Combination Chemotherapy in Treating Patients With Non-Metastatic Extracranial Ewing Sarcoma
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| ClinicalTrials.gov Identifier: NCT01231906 |
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Recruitment Status :
Active, not recruiting
First Posted : November 1, 2010
Results First Posted : May 4, 2021
Last Update Posted : August 31, 2023
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Sponsor:
Children's Oncology Group
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group
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Brief Summary:
This trial examined the outcome benefit to patients of adding a new chemotherapy drug combination to the established treatment approach for patients with extracranial Ewing sarcoma, that had not spread from the primary site to other places in the body. The trial randomly assigned patients at the time of study entry to receive established standard treatment with the following 5-drugs: vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, ifosfamide and etoposide. The outcome for patients receiving the standard 5-drug combination was compared to the outcome for patients who received the same 5-drugs with an additional drug, topotecan hydrochloride delivered in a novel combination with vincristine sulfate and cyclophosphamide.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Localized Extraskeletal Ewing Sarcoma Peripheral Primitive Neuroectodermal Tumor of Bone Peripheral Primitive Neuroectodermal Tumor of Soft Tissues | Drug: Cyclophosphamide Drug: Dexrazoxane Drug: Doxorubicin Hydrochloride Drug: Etoposide Drug: Ifosfamide Other: Laboratory Biomarker Analysis Drug: Topotecan Hydrochloride Drug: Vincristine Sulfate | Phase 3 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 642 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Phase III Randomized Trial of Adding Vincristine-Topotecan-Cyclophosphamide to Standard Chemotherapy in Initial Treatment of Non-Metastatic Ewing Sarcoma |
| Actual Study Start Date : | November 22, 2010 |
| Actual Primary Completion Date : | March 31, 2020 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Ewing sarcoma
MedlinePlus related topics:
Soft Tissue Sarcoma
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm A (combination chemotherapy)
INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, and 10; doxorubicin hydrochloride IV over 1-15 minutes (or as per institutional policies up to 60-minutes) on days 1 and 2 and cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 5, and 9; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 7, and 11. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7, 8, 9, 10, 13, 14, 17, 18, 21, and 22; doxorubicin hydrochloride IV on days 1 and 2 in weeks 1 and 9; cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 7, 9, 13, 17, and 21; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 5, 11, 15, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 1 and 9. |
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Dexrazoxane Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Drug: Ifosfamide Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Vincristine Sulfate Given IV
Other Names:
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Experimental: Arm B (combination chemotherapy, topotecan hydrochloride)
INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, 10, 11 and 12; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1 and 9; cyclophosphamide IV over 15-30 minutes on days 1-5 in weeks 1 and 9, and over 30-60 minutes on day 1 of weeks 5 and 11; ifosfamide and etoposide as in arm A; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 5 and 11. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7-10, 13-16, 19, and 20; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1, 7, and 15; cyclophosphamide IV over 15-60 minutes on days 1-5 in weeks 1, 7, and 15, and over 30-60 minutes on day 1 in weeks 9, 13, and 19; ifosfamide IV over 1 hour and etoposide IV over 1- 2 hours on days 1-5 in weeks 3, 5, 11, 17, and 21; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 9,13, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 13 and 19. |
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Dexrazoxane Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Drug: Ifosfamide Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Topotecan Hydrochloride Given IV
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
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Primary Outcome Measures :
- Event-Free Survival [ Time Frame: 5 years after enrollment ]Estimated 5-year EFS where EFS is calculated as the time from study enrollment to disease progression, disease relapse, occurrence of a second malignant neoplasm, death from any cause or last follow-up whichever occurs first. Kaplan-Meier method is used for estimation. Patients without an event are censored at last contact.
Other Outcome Measures:
- Overall Survival [ Time Frame: 5 years after enrollment ]Time from study enrollment to death or last patient contact.
- Histological Response, in Terms of Event Free Survival After Local Control in Patients Who Received Local Control Therapy [ Time Frame: At the end of INDUCTION THERAPY (84 days) ]Percent of viable tumor in the resected tumor specimen after the patient receives 2 cycles of induction chemotherapy. Patients will be classified into groups according to: (1) good risk - less than 10% viable tumor in the resection specimen; and (2) standard risk - 10% or more viable tumor in the resection specimen. Patients who receive radiation therapy to the primary tumor prior to tumor resection or whose tumor is resected prior to the start of systemic therapy are not evaluable for this outcome measure.
- SUVmax as Determined by Positron Emission Tomography (PET)-Determined Response at Enrollment [ Time Frame: At study enrollment ]Patients will be classified into two groups according to SUVmax as: (1) study population median or greater; and (2) less than the study population median.
- SUVmax as Determined by Positron Emission Tomography (PET)-Determined Response After Induction [ Time Frame: At the end of INDUCTION THERAPY (84 days) ]Patients will be classified into two groups according to SUVmax as: (1) study population median or greater; and (2) less than the study population median. Patients who receive radiation therapy to the primary tumor prior to the completion of 2 cycles of induction or who do not receive 2 cycles of induction chemotherapy are not evaluable for this outcome measure.
- Tumor Volume in Milliliters (ml) at Enrollment [ Time Frame: At study enrollment ]Patients will be classified into two groups: (1) tumor volume 200 ml or greater and (2) tumor volume less than 200 ml.
- Radiological Response of Soft Tissue Component of Mass by Radiological Evaluation at the End of Induction Chemotherapy [ Time Frame: At the end of INDUCTION THERAPY (84 days) ]Patients will be classified into two groups: (1) complete resolution of soft tissue mass; and (2) soft tissue mass present after induction chemotherapy. Patients who receive radiation therapy to the primary tumor prior to the completion of 2 cycles of induction, who do not receive 2 cycles of induction chemotherapy or who do not have soft tissue involvement detected at enrollment or at any time prior to the end of induction chemotherapy are not evaluable for this outcome measure.
- Type of Local Control Modality Used for Removal of Primary Tumor Site at Any Time up to the End of the First 6 Cycles of Consolidation Chemotherapy [ Time Frame: 126 days after enrollment ]Patients will be categorized into the following groups: (1) surgery as the local control modality; (2) radiation therapy as the local control modality; (3) surgery and radiation therapy as the local control modality; and (4) no local control modality administered to the primary tumor site. Patients who do not complete induction chemotherapy will not be evaluable for this outcome measure.
- Occurrence of Grade 2 or Higher Musculoskeletal Event (ME), or Surgery Required to Treat a Complication of Local Therapy [ Time Frame: 132 days after enrollment ]Any National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 ME of grade 2 or greater or ME of any grade where surgery is required to treat a complication of local therapy. Patients who do not complete induction chemotherapy or do not have any local control modality administered to the primary tumor site will not be evaluable for this outcome measure.
- Presence of Tumor at the Margin of Resection for Patients Who Have Surgery as the Only Local Control Modality [ Time Frame: 126 days after enrollment ]Patients will be categorized into the following groups: (1) tumor present at the margin of resection; and (2) no tumor present at the margin of resection. Patients who are not classified as having surgery as the only local control modality will not be evaluable for this outcome measure.
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| Ages Eligible for Study: | up to 50 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
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Patients with newly diagnosed, biopsy confirmed, extracranial, non-metastatic Ewing sarcoma or primitive neuroectodermal tumor (PNET) of bone or soft tissue are eligible for this study; note:
- For the purpose of this study, chest wall tumors with ipsilateral pleural effusions, ipsilateral positive pleural fluid cytology or ipsilateral pleural based secondary tumor nodules will be considered localized disease
- Patients with regional node involvement, based on clinical suspicion confirmed by pathologic documentation are considered to be non-metastatic
- Patients with discontinuous osseous lesions within the same bone are considered to be non-metastatic
- Tumors arising in the bony skull (extra-dural) are considered to be extracranial
- Patient eligibility will be based on a diagnosis of Ewing sarcoma or PNET by institutional pathologist
- No prior chemotherapy or radiation therapy is allowed; patients should only have had a biopsy of the primary tumor without an attempt at complete or partial resection; patients will still be eligible if unplanned excision was attempted or accomplished as long as adequate imaging was obtained prior to surgery
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Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70mL/min/1.73 m^2 or serum creatinine based on age/gender as follows:
- 1 month to < 6 months: 0.4 mg/dL
- 6 months to < 1 year: 0.5 mg/dL
- 1 to < 2 years: 0.6 mg/dL
- 2 to < 6 years: 0.8 mg/dL
- 6 to < 10 years: 1 mg/dL
- 10 to < 13 years: 1.2 mg/dL
- 13 to < 16 years: 1.5 mg/dL (male), 1.4 mg/dL (female)
- >= 16 years: 1.7 mg/dL (male), 1.4 mg/dL (female)
- Total bilirubin < 1.5 x upper limit of normal (ULN) for age
- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x upper limit of normal (ULN) for age
- Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by radionuclide angiogram
Exclusion Criteria:
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Patients must have no evidence of metastatic disease; metastatic disease are lesions which are discontinuous from the primary tumor, are not regional lymph nodes and do not share a body cavity with the primary tumor; if there is any doubt whether lesions are metastatic, a biopsy of those lesions should be taken
- Skeletal lesions in adjacent bones (trans-articular)
- Contralateral pleural effusion and contralateral pleural nodules
- Distant lymph node involvement
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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 biopsied and negative for Ewing's
- Biopsies of solitary nodule =< 0.5 cm or multiple nodules =< 0.3 cm are not required but if performed and positive indicate metastatic disease
- Patients whose tumors arise in the dural and intra-dural soft tissues of the cranium and spine are not eligible
- Patients with pathologic diagnoses other than Ewing sarcoma will be excluded
- Patients diagnosed with Ewing Sarcoma as a second malignant neoplasm are not eligible if they have received chemotherapy or radiation for the treatment of their primary malignancy
- Pregnant women will not be entered on this study; pregnancy tests must be obtained in female patients who are post-menarchal; lactating females may not participate unless they have agreed not to breastfeed their infants; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of the study treatment
- 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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01231906
Locations
Show 243 study locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Patrick J Leavey | Children's Oncology Group |
Study Documents (Full-Text)
Documents provided by Children's Oncology Group:
Documents provided by Children's Oncology Group:
Study Protocol and Statistical Analysis Plan [PDF] March 4, 2016
Additional Information:
Study Data/Documents: Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Study Data/Documents: Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Children's Oncology Group |
| ClinicalTrials.gov Identifier: | NCT01231906 |
| Other Study ID Numbers: |
AEWS1031 NCI-2011-02611 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) S12-01231 CDR0000687639 COG-AEWS1031 AEWS1031 ( Other Identifier: Children's Oncology Group ) AEWS1031 ( Other Identifier: CTEP ) P30CA013330 ( U.S. NIH Grant/Contract ) U10CA180830 ( U.S. NIH Grant/Contract ) U10CA180886 ( U.S. NIH Grant/Contract ) U10CA098543 ( U.S. NIH Grant/Contract ) |
| First Posted: | November 1, 2010 Key Record Dates |
| Results First Posted: | May 4, 2021 |
| Last Update Posted: | August 31, 2023 |
| Last Verified: | May 2023 |
Additional relevant MeSH terms:
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Sarcoma Sarcoma, Ewing Neuroectodermal Tumors Neuroectodermal Tumors, Primitive Neuroectodermal Tumors, Primitive, Peripheral Soft Tissue Neoplasms Neoplasms Neoplasms, Connective and Soft Tissue Neoplasms by Histologic Type Osteosarcoma Neoplasms, Bone Tissue Neoplasms, Connective Tissue Neoplasms, Germ Cell and Embryonal Neoplasms, Nerve Tissue Neoplasms, Neuroepithelial |
Neoplasms, Glandular and Epithelial Neoplasms by Site Cyclophosphamide Ifosfamide Isophosphamide mustard Doxorubicin Liposomal doxorubicin Etoposide Vincristine Etoposide phosphate Topotecan Podophyllotoxin Dexrazoxane Razoxane 3,6-bis(5-chloro-2-piperidyl)-2,5-piperazinedione |