWS Tumor Board
The National Ewing Sarcoma Tumor Board (NEWS) pulls multidisciplinary experts from across the country to consult on cases. Leaders in the fields of pediatric & medical oncology, radiation oncology, orthopedic oncology, radiology/IR, pathology and other surgical specialties participate representing leading institutions such as Dana-Farber, Duke, Nationwide Children’s, Seattle Children’s, and Stanford. Recommendations will be delivered back to your oncologist (not to the patient directly).
Your oncologist can submit your case with a question for the board.
Learn More »
Second Opinions
Finding Second Opinions
Ewing Sarcoma is rare enough that the average oncologist will see only a handful of cases in their career. That's not a criticism of your local team — it's just the reality of this disease. Expertise matters enormously here, and the doctors who live and breathe sarcoma every day think about it differently than those who don't.
If you are not already being treated at a sarcoma center, seek a second opinion from one. Most offer remote consultations, which means you don't necessarily have to travel. By establishing a relationship with a specialist early, you have someone to reach out to quickly when challenges arise.
NOTE: If your local team is resistant to collaborating with a sarcoma specialist — that's concerning. A confident, experienced oncologist will welcome the extra eyes.
Options for Relapsed & Refractory Disease
Common Relapse Protocols
Two chemotherapy combinations are most commonly recommended starting points when Ewing sarcoma comes back. Neither is experimental — both have been used for years, are familiar to most pediatric oncology teams, and have similar response rates of roughly 25–35%. The choice between them usually comes down to what your child has already received, current blood counts, and which side-effect profile fits your family's situation, as well as the availability and interest in clinical trials.
Irinotecan + Temozolomide (often called "I/T" or "Tem-Iri")
A lower-intensity regimen that's typically given outpatient. Temozolomide is an oral pill taken at home for five days; irinotecan is an IV infusion given over the same five days, often in clinic without hospitalization. Sometimes, vincristine is added — a VIT protocol.
A practical note: Many of the trials in this list are built directly on top of I/T or VIT. So if your child tolerates and responds to I/T, several of those trials become natural next steps that layer a targeted therapy on a backbone you already know.
Cyclophosphamide + Topotecan (often called "C/T")
A more intensive regimen, usually given as a five-day inpatient stay repeated every three weeks. Both drugs are IV.
Comparing The Protocols: rEECur
The European rEECur trial directly compared the most common relapse regimens head-to-head (I/T, C/T, gemcitabine/docetaxel, and high-dose ifosfamide). The takeaway is often summarized as "no single clear winner" — high-dose ifosfamide showed a numerical advantage on some endpoints but is much harder on the body, while I/T and C/T held up well as more livable options. This is why your team's recommendation will likely be individualized rather than formulaic. And why consulting with a Sarcoma Center is important.
Adding a Targeted Drug to Salvage Chemo
These trials layer a new drug on top of standard salvage chemotherapy (I/T or VIT). If your child is already on or responding to irinotecan/temozolomide, these are the most common next step — the backbone is familiar, and side effects are largely predictable.
ONITT
Lead Site: St. Jude | Sara Federico, MD
PARP Inhibitor + Liposomal Irinotecan
This study is testing two drug combinations for children and young adults with solid tumors, including Ewing sarcoma: Onivyde (liposomal irinotecan) with talazoparib, or Onivyde with temozolomide. These medicines work by damaging the DNA inside cancer cells or by preventing the cells from repairing that damage.
Ewing's U Episode: November 2023
ClinicalTrials.gov: NCT04901702
Location: Multiple Locations, US & Canada
Status: Recruiting
INBRX-109 (Ozekibart) + Irinotecan/Temozolomide
Multi-site (CHOP, Nationwide, Stanford, others) | Sponsor: Inhibrx Biosciences, Inc
EWS::FLI1 transcription inhibitor (monotherapy)
INBRX-109 (ozekibart) is a tetravalent antibody that activates death receptor 5 (DR5) on cancer cells, triggering cell death. In the Ewing sarcoma cohort, it's given with irinotecan and temozolomide. An expansion cohort is enrolling up to 50 patients; preliminary data reported a 64% overall response rate in evaluable patients, well above the 15–30% typically seen with I/T alone. For patients age 12 and older.
ClinicalTrials.gov: NCT03715933
Location: Multiple Locations, US, France, Italy, Netherlands, Spain, UK.
Status: Recruiting
Silmitasertib (CX-4945) + VIT
Multi-Site via Beat Childhood Cancer Consortium | Chandrika Behura, MD & Giselle Sholler, MD
CK2 inhibitor + VIT chemotherapy
Silmitasertib is a first-in-class CK2 inhibitor. CK2 is an enzyme that stabilizes the EWS-FLI1 fusion protein driving Ewing sarcoma — so blocking CK2 may weaken the oncogene directly. This Phase 1/2 trial combines silmitasertib with VIT chemotherapy in pediatric and young adult patients with relapsed/refractory Ewing sarcoma and other solid tumors.
Ewing's U Episode: October 2024
ClinicalTrials.gov: NCT06541262
Location: Multiple Locations, US & Canada
Status: Completed
Tegavivint (BC2059) — PEPN2011
Children’s Oncology Group | Sarah Brackley Whittle, MD
Wnt/β-catenin pathway inhibitor (TBL1 inhibitor)
Tegavivint is a first-in-class small-molecule inhibitor of TBL1 that blocks the Wnt/β-catenin signaling pathway. The PEPN2011 Phase 1/2 trial treats pediatric and young adult patients with recurrent or refractory solid tumors, with dedicated Phase 2 cohorts that include Ewing sarcoma, osteosarcoma, desmoid tumors, liver tumors, and Wilms tumor.
ClinicalTrials.gov: NCT04851119
NCI ID: NCI-2021-02852
Location: Multiple Locations, US & Canada
Status: Recruiting
PEN-866 (formerly STA-8666) + Vincristine and Temozolomide
National Cancer Institute | Dr. Christine Heske
HSP90-targeted drug conjugate (delivers SN-38) + standard chemo
PEN-866 — originally developed as STA-8666 — is a "miniature drug conjugate" that uses a small HSP90-binding molecule as a homing device to deliver SN-38 (the active form of irinotecan) directly into tumor tissue. HSP90 is overexpressed in Ewing sarcoma, so the conjugate accumulates preferentially in the tumor and spares healthy tissue. This trial pairs PEN-866 with vincristine and temozolomide — in effect, a "smart VIT" where the conjugate replaces standard IV irinotecan.
Ewings U: May 2025
ClinicalTrials.gov: NCT04890093
Background: HSP90 conjugate blog post
Location: Washington DC, Maryland
Status: Temporarily Suspended (Status: “Pending updated agreements in order to enroll additional participants.”)
VPT — Vincristine + PEEL-224 + Temozolomide
Lead Site: Dana-Farber Cancer Institute | David Shulman, MD
Topoisomerase I inhibitor combination
This Phase 1/2 study combines vincristine, temozolomide (an alkylating chemo), and PEEL-224 — a newer topoisomerase I inhibitor — in adolescents and young adults with relapsed or refractory Ewing sarcoma and other sarcomas. Phase 1 establishes safe dosing; Phase 2 measures efficacy in separate cohorts.
Ewing's U Episode: March 2025
ClinicalTrials.gov: NCT06709495
Location: Multiple Locations, US & Canada
Status: Recruiting
Other Treatment Approaches
For families whose child has already tried the standard I/T or VIT combinations, or who want a different approach. Some of these trials still involve chemotherapy — but delivered differently, in different combinations, or as single agents — and others step away from chemo entirely.
Eflornithine (DFMO) | BCC020
Milton S. Hershey Medical Center (Penn State) | Giselle Sholler, MD
Polyamine synthesis inhibitor (oral)
This Phase 1/2 study combines vincristine, temozolomide (an alkylating chemo), and PEEL-224 — a newer topoisomerase I inhibitor — in adolescents and young adults with relapsed or refractory Ewing sarcoma and other sarcomas. Phase 1 establishes safe dosing; Phase 2 measures efficacy in separate cohorts.
Ewing's U Episode: March 2025
ClinicalTrials.gov: NCT06709495
Location: Multiple Locations, US & Canada
Status: Recruiting
Note: Little Warrior Foundation has provided funding for this trial.
Emerege 101 - Lurbinectedin
Multi-Site | Sponsor: Jazz Pharamaceuticals
EWS::FLI1 transcription inhibitor (monotherapy)
Lurbinectedin is a selective inhibitor of oncogene transcription that targets the EWS::FLI1 fusion protein. This Phase 1/2 trial tests lurbinectedin as a single agent in children and young adults with previously treated recurrent or refractory Ewing sarcoma. Patients receive IV infusions every three weeks.
ClinicalTrials.gov: NCT05734066
Location: Multiple Locations, US & Canada
Status: Recruiting
ANGIO-1 Anti-Angiogenic Protocol (Prescribable Off-Trial)
Developed by St. Jude’s Children’s Research Hospital | Dr. Sarah Federico
ANGIO-1 is a 21-day cycle regimen that targets the disorganized blood vessels tumors rely on to grow. Importantly, this is not a clinical trial — it is a protocol that any oncologist can prescribe. It consists of three medications:
Bevacizumab — an IV monoclonal antibody that blocks new blood vessel formation
Sorafenib — an oral targeted therapy
Cyclophosphamide — a daily low-dose (metronomic) oral chemotherapy
Dr. Federico has noted that ANGIO-1 can control disease burden — stabilizing rather than shrinking tumors — and that some patients have experienced years of stable disease with a favorable quality of life and low toxicity profile. This treatment is considered when a patient needs a break from harsh treatments, or as a bridge to another trial.
Ewing's U Episode: November 2023. (This protocol is discussed around 39:15)
NIH Summary: Read more
Location: Any, as this not a trial, but a protocol. Ask your doctor if ANGIO-1 is a good fit for you.
ANGIO-A
St. Jude Children's Research Hospital | Dr. Sarah Federico
Anti-Angiogenic Protocol & Checkpoint Inhibitor
ANGIO-A builds directly on the ANGIO-1 backbone by adding Atezolizumab, an immune checkpoint inhibitor. The hypothesis: by first disrupting the tumor's blood vessel architecture with the three ANGIO-1 drugs, the immunotherapy can penetrate the tumor more effectively and help the immune system recognize and destroy cancer cells.
Ewing's U Episode: November 2023
ClinicalTrials.gov: NCT05468359
Location: St. Jude Children's Research Hospital, Memphis, TN
Status: Recruiting
Cellular & Immunotherapies
These trials are exploring new ways to help the immune system recognize and attack Ewing sarcoma. These approaches may include engineered immune cells, cancer vaccines, antibodies, and treatments that strengthen or redirect the body’s natural defenses.
“SupraVax” EWSR1 mRNA Immunotherapy — Alone or with Dual Checkpoint Inhibitors
Cleveland Clinic Taussig Cancer Institute | Case Comprehensive Cancer Center
Drs. Pete Anderson, Matteo Trucco, Timothy Chan, Rabi Hanna
This Phase 1 trial tests an mRNA cancer vaccine designed specifically for Ewing sarcoma and desmoplastic small round cell tumor (DSRCT). The vaccine — a lipid nanoparticle carrying mRNA for pieces of the EWSR1 fusion protein — is given as an intramuscular shot at weeks 0, 4, 12, and 24, with the goal of teaching the immune system to recognize the fusion (a genetic change found only in cancer cells, not in healthy tissue). A second cohort adds two IV checkpoint inhibitors (botensilimab, an anti-CTLA-4, and balstilimab, an anti-PD-1) to try to strengthen the immune response in tumors that would resist the vaccine alone.
Initial eligibility criteria can be found at the ClinicalTrials.gov listing. For questions and information, please email Dr. Pete Anderson at: andersp@ccf.org.
ClinicalTrials.gov:NCT07695311
Location: Cleveland Clinic Taussig Cancer Institute — Cleveland, OH (part of Case Comprehensive Cancer Center)
Status: Pre-Phase 1 — Not Yet Recruiting (planned start late 2026). This trial has not yet been approved by the FDA.
Note: Little Warrior Foundation has provided funding for this trial.
TiNKs — TGFβ-Imprinted NK Cell Therapy
Nationwide Children's Hospital (lead) + other sites | Dr. Bhuvana Setty
Universal-donor NK cell immunotherapy + chemotherapy
ANGIO-A builds directly on the ANGIO-1 backbone by adding Atezolizumab, an immune checkpoint inhibitor. The hypothesis: by first disrupting the tumor's blood vessel architecture with the three ANGIO-1 drugs, the immunotherapy can penetrate the tumor more effectively and help the immune system recognize and destroy cancer cells.
Ewing's U Episode: November 2024
ClinicalTrials.gov NCT05634369
Location: Multiple Locations, US
Status: Phase 1/2 — Recruiting
GD2-IL18 CAR-T (Europe)
University of Münster, Germany | Dr. Claudia Rössig
GD2-targeted CAR-T expressing IL-18
This European Phase 1 trial uses T cells engineered to target GD2 — an antigen expressed on Ewing sarcoma and other pediatric solid tumors — with an added IL-18 component designed to help the CAR-T cells stay active inside the tumor environment.
Ewing's U episode: January 2023
EU Clinical Trials Register ID: EU CT 2022-501725-21-00
Locations: Multiple sites in Germany
Status: Active, Recruiting
Autologous B7-H3 Chimeric Antigen Receptor T Cells
Stanford Cancer Institute | Dr. Sneha Ramakrishna
Autologous CAR-T targeting B7-H3
Stanford's Phase 1 trial uses the patient's own T cells, engineered to target B7-H3 — a protein expressed on many pediatric solid tumors including Ewing sarcoma. Open to patients ages 2–26 with relapsed/refractory Ewing sarcoma, osteosarcoma, Wilms tumor, neuroblastoma, and soft tissue sarcomas.
ClinicalTrials.gov: NCT06500819
Locations: Stanford University - Palo Alto, CA
Status: Active, Recruiting
Local Control
Surgical Decision Resource Guide
The Osteosarcoma Decision Aid is one of the most thorough patient-facing resources we know of for thinking through the surgical decisions that come with a bone sarcoma diagnosis. It was built specifically for osteosarcoma — and is upfront about that — but for Ewing sarcoma families whose child's tumor is in a long bone, the surgical pathways it walks through (limb salvage with an internal prosthesis or allograft, amputation, rotationplasty) and the trade-offs it lays out apply directly to your decision too.
Surgical teams typically explain these options across multiple appointments, in fragments — often during one of the most overwhelming weeks of your life. The Decision Aid pulls everything into one place at your own pace: what each option actually means day-to-day, how functional outcomes compare over time, complication and revision rates, what changes when the patient is still growing, and stories from families who chose each path. Many parents have told us this is the resource that finally let the surgical conversation make sense.
A few caveats worth naming up front: pelvic and chest-wall Ewing tumors involve different surgical considerations than long-bone disease, so the Decision Aid is less directly applicable there — though the general framework (oncologic vs. functional trade-offs, questions to ask, how to weigh family priorities) still translates. Some details around chemotherapy timing differ between osteosarcoma and Ewing, but the surgical decision itself is framed similarly. And this is meant to support — not replace — the conversation with your pediatric orthopedic oncology team. The best way to use it is to read through, mark down your questions, and bring those back to your team.
Visit the Osteosarcoma Decision Aid: osteosarcomadecisionaid.com
Ewing’s U Episode: June 2023
Discussion with Hillary
Cryoablation Trial & Ewings U?
SBRT? (Dr Murphy? Trial or just Ewings U?)
Proton vs. Photon?
Distraction Osteogenesis?
Dr. Pete Anderson | Cleveland Clinic
One of the premier Ewing Sarcoma experts, Dr. Pete conducts hundreds of remote consults per year. He has retired from the clinic, but sill offers virtual guidance. Appointments can be made via his admin, Sammi Garzone: garzones@ccf.org
Dr. Jonathan Gill & Dr. Karen Moody | MD Anderson
This team offers a much sought-after integrative oncology approach—they treat Ewing sarcoma with both cutting-edge medical therapy and comprehensive symptom, emotional, and quality-of-life support. Do we know how this team sets up second opinions? Virtual? In Person only? By referral?