CIC-Rearranged SarcomaPhase 2/3NCT06820957
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
A Phase 2/3 study testing Biopsy Procedure, Biospecimen Collection and Bone Marrow Aspiration in people with CIC-Rearranged Sarcoma and Metastatic Ewing Sarcoma, run by Children's Oncology Group at 8 sites in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 12 to 50 years
- Conditions the study is for
- CIC-Rearranged Sarcoma, Metastatic Ewing Sarcoma, Metastatic High Grade Sarcoma
- What is being tested?
- Biopsy Procedure, Biospecimen Collection and Bone Marrow Aspiration
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 2 participants
- Where
- 8 sitesUnited States
- Study dates
- 10 Nov 2025to 22 Sep 2026
- Phase
- Phase 2/3
- Are there results?
- None posted in the registry
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 12 to 50 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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
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- 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
- Desmoplastic small round cell tumor
- Clear cell sarcoma
- Myxoid liposarcoma
- If clinical molecular testing that reports both fusion partners has been successfully completed by the site prior to enrollment, patients may only enroll if that testing reported one of the eligible fusions
- All patients must have evidence of distant metastatic disease. Biopsy of metastatic sites is not required. For this study, distant metastatic disease is defined as one or more of the following:
- Lesions which are discontinuous from the primary tumor, are not regional lymph nodes, and do not share a bone or body cavity with the primary tumor. Skip lesions in the same bone as the primary tumor do not constitute metastatic disease. Skip lesions in an adjacent bone are considered bone metastasis. If there is any doubt whether lesions are metastatic, a biopsy of those lesions should be performed
- Contralateral pleural effusion and/or contralateral pleural nodules
- Distant lymph node involvement
- Patients with pulmonary nodules are considered to have metastatic disease if the patient has:
- Solitary nodule ≥ 0.5 cm or multiple nodules of ≥ 0.3 cm unless lesion is biopsied and negative for tumor
- Patients with solitary nodule < 0.5 cm or multiple nodules < 0.3 cm are not considered to have lung metastasis unless biopsy documents tumor
- Bone marrow metastatic disease (bone marrow disease) is based on morphologic evidence of Ewing sarcoma based on hematoxylin and eosin (H\&E) stains. In the absence of morphologic evidence of marrow involvement on H\&E, patients with bone marrow involvement detected ONLY by flow cytometry, reverse transcriptase-polymerase chain reaction (RT-PCR), fluorescence in situ hybridization (FISH), immunohistochemistry or PET-CT will NOT be considered to have clinical bone marrow involvement for the purposes of this study
- Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m^2 or serum creatinine based on age/sex as follows:
- Age: 1 to < 2 years: Male 0.6; female 0.6
- Age: 2 to < 6 years: Male 0.8; female 0.8
- Age: 6 to < 10 years: Male 1; female 1
- Age: 10 to < 13 years: Male 1.2; female 1.2
- Age: 13 to < 16 years: Male 1.5; female 1.4
- Age: ≥ 16 years: Male 1.7; female 1.4 OR
- A 24-hour urine creatinine clearance ≥ 50 mL/min/1.73 m^2 OR
- A GFR ≥ 50 mL/min/1.73 m^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard)
- Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age
- Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) ≤ 3 x ULN for age (except for patients with liver metastasis who may enroll if ALT ≤ 5 times ULN for age)
- Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
- Shortening fraction of ≥ 27% by echocardiogram, or ejection fraction of ≥ 50% by echocardiogram
- No known congenital QT syndrome
- No known family history of congenital QT syndrome
- Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better
- Known HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
Who cannot join
- 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
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- 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
- Male patients with female partners of childbearing potential must agree to either practice a medically accepted highly-effective methods of contraception or abstain from heterosexual intercourse for the duration of the protocol therapy through 6 months after the last dose of doxorubicin and ifosfamide, 4 months after the last dose of cyclophosphamide, etoposide and regorafenib, and 3 months after the last dose of irinotecan, whichever is longer
- All patients and/or their parents or legal guardians must sign a written informed consent
- All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Trial locations and contacts
8 sites in 1 country.
8 sites in 1 country
United States8 sites
Children's Hospital of Alabama
Birmingham, Alabama, 35233
Lurie Children's Hospital-Chicago
Chicago, Illinois, 60611
Prisma Health Richland Hospital
Columbia, South Carolina, 29203
BI-LO Charities Children's Cancer Center
Greenville, South Carolina, 29605
Kapiolani Medical Center for Women and Children
Honolulu, Hawaii, 96826
East Tennessee Childrens Hospital
Knoxville, Tennessee, 37916
OSF Children's Hospital of Illinois
Peoria, Illinois, 61637
Saint Christopher's Hospital for Children
Philadelphia, Pennsylvania, 19134
About this study
Official title: Randomized Phase 2/3 Trial of Vincristine-Irinotecan-Regorafenib in Combination With Vincristine-Doxorubicin-Cyclophosphamide (VDC) and Ifosfamide-Etoposide (IE) in Patients With Newly Diagnosed Metastatic Ewing Sarcoma
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.
Read the detailed description
PRIMARY OBJECTIVE:
- To determine if the event-free survival (EFS) in patients with newly diagnosed metastatic Ewing sarcoma is improved when treated with vincristine-irinotecan-regorafenib (VIrR) after initial treatment with vincristine-doxorubicin-cyclophosphamide (VDC) and ifosfamide-etoposide (IE) compared to patients treated with 17 cycles of interval compressed VDC and IE chemotherapy.
SECONDARY OBJECTIVES:
- To compare the overall survival (OS) of patients with newly diagnosed metastatic Ewing sarcoma treated with VDC/IE/VIrR versus VDC/IE.
II. To compare the toxicity profile of VDC/IE/VIrR to VDC/IE in patients with newly diagnosed metastatic Ewing sarcoma, using both investigator-reported and patient-reported Common Terminology Criteria for Adverse Events (CTCAE).
III. To describe the feasibility and toxicity of augmented dose radiotherapy with 64.8 Gy as local control for patients with newly diagnosed metastatic Ewing sarcoma with large primary tumors.
IV. To prospectively validate that circulating tumor-derived DNA (ctDNA) levels greater than or equal to 5% at the time of diagnosis are associated with increased risk of EFS-event for patients with newly diagnosed metastatic Ewing sarcoma.
- To prospectively validate that elevated ctDNA levels greater than or equal to 0.5% burden following one cycle of chemotherapy are associated with increased risk of EFS-event for patients with newly diagnosed metastatic Ewing sarcoma.
EXPLORATORY OBJECTIVES:
- To estimate 1- and 2-year EFS and response rate for patients with newly diagnosed, eligible metastatic round cell sarcomas other than Ewing sarcoma.
II. To characterize the change in fludeoxyglucose F-18 (FDG)-positron emission tomography (PET) imaging response of primary disease site at the end of Induction chemotherapy and its association with EFS.
III. To explore distinguishing histologic attributes of Ewing sarcoma and round cell sarcomas that mimic Ewing sarcoma.
IV. To collect bone marrow and tissue samples to bank for future research. V. To explore other ctDNA predictor variables, time points, and potential association with EFS in patients with newly diagnosed metastatic Ewing sarcoma.
VI. To estimate the frequency of selected toxicities by Patient Reported Outcomes (PRO)-CTCAE and symptom bother by Functional Assessment of Cancer Therapy General Questionnaire (FACT-G) and to evaluate if these findings are associated with duration of protocol therapy and treatment arm.
OUTLINE:
INDUCTION: Patients receive vincristine intravenously (IV) on days 1 and 8, doxorubicin IV over 3-15 minutes on days 1 and 2, and cyclophosphamide IV over 30-60 minutes on day 1 of cycles 1, 3 and 5. Patients also receive ifosfamide IV over 1 hour and etoposide IV over 1 hour on days 1-5 of cycles 2, 4 and 6. Cycles repeat every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery or radiation therapy per investigator choice.
CONSOLIDATION I: Patients receive vincristine IV on days 1 and 8, doxorubicin IV over 3-15 minutes on days 1 and 2, and cyclophosphamide IV over 30-60 minutes on day 1 of cycles 1 and 2. Patients also receive ifosfamide IV over 1 hour and etoposide IV over 1 hour on days 1-5 of cycles 3 and 4. Cycles repeat every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION II: After 10 cycles of therapy, patients with Ewing Sarcoma are randomized to 1 of 2 regimens. Patients with a diagnosis of other eligible metastatic round cell sarcomas are assigned to Regimen A.
REGIMEN A: Patients receive vincristine IV on days 1 and 8 and cyclophosphamide IV over 30-60 minutes on day 1 of cycles 1, 3, 5 and 7. Patients also receive ifosfamide IV over 1 hour and etoposide IV over 1 hour on days 1-5 of cycles 2, 4 and 6. Cycles repeat every 14 days for up to 7 cycles in the absence of disease progression or unacceptable toxicity. After systemic therapy completed, patients undergo metastatic site radiation therapy.
REGIMEN B: Patients receive vincristine IV on days 1 and 8 and irinotecan IV over 90 minutes on days 1-5 of each cycle. Patients also receive regorafenib orally (PO) on days 8-14 or 15-21 of cycle 1, and then on days 8-21 of cycles thereafter. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. After systemic therapy completed, patients undergo metastatic site radiation therapy.
Additionally, patients undergo blood sample collection, echocardiography, magnetic resonance imaging (MRI), computed tomography (CT), chest CT, and/or FDG-PET throughout the study. Patients may also undergo optional collection of tumor tissue and/or bone marrow aspiration and biopsy on study.
After completion of study treatment, patients are followed every 3 months for years 1 and 2, every 6 months for years 3 and 4 then every 12 months for years 5-10.
- 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
- Being tested
- Biopsy Procedure, Biospecimen Collection, Bone Marrow Aspiration, Bone Marrow Biopsy, Computed Tomography
- Medical subject headings
- Sarcoma, Ewing
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Biopsy ProcedureProcedure or surgery
Also called Biopsy, BIOPSY_TYPE, Bx
Undergo bone marrow aspiration and biopsy
Biospecimen CollectionProcedure or surgery
Also called Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection
Undergo tissue and/or blood sample collection
Bone Marrow AspirationProcedure or surgery
Undergo bone marrow aspiration and biopsy
Bone Marrow BiopsyProcedure or surgery
Also called Biopsy of Bone Marrow, Biopsy, Bone Marrow
Undergo bone marrow aspiration and biopsy
Computed TomographyProcedure or surgery
Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography
Undergo CT
CyclophosphamideDrug
Also called (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Asta B 518, B 518
Given IV
Also called 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
Given IV
Echocardiography TestProcedure or surgery
Also called EC, Echocardiography
Undergo echocardiography
EtoposideDrug
Also called Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar
Given IV
Fludeoxyglucose F-18Other
Also called 18FDG, FDG, Fludeoxyglucose (18F), fludeoxyglucose F 18
Given FDG
IfosfamideDrug
Also called Asta Z 4942, Asta Z-4942, Cyfos, Holoxan
Given IV
Also called Campto, Camptosar, Camptothecin 11, Camptothecin-11
Given IV
Magnetic Resonance ImagingProcedure or surgery
Also called Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan
Undergo MRI
Positron Emission TomographyProcedure or surgery
Also called Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure)
Undergo FDG PET
Questionnaire AdministrationOther
Ancillary studies
Radiation TherapyRadiation
Also called Cancer Radiotherapy, Energy Type, ENERGY_TYPE, Irradiate
Undergo radiation
RegorafenibDrug
Also called BAY 73-4506 Monohydrate, BAY-73-4506 Monohydrate, Regorafenib Monohydrate, Stivarga
Given PO
Surgical ProcedureProcedure or surgery
Also called Operation, Surgery, Surgery Type, Surgery, NOS
Undergo surgery
Also called Kyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin
Given IV
| Study group | Role | What they receive |
|---|---|---|
| Regimen A (VDC/IE) | Active comparator | See Detailed description Receives: 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 Receives: 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 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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 (6)
Overall survival-C1
The stratified one-sided logrank test will be the primary statistical methodology for assessing the null statistical hypothesis.
Measured: From randomization to death or last patient contact, whichever occurs first, assessed up to 10 years
Incidence of adverse events
Toxicity will be coded according to the Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.
Measured: Up to 30 days after last dose of study treatment
Feasibility of augmented dose radiotherapy (ADRT) as local control
The actual RT delivered will be compared with the treatment plan until the point of RT termination as assessed by central review. Will consider ADRT to be feasible to deliver if there is evidence that the patient-specific probability of feasibility-failure is less than 15%.
Measured: Up to point of radiation therapy (RT) termination
Toxicity of ADRT as local control
Will be evaluated using CTCAE v 5.
Measured: Up to 30 days after ADRT is completed
Validation of circulating tumor-derived deoxyribonucleic acid (ctDNA) levels greater than or equal to 5% at the time of diagnosis are associated with increased risk of EFS-event
Will compare the risk for EFS-event from enrollment for groups of patients defined by percent ctDNA at diagnosis using a two-sided logrank test.
Measured: At time of diagnosis
Validation of ctDNA levels greater than or equal to 0.5% following one cycle of chemotherapy are associated with increased risk of EFS-event
Will compare the risk for EFS-event from enrollment for groups of patients defined by percent ctDNA at induction cycle 1 day 14 using a two-sided logrank test.
Measured: Following one cycle of chemotherapy at induction (cycle length = 14 days)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Feb 2025
- Study start10 Nov 2025
- Primary completion30 Jun 2026
- Study completion22 Sep 2026
Why it stopped: Drug supply issues
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for CIC-Rearranged SarcomaStudies of the same condition, open and under way.
- More trials run by Children's Oncology GroupThe sponsor's other registered studies.
- 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 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 2 participants (actual)
Sponsor and investigators
- Lead sponsor
- Children's Oncology Group
- Sponsor type
- Research network
- Responsible party
- Sponsor
- Investigators
- Bhuvana A Setty, Principal investigator, Children's Oncology Group
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06820957
- Sponsor's protocol ID
- AEWS2431
- Other IDs
- NCI-2025-00801, AEWS2431, AEWS2431, U10CA180886
- Status last verified
- Oct 2026
- First submitted
- 6 Feb 2025
- Last updated
- 5 Oct 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 5 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized Phase 2/3 Trial of Vincristine-Irinotecan-Regorafenib in Combination With Vincristine-Doxorubicin-Cyclophosphamide (VDC) and Ifosfamide-Etoposide (IE) in Patients With Newly Diagnosed Metastatic Ewing Sarcoma
- ClinicalTrials.gov ID
- NCT06820957
- Acronym / sponsor ID
- AEWS2431
- 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
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Drug supply issues
- Enrolment
- 2 participants (actual)
- Lead sponsor
- Children's Oncology GroupResearch network
- Study start
- 10 Nov 2025 (actual)
- Primary completion
- 30 Jun 2026 (actual)
- Study completion
- 22 Sep 2026 (actual)
- First posted
- 11 Feb 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
PRIMARY OBJECTIVE:
- To determine if the event-free survival (EFS) in patients with newly diagnosed metastatic Ewing sarcoma is improved when treated with vincristine-irinotecan-regorafenib (VIrR) after initial treatment with vincristine-doxorubicin-cyclophosphamide (VDC) and ifosfamide-etoposide (IE) compared to patients treated with 17 cycles of interval compressed VDC and IE chemotherapy.
SECONDARY OBJECTIVES:
- To compare the overall survival (OS) of patients with newly diagnosed metastatic Ewing sarcoma treated with VDC/IE/VIrR versus VDC/IE.
II. To compare the toxicity profile of VDC/IE/VIrR to VDC/IE in patients with newly diagnosed metastatic Ewing sarcoma, using both investigator-reported and patient-reported Common Terminology Criteria for Adverse Events (CTCAE).
III. To describe the feasibility and toxicity of augmented dose radiotherapy with 64.8 Gy as local control for patients with newly diagnosed metastatic Ewing sarcoma with large primary tumors.
IV. To prospectively validate that circulating tumor-derived DNA (ctDNA) levels greater than or equal to 5% at the time of diagnosis are associated with increased risk of EFS-event for patients with newly diagnosed metastatic Ewing sarcoma.
- To prospectively validate that elevated ctDNA levels greater than or equal to 0.5% burden following one cycle of chemotherapy are associated with increased risk of EFS-event for patients with newly diagnosed metastatic Ewing sarcoma.
EXPLORATORY OBJECTIVES:
- To estimate 1- and 2-year EFS and response rate for patients with newly diagnosed, eligible metastatic round cell sarcomas other than Ewing sarcoma.
II. To characterize the change in fludeoxyglucose F-18 (FDG)-positron emission tomography (PET) imaging response of primary disease site at the end of Induction chemotherapy and its association with EFS.
III. To explore distinguishing histologic attributes of Ewing sarcoma and round cell sarcomas that mimic Ewing sarcoma.
IV. To collect bone marrow and tissue samples to bank for future research. V. To explore other ctDNA predictor variables, time points, and potential association with EFS in patients with newly diagnosed metastatic Ewing sarcoma.
VI. To estimate the frequency of selected toxicities by Patient Reported Outcomes (PRO)-CTCAE and symptom bother by Functional Assessment of Cancer Therapy General Questionnaire (FACT-G) and to evaluate if these findings are associated with duration of protocol therapy and treatment arm.
OUTLINE:
INDUCTION: Patients receive vincristine intravenously (IV) on days 1 and 8, doxorubicin IV over 3-15 minutes on days 1 and 2, and cyclophosphamide IV over 30-60 minutes on day 1 of cycles 1, 3 and 5. Patients also receive ifosfamide IV over 1 hour and etoposide IV over 1 hour on days 1-5 of cycles 2, 4 and 6. Cycles repeat every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery or radiation therapy per investigator choice.
CONSOLIDATION I: Patients receive vincristine IV on days 1 and 8, doxorubicin IV over 3-15 minutes on days 1 and 2, and cyclophosphamide IV over 30-60 minutes on day 1 of cycles 1 and 2. Patients also receive ifosfamide IV over 1 hour and etoposide IV over 1 hour on days 1-5 of cycles 3 and 4. Cycles repeat every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION II: After 10 cycles of therapy, patients with Ewing Sarcoma are randomized to 1 of 2 regimens. Patients with a diagnosis of other eligible metastatic round cell sarcomas are assigned to Regimen A.
REGIMEN A: Patients receive vincristine IV on days 1 and 8 and cyclophosphamide IV over 30-60 minutes on day 1 of cycles 1, 3, 5 and 7. Patients also receive ifosfamide IV over 1 hour and etoposide IV over 1 hour on days 1-5 of cycles 2, 4 and 6. Cycles repeat every 14 days for up to 7 cycles in the absence of disease progression or unacceptable toxicity. After systemic therapy completed, patients undergo metastatic site radiation therapy.
REGIMEN B: Patients receive vincristine IV on days 1 and 8 and irinotecan IV over 90 minutes on days 1-5 of each cycle. Patients also receive regorafenib orally (PO) on days 8-14 or 15-21 of cycle 1, and then on days 8-21 of cycles thereafter. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. After systemic therapy completed, patients undergo metastatic site radiation therapy.
Additionally, patients undergo blood sample collection, echocardiography, magnetic resonance imaging (MRI), computed tomography (CT), chest CT, and/or FDG-PET throughout the study. Patients may also undergo optional collection of tumor tissue and/or bone marrow aspiration and biopsy on study.
After completion of study treatment, patients are followed every 3 months for years 1 and 2, every 6 months for years 3 and 4 then every 12 months for years 5-10.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Regimen A (VDC/IE) | Active comparator | 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 SulfateSee Detailed description |
| Regimen B (VIrR/VDC/IE) | Experimental | 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 SulfateSee Detailed Description |
Who may qualify
- Ages
- 12 to 50 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (44 listed)
- 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:
- Patients with the following pathologic diagnoses that are known to contain EWSR1 or FUS fusions are not eligible:
- If clinical molecular testing that reports both fusion partners has been successfully completed by the site prior to enrollment, patients may only enroll if that testing reported one of the eligible fusions
Key exclusion criteria (18 listed)
- 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)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Biopsy ProcedureAlso: Biopsy, BIOPSY_TYPE, BxUndergo bone marrow aspiration and biopsy | Procedure or surgery | Regimen A (VDC/IE), Regimen B (VIrR/VDC/IE) |
| Biospecimen CollectionAlso: Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen CollectionUndergo tissue and/or blood sample collection | Procedure or surgery | Regimen A (VDC/IE), Regimen B (VIrR/VDC/IE) |
| Bone Marrow AspirationUndergo bone marrow aspiration and biopsy | Procedure or surgery | Regimen A (VDC/IE), Regimen B (VIrR/VDC/IE) |
| Bone Marrow BiopsyAlso: Biopsy of Bone Marrow, Biopsy, Bone MarrowUndergo bone marrow aspiration and biopsy | Procedure or surgery | Regimen A (VDC/IE), Regimen B (VIrR/VDC/IE) |
| Computed TomographyAlso: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial TomographyUndergo CT | Procedure or surgery | Regimen A (VDC/IE), Regimen B (VIrR/VDC/IE) |
| CyclophosphamideAlso: (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Asta B 518, B 518Given IV | Drug | Regimen A (VDC/IE), Regimen B (VIrR/VDC/IE) |
| Doxorubicin HydrochlorideAlso: 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, AdriamycinGiven IV | Drug | Regimen A (VDC/IE), Regimen B (VIrR/VDC/IE) |
| Echocardiography TestAlso: EC, EchocardiographyUndergo echocardiography | Procedure or surgery | Regimen A (VDC/IE), Regimen B (VIrR/VDC/IE) |
| EtoposideAlso: Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, ToposarGiven IV | Drug | Regimen A (VDC/IE), Regimen B (VIrR/VDC/IE) |
| Fludeoxyglucose F-18Also: 18FDG, FDG, Fludeoxyglucose (18F), fludeoxyglucose F 18Given FDG | Other | Regimen A (VDC/IE), Regimen B (VIrR/VDC/IE) |
| IfosfamideAlso: Asta Z 4942, Asta Z-4942, Cyfos, HoloxanGiven IV | Drug | Regimen A (VDC/IE), Regimen B (VIrR/VDC/IE) |
| Irinotecan HydrochlorideAlso: Campto, Camptosar, Camptothecin 11, Camptothecin-11Given IV | Drug | Regimen B (VIrR/VDC/IE) |
| Magnetic Resonance ImagingAlso: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging ScanUndergo MRI | Procedure or surgery | Regimen A (VDC/IE), Regimen B (VIrR/VDC/IE) |
| Positron Emission TomographyAlso: Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure)Undergo FDG PET | Procedure or surgery | Regimen A (VDC/IE), Regimen B (VIrR/VDC/IE) |
| Questionnaire AdministrationAncillary studies | Other | Regimen A (VDC/IE), Regimen B (VIrR/VDC/IE) |
| Radiation TherapyAlso: Cancer Radiotherapy, Energy Type, ENERGY_TYPE, IrradiateUndergo radiation | Radiation | Regimen A (VDC/IE), Regimen B (VIrR/VDC/IE) |
| RegorafenibAlso: BAY 73-4506 Monohydrate, BAY-73-4506 Monohydrate, Regorafenib Monohydrate, StivargaGiven PO | Drug | Regimen B (VIrR/VDC/IE) |
| Surgical ProcedureAlso: Operation, Surgery, Surgery Type, Surgery, NOSUndergo surgery | Procedure or surgery | Regimen A (VDC/IE), Regimen B (VIrR/VDC/IE) |
| Vincristine SulfateAlso: Kyocristine, Leurocristine Sulfate, Leurocristine, sulfate, OncovinGiven IV | Drug | Regimen A (VDC/IE), Regimen B (VIrR/VDC/IE) |
Primary outcome
Time to event-free survival (EFS) post-Consolidation I (C1)
Time frame: 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
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.
6 secondary outcomes
Overall survival-C1
Time frame: From randomization to death or last patient contact, whichever occurs first, assessed up to 10 years
Incidence of adverse events
Time frame: Up to 30 days after last dose of study treatment
Feasibility of augmented dose radiotherapy (ADRT) as local control
Time frame: Up to point of radiation therapy (RT) termination
Toxicity of ADRT as local control
Time frame: Up to 30 days after ADRT is completed
Validation of circulating tumor-derived deoxyribonucleic acid (ctDNA) levels greater than or equal to 5% at the time of diagnosis are associated with increased risk of EFS-event
Time frame: At time of diagnosis
Validation of ctDNA levels greater than or equal to 0.5% following one cycle of chemotherapy are associated with increased risk of EFS-event
Time frame: Following one cycle of chemotherapy at induction (cycle length = 14 days)
Results and safety
The study was stopped early (reason given: Drug supply issues). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Oct 2026.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bhuvana A Setty principal investigator
Children's Oncology Group
8 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Biopsy Procedure, Biospecimen Collection and Bone Marrow Aspiration in people with CIC-Rearranged Sarcoma and Metastatic Ewing Sarcoma, run by Children's Oncology Group at 8 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 44 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 5 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Drug supply issues). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to event-free survival (EFS) post-Consolidation I (C1) (time frame: 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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Oct 2026.