A Phase III Randomized Trial of Adding Vincristine-Topotecan-Cyclophosphamide to Standard Chemotherapy in Initial Treatment of Non-Metastatic Ewing Sarcoma

Location:

Rochester, Minn.

Trial status:

Open for Enrollment

Why is this study being done?

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.

Who is eligible to participate?

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

Last updated:

8/6/2014

NCT ID:

NCT01231906

IRB Number:

10-008248