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

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Children's Oncology Group
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT01231906
First received: October 29, 2010
Last updated: September 11, 2014
Last verified: September 2014

October 29, 2010
September 11, 2014
November 2010
September 2019   (final data collection date for primary outcome measure)
  • EFS [ Time Frame: Time from study enrollment to disease progression, appearance of disease at sites considered previously uninvolved, diagnosis of a second malignant neoplasm, death or last patient contact, assessed up to 5 years ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: Time from study enrollment to death or last patient contact, assessed up to 5 years ] [ Designated as safety issue: No ]
  • Event-free survival (EFS) [ Designated as safety issue: No ]
  • Overall survival [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01231906 on ClinicalTrials.gov Archive Site
  • Relative risk for death [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Estimated using the stratified partial likelihood for the relative risk regression model accounting for the factors used to stratify randomization at the time full information is obtained for the EFS comparison. Methods for censored survival data, including but not limited to log-rank comparisons and proportional hazards regression modeling will be used to assess prognostic significance.
  • Histological response, in terms of event free survival after local control in patients who received local control therapy [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Methods for censored survival data, including but not limited to log-rank comparisons and proportional hazards regression modeling will be used.
  • Positron emission tomography (PET)-determined response, in terms of event free survival after local control [ Time Frame: Up to week 13 ] [ Designated as safety issue: No ]
    Methods for censored survival data, including but not limited to log-rank comparisons and proportional hazards regression modeling will be used.
  • Probabilities of identifying tumors of at least 200 ml [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    A two sided log-rank test of size 0.05 as a function of the percent of patients for whom measurements can be obtained will be used.
  • Extent of tumor necrosis according to the necrosis grading criteria in patients who have surgical resection of tumor [ Time Frame: Week 13 ] [ Designated as safety issue: No ]
    The probabilities of identifying patients with 'standard' necrosis grading as associated with increased risk using a two sided log-rank test of size 0.05 as a function of the percent of patients with 'standard' necrosis grading and its associated relative risk will be used.
  • Radiological response of soft tissue component of mass by PET [ Time Frame: Up to week 13 ] [ Designated as safety issue: No ]
    The probabilities of identifying patients with complete response (CR) as associated with decreased risk for EFS-event when compared with patients with less-than-CR using a two sided log-rank test of size 0.05 as a function of the percent of patients with standard response and its associated relative risk will be used.
  • Differences associated with local control modality on risk for EFS event, according to surgery only v. radiation therapy only v. surgery and radiation therapy [ Time Frame: Up to week 13 ] [ Designated as safety issue: No ]
    Stratified according to primary site of tumor as pelvis v. bone but not pelvis v. extra-osseous site. An omnibus log-rank test of size 0.05 will be used to assess whether there are differences associated with local control modality.
  • Number and proportion of patients who experience any grade 2 or higher musculoskeletal event (ME), or surgery required to treat a complication of local therapy [ Time Frame: Up to 3 months post-local control therapy ] [ Designated as safety issue: Yes ]
    Will be based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The proportion of patients who experience any ME will be compared across the three regimens using an exact test of proportions of size 0.05.
  • Proportion of patients who have tumor present at the margin of resection on risk for EFS event in patients undergoing surgery [ Time Frame: Week 13 ] [ Designated as safety issue: No ]
  • Histologic response [ Designated as safety issue: No ]
  • Initial volumetric tumor size as a prognostic factor for EFS [ Designated as safety issue: No ]
  • Prognostic significance of imaging response by FDG-positron emission tomography (PET) and EFS [ Designated as safety issue: No ]
  • Effect of local surgical margins in conjunction with histologic response on EFS [ Designated as safety issue: No ]
  • Effect of local therapy modality (surgery, radiotherapy or a combination) as well as the type of surgical reconstruction on musculoskeletal complications [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Combination Chemotherapy in Treating Patients With Non-Metastatic Extracranial Ewing Sarcoma
A Phase III Randomized Trial of Adding Vincristine-Topotecan-Cyclophosphamide to Standard Chemotherapy in Initial Treatment of Non-Metastatic Ewing Sarcoma

This randomized phase III trial studies combination chemotherapy to see how well it works compared to combination chemotherapy with topotecan hydrochloride in treating patients with non-metastatic extracranial Ewing sarcoma. Drugs used in chemotherapy, such as vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, ifosfamide, etoposide, and topotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. It is not yet known whether combination chemotherapy is more effective with topotecan hydrochloride in treating Ewing sarcoma.

PRIMARY OBJECTIVES:

l. Test the effect of the combination of vincristine (vincristine sulfate), cyclophosphamide, and topotecan (topotecan hydrochloride) (VTC) added to the standard 5-drug chemotherapy interval-compressed backbone on event-free and overall survival of children and young adults with Ewing sarcoma.

SECONDARY OBJECTIVES:

I. To evaluate initial volumetric tumor size as a prognostic factor for event free survival (EFS) in patients with localized Ewing tumors.

II. To evaluate histologic response as a prognostic factor for EFS in patients with localized Ewing tumors.

III. To continue evaluation of biologic markers both as related to prognosis and as eventual therapeutic targets via encouraging concurrent enrollment on a Ewing sarcoma specimen-collection study.

IV. To evaluate imaging response by fludeoxyglucose F 18 (FDG)-positron emission tomography (PET) as a prognostic factor for EFS.

V. To evaluate the effects of the type of local therapy on EFS and overall survival.

VI. To evaluate the effect of local surgical margins in conjunction with histologic response on EFS in patients with localized Ewing tumors.

VII. To evaluate the effect of local therapy modality (surgery, radiotherapy, or a combination) as well as the type of surgical reconstruction on musculoskeletal complications.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I:

INDUCTION THERAPY: Patients receive vincristine sulfate intravenously (IV) on day 1 in weeks 1, 2, 5, 6, 9, and 10; doxorubicin hydrochloride IV 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.

ARM II:

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 15-60 minutes on days 1-5 in weeks 1 and 9, and on day 1 of weeks 5 and 11; ifosfamide and etoposide as in arm I; 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 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 with responsive or stable disease undergo may undergo surgery alone in week 13 if lesion can be complete resected with negative margins and with reasonable functional result. Patients with unresectable lesions or inadequate margins after surgery receive radiotherapy during weeks 1-7. Patients with bulky lesions in surgically difficult sites such as the spine, skull, and periacetabular pelvis, patients with a poor response to induction chemotherapy, or those patients in whom surgery would result in unacceptable functional results may undergo radiotherapy alone in weeks 1-7 of consolidation therapy, and surgery should be performed after completion of consolidation chemotherapy. Patients with microscopic residual disease after planned pre-operative radiotherapy receive additional radiotherapy.

After completion of study therapy, patients are followed up every 3 months for 3 years and then every 6 months for 2 years.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Adult Supratentorial Primitive Neuroectodermal Tumor (PNET)
  • Childhood Supratentorial Primitive Neuroectodermal Tumor
  • Ewing Sarcoma of Bone
  • Extraosseous Ewing Sarcoma
  • Extraosseous Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
  • Localized Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
  • Peripheral Primitive Neuroectodermal Tumor of the Kidney
  • Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor
  • Drug: vincristine sulfate
    Given IV
    Other Names:
    • leurocristine sulfate
    • VCR
    • Vincasar PFS
  • Drug: doxorubicin hydrochloride
    Given IV
    Other Names:
    • ADM
    • ADR
    • Adria
    • Adriamycin PFS
    • Adriamycin RDF
  • Drug: cyclophosphamide
    Given IV
    Other Names:
    • CPM
    • CTX
    • Cytoxan
    • Endoxan
    • Endoxana
  • Drug: ifosfamide
    Given IV
    Other Names:
    • Cyfos
    • Holoxan
    • IFF
    • IFX
    • IPP
  • Drug: etoposide
    Given IV
    Other Names:
    • EPEG
    • VP-16
    • VP-16-213
  • Drug: topotecan hydrochloride
    Given IV
    Other Names:
    • hycamptamine
    • Hycamtin
    • SKF S-104864-A
    • TOPO
  • Other: laboratory biomarker analysis
    Correlative studies
  • Experimental: Arm I (combination chemotherapy)

    INDUCTION THERAPY: Patients receive vincristine sulfate (IV) on day 1 in weeks 1, 2, 5, 6, 9, and 10; doxorubicin hydrochloride IV 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.

    Interventions:
    • Drug: vincristine sulfate
    • Drug: doxorubicin hydrochloride
    • Drug: cyclophosphamide
    • Drug: ifosfamide
    • Drug: etoposide
    • Other: laboratory biomarker analysis
  • Experimental: Arm II (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 15-60 minutes on days 1-5 in weeks 1 and 9, and on day 1 of weeks 5 and 11; ifosfamide and etoposide as in arm I; 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 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.

    Interventions:
    • Drug: vincristine sulfate
    • Drug: doxorubicin hydrochloride
    • Drug: cyclophosphamide
    • Drug: ifosfamide
    • Drug: etoposide
    • Drug: topotecan hydrochloride
    • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
693
Not Provided
September 2019   (final data collection date for primary outcome measure)

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
Both
up to 50 Years
No
United States,   Australia,   Canada,   New Zealand,   Puerto Rico
 
NCT01231906
AEWS1031, NCI-2011-02611, COG-AEWS1031, CDR0000687639, AEWS1031, AEWS1031, U10CA098543
Yes
Children's Oncology Group
Children's Oncology Group
National Cancer Institute (NCI)
Principal Investigator: Patrick Leavey, MD Children's Oncology Group
Children's Oncology Group
September 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP