Testing a New Combination of Anti-cancer Drugs in Patients Newly Diagnosed With Ewing Sarcoma Who Have Cancer That Has Spread to Other Parts of the Body

NCT06820957 | Active Not Recruiting Phase 2 FDA Drug

• 3 other identifiers: AEWS2431NCI-2025-00801U10CA180886
• Study Type: interventional
• Target: 437
• Locations: 1 country
• Sites: 9

Brief Summary

This phase II/III trial compares the effect of vincristine, irinotecan, and regorafenib (VIrR) in combination with vincristine, doxorubicin, cyclophosphamide (VDC), ifosfamide and etoposide (IE) to usual treatment with VDC/IE for the treatment of newly diagnosed Ewing sarcoma or other round cell sarcomas that have spread from where they first started (primary site) to other places in the body (metastatic). Vincristine is in a class of medications called vinca alkaloids. It works by stopping tumor cells from growing and dividing and may kill them. Irinotecan is in a class of antineoplastic medications called topoisomerase I inhibitors. It blocks a certain enzyme needed for cell division and deoxyribonucleic acid (DNA) repair and may kill tumor cells. Regorafenib, a type of kinase inhibitor and a type of antiangiogenesis agent, blocks certain proteins, which may help keep tumor cells from growing. It may also prevent the growth of new blood vessels that tumors need to grow. Doxorubicin is in a class of medications called anthracyclines. Doxorubicin damages the cell's DNA and may kill tumor cells. It also blocks a certain enzyme needed for cell division and DNA repair. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill tumor cells. It may also lower the body's immune response. Ifosfamide, a type of alkylating agent and a type of antimetabolite, attaches to DNA in cells and may kill tumor cells. Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and DNA repair and may kill tumor cells. Giving VIrR/VDC/IE may be more effective than usual treatment with VDC/IE in treating patients with newly diagnosed metastatic Ewing sarcoma or other round cell sarcomas.

Conditions

CIC-Rearranged Sarcoma; Metastatic Ewing Sarcoma; Metastatic High Grade Sarcoma; Metastatic Undifferentiated Round Cell Sarcoma; Metastatic Undifferentiated Sarcoma, Not Otherwise Specified; Round Cell Sarcoma With EWSR1-non-ETS Fusion; Sarcoma With BCOR Genetic Alterations

Outcome Measures

Primary Outcomes (1)

• Time to event-free survival (EFS) post-Consolidation I (C1)

  Analysis will be done by associating each patient's outcome with the individual's randomized treatment assignment. The associated statistical tests will be stratified according to grouping.

  From randomization to progression or relapse, diagnosis of a second malignant neoplasm, death, or last patient contact, whichever occurs first, assessed up to 10 years

Secondary Outcomes (7)

• Overall survival-C1

  From randomization to death or last patient contact, whichever occurs first, assessed up to 10 years

• EFS

  From enrollment to progression or relapse, diagnosis of a second malignant neoplasm, death, or last patient contact, whichever occurs first, assessed up to 10 years

• Incidence of adverse events (AEs)

  Up to 30 days after last dose of study treatment

• Feasibility of augmented dose radiotherapy (ADRT) as local control

  Up to point of radiation therapy (RT) termination

• Toxicity of ADRT as local control

  Up to 30 days after ADRT is completed

Other Outcomes (8)

• EFS and response rate

  At 1 and 2 years

• Change in fludeoxyglucose F-18 positron emission tomography imaging response of primary disease site and its association with EFS

  At the end of 6 cycles of induction chemotherapy (cycle length = 14 days)

• Histologic attributes of Ewing sarcoma and round cell sarcomas that mimic Ewing sarcoma

  Up to 10 years

Study Arms (2)

Regimen A (VDC/IE)

ACTIVE COMPARATOR

See Detailed description

Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Procedure: Computed Tomography; Drug: Cyclophosphamide; Drug: Doxorubicin Hydrochloride; Procedure: Echocardiography Test; Drug: Etoposide; Other: Fludeoxyglucose F-18; Drug: Ifosfamide; Procedure: Magnetic Resonance Imaging; Procedure: Positron Emission Tomography; Other: Questionnaire Administration; Radiation: Radiation Therapy; Procedure: Surgical Procedure; Drug: Vincristine Sulfate

Regimen B (VIrR/VDC/IE)

EXPERIMENTAL

See Detailed Description

Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Procedure: Computed Tomography; Drug: Cyclophosphamide; Drug: Doxorubicin Hydrochloride; Procedure: Echocardiography Test; Drug: Etoposide; Other: Fludeoxyglucose F-18; Drug: Ifosfamide; Drug: Irinotecan Hydrochloride; Procedure: Magnetic Resonance Imaging; Procedure: Positron Emission Tomography; Other: Questionnaire Administration; Radiation: Radiation Therapy; Drug: Regorafenib; Procedure: Surgical Procedure; Drug: Vincristine Sulfate

Interventions

Bone Marrow Biopsy PROCEDURE

Undergo bone marrow aspiration and biopsy

Also known as: Biopsy of Bone Marrow, Biopsy, Bone Marrow

Regimen A (VDC/IE); Regimen B (VIrR/VDC/IE)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

Regimen A (VDC/IE); Regimen B (VIrR/VDC/IE)

Cyclophosphamide DRUG

Given IV

Also known as: (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Asta B 518, B 518, B-518, B518, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR 138719, WR- 138719, WR-138719, WR138719

Regimen A (VDC/IE); Regimen B (VIrR/VDC/IE)

Doxorubicin Hydrochloride DRUG

Given IV

Also known as: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin HCl, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, FI106, hydroxydaunorubicin, Rubex

Regimen A (VDC/IE); Regimen B (VIrR/VDC/IE)

Echocardiography Test PROCEDURE

Undergo echocardiography

Also known as: EC, Echocardiography

Regimen A (VDC/IE); Regimen B (VIrR/VDC/IE)

Etoposide DRUG

Given IV

Also known as: Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP 16213, VP-16, VP-16-213, VP-16213, VP16, VP16213

Regimen A (VDC/IE); Regimen B (VIrR/VDC/IE)

Fludeoxyglucose F-18 OTHER

Given FDG

Also known as: 18FDG, FDG, Fludeoxyglucose (18F), fludeoxyglucose F 18, Fludeoxyglucose F18, Fluorine-18 2-Fluoro-2-deoxy-D-Glucose, Fluorodeoxyglucose F18

Regimen A (VDC/IE); Regimen B (VIrR/VDC/IE)

Ifosfamide DRUG

Given IV

Also known as: Asta Z 4942, Asta Z-4942, Cyfos, Holoxan, Holoxane, Ifex, IFO, IFO-Cell, Ifolem, Ifomida, Ifomide, Ifosfamidum, Ifoxan, IFX, Iphosphamid, Iphosphamide, Iso-Endoxan, Isoendoxan, Isophosphamide, Mitoxana, MJF 9325, MJF-9325, Naxamide, Seromida, Tronoxal, Z 4942, Z-4942

Regimen A (VDC/IE); Regimen B (VIrR/VDC/IE)

Irinotecan Hydrochloride DRUG

Given IV

Also known as: Campto, Camptosar, Camptothecin 11, Camptothecin-11, CPT 11, CPT-11, CPT11, Irinomedac, Irinotecan Hydrochloride Trihydrate, Irinotecan Monohydrochloride Trihydrate, U 101440E, U-101440E, U101440E

Regimen B (VIrR/VDC/IE)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Regimen A (VDC/IE); Regimen B (VIrR/VDC/IE)

Positron Emission Tomography PROCEDURE

Undergo FDG PET

Also known as: Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure), Positron Emission Tomography Scan, Positron-Emission Tomography, PT

Regimen A (VDC/IE); Regimen B (VIrR/VDC/IE)

Questionnaire Administration OTHER

Ancillary studies

Regimen A (VDC/IE); Regimen B (VIrR/VDC/IE)

Radiation Therapy RADIATION

Undergo radiation

Also known as: Cancer Radiotherapy, Energy Type, ENERGY_TYPE, Irradiate, Irradiated, Irradiation, Radiation, Radiation Therapy, NOS, Radiotherapeutics, Radiotherapy, RT, Therapy, Radiation

Regimen A (VDC/IE); Regimen B (VIrR/VDC/IE)

Regorafenib DRUG

Given PO

Also known as: BAY 73-4506 Monohydrate, BAY-73-4506 Monohydrate, Regorafenib Monohydrate, Stivarga

Regimen B (VIrR/VDC/IE)

Surgical Procedure PROCEDURE

Undergo surgery

Also known as: Operation, Surgery, Surgery Type, Surgery, NOS, Surgical, Surgical Intervention, Surgical Interventions, Surgical Procedures, Type of Surgery

Regimen A (VDC/IE); Regimen B (VIrR/VDC/IE)

Vincristine Sulfate DRUG

Given IV

Also known as: Kyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfate

Regimen A (VDC/IE); Regimen B (VIrR/VDC/IE)

Biopsy Procedure PROCEDURE

Undergo bone marrow aspiration and biopsy

Also known as: Biopsy, BIOPSY_TYPE, Bx

Regimen A (VDC/IE); Regimen B (VIrR/VDC/IE)

Biospecimen Collection PROCEDURE

Undergo tissue and/or blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Regimen A (VDC/IE); Regimen B (VIrR/VDC/IE)

Bone Marrow Aspiration PROCEDURE

Undergo bone marrow aspiration and biopsy

Regimen A (VDC/IE); Regimen B (VIrR/VDC/IE)

Eligibility Criteria

• Age: 12 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• All patients must be enrolled on APEC14B1 and consented to the Molecular Characterization Initiative (Part A) prior to enrollment and treatment on AEWS2431
• Patients must be ≥ 12 months to ≤ 50 years of age at time of enrollment
• Newly diagnosed Ewing sarcoma and other round cell sarcomas as follows. For the purposes of eligibility, the following pathology diagnoses are eligible and molecular confirmation is not required to enroll:
• Histologically confirmed Ewing sarcoma
• Suspected Ewing sarcoma with molecular confirmation pending
• Suspected high grade round cell sarcomas/sarcomas with eligible molecular alterations, pending molecular confirmation
• Round cell sarcoma consistent with Ewing sarcoma
• Round cell sarcoma not otherwise specified
• Round cell sarcoma
• Round cell sarcomas with EWSR1-non-ETS fusion
• CIC-rearranged sarcoma
• Sarcoma with BCOR genetic alterations
• Patients with the following pathologic diagnoses that are known to contain EWSR1 or FUS fusions are not eligible:
• Angiomatoid fibrous histiocytoma
• Extraskeletal myxoid chondrosarcoma

You may not qualify if:

• Patients with regional node involvement as their only site of disease beyond the primary tumor
• Patients whose primary tumors arise in the intra-dural soft tissue (e.g., brain and spinal cord)
• Note: metastatic disease is allowable
• Patients with known Charcot-Marie-Tooth disease
• Patients who have had complete or partial resection of the primary tumor at initial diagnosis will only be eligible if adequate imaging (CT or MRI for most primary tumor sites) was obtained prior to surgery
• Patients who have received prior chemotherapy for current diagnosis, except for patients who have started cycle 1 VDC post-consent and within the timelines allowed for
• Patients who have received prior radiation therapy for current diagnosis
• Patients previously treated with a multitargeted tyrosine kinase inhibitor
• History of organ allograft (including allogeneic bone marrow transplant)
• Known hypersensitivity to regorafenib
• Active or chronic hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy
• Patients receiving strong CYP3A4 inducers or strong CYP3A4 inhibitors
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Females of childbearing potential must agree to either practice medically accepted highly-effective methods of contraception or abstain from heterosexual intercourse for the duration of the protocol therapy through 12 months after the last dose of cyclophosphamide or ifosfamide, 6 months after the last dose of doxorubicin, etoposide, and irinotecan, and 7 months after the last dose of regorafenib, whichever is longer

Sponsors & Collaborators

• Children's Oncology Group: lead

Study Sites (9)

Children's Hospital of Alabama

Birmingham, Alabama, 35233, United States

Location

Kapiolani Medical Center for Women and Children

Honolulu, Hawaii, 96826, United States

Location

Lurie Children's Hospital-Chicago

Chicago, Illinois, 60611, United States

Location

Saint Jude Midwest Affiliate

Peoria, Illinois, 61637, United States

Location

NYU Langone Hospital - Long Island

Mineola, New York, 11501, United States

Location

Saint Christopher's Hospital for Children

Philadelphia, Pennsylvania, 19134, United States

Location

Prisma Health Richland Hospital

Columbia, South Carolina, 29203, United States

Location

BI-LO Charities Children's Cancer Center

Greenville, South Carolina, 29605, United States

Location

East Tennessee Childrens Hospital

Knoxville, Tennessee, 37916, United States

Location

MeSH Terms

Conditions

Sarcoma, Ewing

Interventions

Biopsy; Specimen Handling; Cyclophosphamide; Doxorubicin; Etoposide; Fluorodeoxyglucose F18; Ifosfamide; Irinotecan; Magnetic Resonance Spectroscopy; Radiotherapy; Radiation; regorafenib; Surgical Procedures, Operative; Vincristine

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Surgical; Investigative Techniques; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Glucosides; Deoxyglucose; Deoxy Sugars; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Camptothecin; Alkaloids; Spectrum Analysis; Chemistry Techniques, Analytical; Therapeutics; Physical Phenomena; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines

Study Officials

• Bhuvana A Setty

  Children's Oncology Group

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 6, 2025
• First Posted: February 11, 2025
• Study Start: November 10, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: February 17, 2026

Record last verified: 2026-02

Locations

US (9)