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Combination Chemotherapy in Treating Patients With Non-Metastatic Extracranial Ewing Sarcoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01231906
Recruitment Status : Active, not recruiting
First Posted : November 1, 2010
Results First Posted : May 4, 2021
Last Update Posted : May 6, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

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

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Layout table for study information
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
Estimated Study Completion Date : July 14, 2026


Arm Intervention/treatment
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:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • 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

Drug: Dexrazoxane
Other Names:
  • 2, 6-Piperazinedione, 4,4''-propylenedi-, (P)- (8CI)
  • 2,6-Piperazinedione, 4, 4''-(1-methyl-1,2-ethanediyl)bis-, (S)- (9CI)
  • ADR-529
  • ICRF-187
  • Razoxane (+)-form
  • Soluble ICRF (L-isomer)

Drug: Doxorubicin Hydrochloride
Given IV
Other Names:
  • 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
  • hydroxydaunorubicin
  • Rubex

Drug: Etoposide
Given IV
Other Names:
  • Demethyl Epipodophyllotoxin Ethylidine Glucoside
  • EPEG
  • Lastet
  • Toposar
  • Vepesid
  • VP 16
  • VP 16-213
  • VP-16
  • VP-16-213
  • VP16

Drug: Ifosfamide
Given IV
Other Names:
  • 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

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Vincristine Sulfate
Given IV
Other Names:
  • Kyocristine
  • Leurocristine Sulfate
  • Leurocristine, sulfate
  • Oncovin
  • Vincasar
  • Vincosid
  • Vincrex
  • Vincristine, sulfate

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:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • 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

Drug: Dexrazoxane
Other Names:
  • 2, 6-Piperazinedione, 4,4''-propylenedi-, (P)- (8CI)
  • 2,6-Piperazinedione, 4, 4''-(1-methyl-1,2-ethanediyl)bis-, (S)- (9CI)
  • ADR-529
  • ICRF-187
  • Razoxane (+)-form
  • Soluble ICRF (L-isomer)

Drug: Doxorubicin Hydrochloride
Given IV
Other Names:
  • 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
  • hydroxydaunorubicin
  • Rubex

Drug: Etoposide
Given IV
Other Names:
  • Demethyl Epipodophyllotoxin Ethylidine Glucoside
  • EPEG
  • Lastet
  • Toposar
  • Vepesid
  • VP 16
  • VP 16-213
  • VP-16
  • VP-16-213
  • VP16

Drug: Ifosfamide
Given IV
Other Names:
  • 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

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Topotecan Hydrochloride
Given IV
Other Names:
  • Hycamptamine
  • Hycamtin
  • SKF S-104864-A
  • Topotecan HCl
  • topotecan hydrochloride (oral)

Drug: Vincristine Sulfate
Given IV
Other Names:
  • Kyocristine
  • Leurocristine Sulfate
  • Leurocristine, sulfate
  • Oncovin
  • Vincasar
  • Vincosid
  • Vincrex
  • Vincristine, sulfate




Primary Outcome Measures :
  1. 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:
  1. Overall Survival [ Time Frame: 5 years after enrollment ]
    Time from study enrollment to death or last patient contact.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   up to 50 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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
  • 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:

  • 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
    • 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 Show 243 study locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Patrick J Leavey Children's Oncology Group
  Study Documents (Full-Text)

Documents provided by Children's Oncology Group:
Layout table for additonal information
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: May 6, 2021
Last Verified: March 2021
Additional relevant MeSH terms:
Layout table for MeSH terms
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