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
  Purpose

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.


Condition Intervention Phase
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
Drug: doxorubicin hydrochloride
Drug: cyclophosphamide
Drug: ifosfamide
Drug: etoposide
Drug: topotecan hydrochloride
Other: laboratory biomarker analysis
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Children's Oncology Group:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 693
Study Start Date: November 2010
Estimated Primary Completion Date: September 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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
Other: laboratory biomarker analysis
Correlative studies
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.

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

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   up to 50 Years
Genders Eligible for Study:   Both
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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01231906

  Show 214 Study Locations
Sponsors and Collaborators
Children's Oncology Group
Investigators
Principal Investigator: Patrick Leavey, MD Children's Oncology Group
  More Information

No publications provided

Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT01231906     History of Changes
Other Study ID Numbers: AEWS1031, NCI-2011-02611, COG-AEWS1031, CDR0000687639, AEWS1031, AEWS1031, U10CA098543
Study First Received: October 29, 2010
Last Updated: September 11, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Sarcoma, Ewing
Sarcoma
Neoplasms
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Neuroectodermal Tumors, Primitive, Peripheral
Kidney 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
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Cyclophosphamide
Ifosfamide
Isophosphamide mustard
Liposomal doxorubicin
Etoposide phosphate
Doxorubicin
Etoposide
Vincristine
Topotecan

ClinicalTrials.gov processed this record on September 18, 2014