Trial Information

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

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.