- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT06820957
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
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
Study Overview
Status
Conditions
Intervention / Treatment
- Drug: Etoposide
- Drug: Ifosfamide
- Other: Questionnaire Administration
- Procedure: Magnetic Resonance Imaging
- Radiation: Radiation Therapy
- Procedure: Computed Tomography
- Drug: Cyclophosphamide
- Drug: Vincristine Sulfate
- Drug: Doxorubicin Hydrochloride
- Procedure: Surgical Procedure
- Drug: Regorafenib
- Drug: Irinotecan Hydrochloride
- Other: Fludeoxyglucose F-18
- Procedure: Bone Marrow Aspiration
- Procedure: Bone Marrow Biopsy
- Procedure: Biospecimen Collection
- Procedure: Positron Emission Tomography
- Procedure: Echocardiography Test
- Procedure: Biopsy Procedure
Detailed Description
PRIMARY OBJECTIVE:
I. 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:
I. 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.
V. 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:
I. 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 Type
Enrollment (Estimated)
Phase
- Phase 2
- Phase 3
Contacts and Locations
Study Locations
-
-
Alabama
-
Birmingham, Alabama, United States, 35233
- Children's Hospital of Alabama
-
-
Hawaii
-
Honolulu, Hawaii, United States, 96826
- Kapiolani Medical Center for Women and Children
-
-
Illinois
-
Chicago, Illinois, United States, 60611
- Lurie Children's Hospital-Chicago
-
Peoria, Illinois, United States, 61637
- Saint Jude Midwest Affiliate
-
-
New York
-
Mineola, New York, United States, 11501
- NYU Langone Hospital - Long Island
-
-
Pennsylvania
-
Philadelphia, Pennsylvania, United States, 19134
- Saint Christopher's Hospital for Children
-
-
South Carolina
-
Columbia, South Carolina, United States, 29203
- Prisma Health Richland Hospital
-
Greenville, South Carolina, United States, 29605
- BI-LO Charities Children's Cancer Center
-
-
Tennessee
-
Knoxville, Tennessee, United States, 37916
- East Tennessee Childrens Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Child
- Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- 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
- 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
Exclusion Criteria:
- 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
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Active Comparator: Regimen A (VDC/IE)
See Detailed description
|
Given IV
Other Names:
Given IV
Other Names:
Ancillary studies
Undergo MRI
Other Names:
Undergo radiation
Other Names:
Undergo CT
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Undergo surgery
Other Names:
Given FDG
Other Names:
Undergo bone marrow aspiration and biopsy
Undergo bone marrow aspiration and biopsy
Other Names:
Undergo tissue and/or blood sample collection
Other Names:
Undergo FDG PET
Other Names:
Undergo echocardiography
Other Names:
Undergo bone marrow aspiration and biopsy
Other Names:
|
|
Experimental: Regimen B (VIrR/VDC/IE)
See Detailed Description
|
Given IV
Other Names:
Given IV
Other Names:
Ancillary studies
Undergo MRI
Other Names:
Undergo radiation
Other Names:
Undergo CT
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Undergo surgery
Other Names:
Given PO
Other Names:
Given IV
Other Names:
Given FDG
Other Names:
Undergo bone marrow aspiration and biopsy
Undergo bone marrow aspiration and biopsy
Other Names:
Undergo tissue and/or blood sample collection
Other Names:
Undergo FDG PET
Other Names:
Undergo echocardiography
Other Names:
Undergo bone marrow aspiration and biopsy
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
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.
|
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 Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
EFS
Time Frame: 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
|
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)
Time Frame: Up to 30 days after last dose of study treatment
|
Toxicity will be coded according to the Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.
|
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
|
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%.
|
Up to point of radiation therapy (RT) termination
|
|
Toxicity of ADRT as local control
Time Frame: Up to 30 days after ADRT is completed
|
Will be evaluated using CTCAE v 5.
|
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
|
At time of diagnosis
|
|
|
Validation of ctDNA burden associated with increased risk of EFS-event
Time Frame: Following one cycle of chemotherapy at induction (cycle length = 14 days)
|
Will compare the risk for EFS-event from enrollment for groups of patients defined by percent ctDNA using a two-sided logrank test.
|
Following one cycle of chemotherapy at induction (cycle length = 14 days)
|
|
Overall survival-C1
Time Frame: From randomization to death or last patient contact, whichever occurs first, assessed up to 10 years
|
The stratified one-sided logrank test will be the primary statistical methodology for assessing the null statistical hypothesis.
|
From randomization to death or last patient contact, whichever occurs first, assessed up to 10 years
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
EFS and response rate
Time Frame: At 1 and 2 years
|
The 95% confidence bounds will be calculated according to the complementary log-log transformation.
Will report the 1-, 2- and 3-year estimate EFS probabilities as well as the confidence intervals.
|
At 1 and 2 years
|
|
Change in fludeoxyglucose F-18 positron emission tomography imaging response of primary disease site and its association with EFS
Time Frame: At the end of 6 cycles of induction chemotherapy (cycle length = 14 days)
|
Will calculate the percent change in standardized uptake value (SUV).
Will fit a Cox proportional hazards regression model for hazard of EFS-event with percent change in SUV included as an independent variable.
Nonlinearity will be formally tested using a two degree of freedom Wald test of size 0.05 for the null hypothesis.
The functional form of the relationship between hazard of EFS-event and percent change in SUV will be explored by plotting the model-predicted hazard on the logarithmic scale against percent change in SUV with 95% confidence bands.
This plot will be examined for natural inflection points in the curve representing potentially informative categories of percent change in SUV.
If the p-value for this test is not significant at the 0.05 level, will remove the nonlinear spline terms refitting the model with linear percent change in SUV, and will report the associated hazard ratio and 95% confidence interval.
|
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
Time Frame: Up to 10 years
|
Qualitative characteristics will be quantified with the observed proportion in each category and the associated confidence interval.
The sample mean, median, standard deviation, 25th percentile and 75th percentile will be used to characterize the distribution of the quantitative characteristics.
|
Up to 10 years
|
|
ctDNA predictor variables, time points, and potential association with EFS
Time Frame: Up to 10 years
|
Up to 10 years
|
|
|
Frequency of selected toxicities
Time Frame: Up to 12 months after completion of systemic therapy
|
Will be evaluated using the Patient Reported Outcomes Version of Common Terminology Criteria for Adverse Events and Functional Assessment of Cancer Therapy General Questionnaire.
|
Up to 12 months after completion of systemic therapy
|
|
Probability of radiation recall AEs
Time Frame: Up to 30 days after RT is completed
|
The probability of radiation recall AEs will be compared.
The reporting period characteristics are indicator variables including the randomized regimen as well as the tumor sites radiated.
The null hypothesis will be tested using a one-sided test against the alternative that the experimental regimen has an increased frequency of toxicity-events each time the study progress report is prepared for this trial.
|
Up to 30 days after RT is completed
|
|
Rate of refusal of randomization
Time Frame: Up to 10 years
|
Up to 10 years
|
|
|
Clinically Significant Treatment Modification Probability
Time Frame: Up to 10 years
|
The null hypothesis will be tested using a one-sided test against the alternative that the experimental regimen has an increased frequency of treatment modification-events after the twentieth patient is randomized to Regimen B (or the first study progress report is due, whichever occurs first) and each time the study progress report is prepared for this trial.
|
Up to 10 years
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Bhuvana A Setty, Children's Oncology Group
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms
- Neoplasms by Histologic Type
- Sarcoma
- Neoplasms, Connective and Soft Tissue
- Osteosarcoma
- Neoplasms, Bone Tissue
- Neoplasms, Connective Tissue
- Sarcoma, Ewing
- Organic Chemicals
- Heterocyclic Compounds, 1-Ring
- Heterocyclic Compounds
- Heterocyclic Compounds, 2-Ring
- Heterocyclic Compounds, Fused-Ring
- Investigative Techniques
- Therapeutics
- Clinical Laboratory Techniques
- Diagnostic Techniques and Procedures
- Diagnosis
- Cytological Techniques
- Cytodiagnosis
- Hydrocarbons
- Hydrocarbons, Cyclic
- Carbohydrates
- Physical Phenomena
- Camptothecin
- Alkaloids
- Podophyllotoxin
- Tetrahydronaphthalenes
- Naphthalenes
- Polycyclic Aromatic Hydrocarbons
- Hydrocarbons, Aromatic
- Polycyclic Compounds
- Glucosides
- Glycosides
- Indoles
- Diagnostic Techniques, Surgical
- Chemistry Techniques, Analytical
- Spectrum Analysis
- Phosphoramide Mustards
- Nitrogen Mustard Compounds
- Mustard Compounds
- Hydrocarbons, Halogenated
- Phosphoramides
- Organophosphorus Compounds
- Vinca Alkaloids
- Secologanin Tryptamine Alkaloids
- Indole Alkaloids
- Indolizidines
- Indolizines
- Anthracyclines
- Naphthacenes
- Aminoglycosides
- Deoxyglucose
- Deoxy Sugars
- Daunorubicin
- Oxazines
- Irinotecan
- Fluorodeoxyglucose F18
- Cyclophosphamide
- Etoposide
- Doxorubicin
- Vincristine
- Ifosfamide
- Radiotherapy
- Radiation
- Biopsy
- Specimen Handling
- Magnetic Resonance Spectroscopy
- Surgical Procedures, Operative
- regorafenib
Other Study ID Numbers
- AEWS2431 (Other Identifier: CTEP)
- U10CA180886 (U.S. NIH Grant/Contract)
- NCI-2025-00801 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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