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

Conditions

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

Trial Phase

Phase 3

Trial Purpose and Description

Trial Purpose

This randomized phase III trial is studying combination chemotherapy in treating patients with non-metastatic extracranial Ewing sarcoma. Drugs used in chemotherapy 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.


Trial Description


PRIMARY OBJECTIVES:

l. To test the effect of the combination of vincristine, cyclophosphamide, and topotecan
(VTC) added to the standard 5-drug chemotherapy interval-compressed backbone on event-free
survival (EFS) 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 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 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: This is a multicenter study. Patients are stratified according to age (= 17 years
vs = 18 years) and primary tumor site (pelvic vs non-pelvic vs extra-osseous). Patients are
randomized to 1 of 2 treatment arms.

ARM I:

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 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 periodically for 10 years.

Participation Guidelines

Age:
N/A - 50 Years
Gender:
Both

Eligibility Criteria


Inclusion Criteria:

- Newly diagnosed extracranial, non-metastatic Ewing sarcoma or primitive
neuroectodermal tumors of bone or soft tissue

- For the purpose of this study, any of the following are considered localized
disease:

- Chest wall tumors with ipsilateral pleural effusions

- Ipsilateral positive pleural fluid cytology

- Ipsilateral pleural-based secondary tumor nodules

- Regional node involvement, based on clinical suspicion confirmed by pathologic
documentation, are considered to be non-metastatic disease

- Tumors arising in the bony skull (extra-dural) are considered to be extracranial

- No evidence of metastatic disease, including the following:

- Lesions that are discontinuous from the primary tumor, are not regional lymph
nodes, and do not share a body cavity with the primary tumor

- Contralateral pleural effusion and contralateral pleural nodules

- Distant lymph node involvement

- Pulmonary nodules that meet the following criteria:

- Solitary nodule > 0.5 cm or multiple nodules of > 0.3 cm unless biopsied
and negative for Ewing sarcoma

- Biopsies of solitary nodule < 0.5 cm or multiple nodules < 3.0 cm (are not
required but if performed) positive for metastatic disease

- No tumors arising in the intra-dural soft tissue

- Creatinine clearance or radioisotope GFR = 70 mL/min OR serum creatinine based on age
and/or gender as follows:

- 0.4 mg/dL (1 month to < 6 months of age)

- 0.5 mg/dL (6 months to < 1 year of age)

- 0.6 mg/dL (1 year to < 2 years of age)

- 0.8 mg/dL (2 years to < 6 years of age)

- 1.0 mg/dL (6 years to < 10 years of age)

- 1.2 mg/dL (10 years to < 13 years of age)

- 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 years to < 16 years of age)

- 1.7 mg/dL (male) or 1.4 mg/dL (female) (= 16 years of age)

- Total bilirubin < 1.5 times upper limit of normal (ULN)

- AST or ALT < 2.5 times ULN

- Shortening fraction of = 27% by echocardiogram OR ejection fraction = 50% by
radionuclide angiogram

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception for the duration of study treatment

- No prior chemotherapy or radiotherapy

- Prior biopsy of the primary tumor without an attempt at complete or partial resection
allowed

- Patients are still allowed if unplanned excision was attempted or accomplished
as long as adequate imaging was obtained prior to surgery

- No other concurrent chemotherapy or immunomodulating agents (including steroids
unless used as an antiemetic)

- No concurrent sargramostim (GM-CSF)
Sponsor:
Children's Oncology Group
National Cancer Institute (NCI)
Dates:
November 2010
Last Updated:
June 10, 2013
Study HIC#:

Clinicaltrials.gov ID: NCT01231906