NCT01231906 · CITED IN SOURCE DOCUMENTS

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

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2026-01-23

This trial examined the outcome benefit to patients of adding a new chemotherapy drug combination to the established treatment approach for patients with extracranial Ewing sarcoma, that had not spread from the primary site to other places in the body. The trial randomly assigned patients at the time of study entry to receive established standard treatment with the following 5-drugs: vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, ifosfamide and etoposide. The outcome for patients receiving the standard 5-drug combination was compared to the outcome for patients who received the same 5-drugs with an additional drug, topotecan hydrochloride delivered in a novel combination with vincristine sulfate and cyclophosphamide.

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What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Event-Free Survival

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outcome · NOT POSTED

Overall Survival

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outcome · NOT POSTED

Histological Response, in Terms of Event Free Survival After Local Control in Patients Who Received Local Control Therapy

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outcome · NOT POSTED

SUVmax as Determined by Positron Emission Tomography (PET)-Determined Response at Enrollment

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outcome · NOT POSTED

SUVmax as Determined by Positron Emission Tomography (PET)-Determined Response After Induction

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outcome · NOT POSTED

Tumor Volume in Milliliters (ml) at Enrollment

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outcome · NOT POSTED

Radiological Response of Soft Tissue Component of Mass by Radiological Evaluation at the End of Induction Chemotherapy

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outcome · NOT POSTED

Type of Local Control Modality Used for Removal of Primary Tumor Site at Any Time up to the End of the First 6 Cycles of Consolidation Chemotherapy

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outcome · NOT POSTED

Occurrence of Grade 2 or Higher Musculoskeletal Event (ME), or Surgery Required to Treat a Complication of Local Therapy

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outcome · NOT POSTED

Presence of Tumor at the Margin of Resection for Patients Who Have Surgery as the Only Local Control Modality

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility 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
healthy Volunteers: false
maximum Age: 50 Years
sex: ALL
std Ages: CHILD
ADULT

Treatment arms and interventions

arm Groups

description
INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, and 10; doxorubicin hydrochloride IV over 1-15 minutes (or as per institutional policies up to 60-minutes) 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. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 1 and 9.
intervention Names
Drug: Cyclophosphamide
Drug: Dexrazoxane
Drug: Doxorubicin Hydrochloride
Drug: Etoposide
Drug: Ifosfamide
Other: Laboratory Biomarker Analysis
Drug: Vincristine Sulfate
label
Arm A (combination chemotherapy)
type
EXPERIMENTAL
description
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 15-30 minutes on days 1-5 in weeks 1 and 9, and over 30-60 minutes on day 1 of weeks 5 and 11; ifosfamide and etoposide as in arm A; 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 over 30-60 minutes 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 received Dexrazoxane with doxorubicin hydrochloride in weeks 13 and 19.
intervention Names
Drug: Cyclophosphamide
Drug: Dexrazoxane
Drug: Doxorubicin Hydrochloride
Drug: Etoposide
Drug: Ifosfamide
Other: Laboratory Biomarker Analysis
Drug: Topotecan Hydrochloride
Drug: Vincristine Sulfate
label
Arm B (combination chemotherapy, topotecan hydrochloride)
type
EXPERIMENTAL

interventions

arm Group Labels
Arm A (combination chemotherapy)
Arm B (combination chemotherapy, topotecan hydrochloride)
description
Given IV
name
Cyclophosphamide
other Names
(-)-Cyclophosphamide
2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
Asta B 518
B 518
B-518
B518
Carloxan
Ciclofosfamida
Ciclofosfamide
Cicloxal
Clafen
Claphene
type
DRUG
arm Group Labels
Arm A (combination chemotherapy)
Arm B (combination chemotherapy, topotecan hydrochloride)
name
Dexrazoxane
other Names
2, 6-Piperazinedione, 4,4'-propylenedi-, (P)- (8CI)
2,6-Piperazinedione, 4, 4'-(1-methyl-1,2-ethanediyl)bis-, (S)- (9CI)
ADR 529
ADR-529
ADR529
ICRF 187
ICRF-187
ICRF187
Razoxane (+)-form
Soluble ICRF (L-isomer)
type
DRUG
arm Group Labels
Arm A (combination chemotherapy)
Arm B (combination chemotherapy, topotecan hydrochloride)
description
Given IV
name
Doxorubicin Hydrochloride
other Names
5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
ADM
Adriacin
Adriamycin
Adriamycin Hydrochloride
Adriamycin PFS
Adriamycin RDF
ADRIAMYCIN, HYDROCHLORIDE
Adriamycine
Adriblastina
Adriblastine
Adrimedac
type
DRUG
arm Group Labels
Arm A (combination chemotherapy)
Arm B (combination chemotherapy, topotecan hydrochloride)
description
Given IV
name
Etoposide
other Names
Demethyl Epipodophyllotoxin Ethylidine Glucoside
EPEG
Lastet
Toposar
Vepesid
VP 16
VP 16-213
VP 16213
VP-16
VP-16-213
VP-16213
VP16
type
DRUG
arm Group Labels
Arm A (combination chemotherapy)
Arm B (combination chemotherapy, topotecan hydrochloride)
description
Given IV
name
Ifosfamide
other Names
Asta Z 4942
Asta Z-4942
Cyfos
Holoxan
Holoxane
Ifex
IFO
IFO-Cell
Ifolem
Ifomida
Ifomide
Ifosfamidum
type
DRUG
arm Group Labels
Arm A (combination chemotherapy)
Arm B (combination chemotherapy, topotecan hydrochloride)
description
Correlative studies
name
Laboratory Biomarker Analysis
type
OTHER
arm Group Labels
Arm B (combination chemotherapy, topotecan hydrochloride)
description
Given IV
name
Topotecan Hydrochloride
other Names
Evotopin
Hycamptamine
Hycamtin
Nogitecan Hydrochloride
Potactasol
SKF S 104864 A
SKF S-104864-A
SKF S104864A
Topotec
Topotecan HCl
topotecan hydrochloride (oral)
type
DRUG
arm Group Labels
Arm A (combination chemotherapy)
Arm B (combination chemotherapy, topotecan hydrochloride)
description
Given IV
name
Vincristine Sulfate
other Names
Kyocristine
Leurocristine Sulfate
Leurocristine, sulfate
Oncovin
Vincasar
Vincosid
Vincrex
Vincristine, sulfate
type
DRUG

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 642
type: ACTUAL

Registered outcome plans (not posted results)

other Outcomes

description
Time from study enrollment to death or last patient contact.
measure
Overall Survival
time Frame
5 years after enrollment
description
Percent of viable tumor in the resected tumor specimen after the patient receives 2 cycles of induction chemotherapy. Patients will be classified into groups according to: (1) good risk - less than 10% viable tumor in the resection specimen; and (2) standard risk - 10% or more viable tumor in the resection specimen. Patients who receive radiation therapy to the primary tumor prior to tumor resection or whose tumor is resected prior to the start of systemic therapy are not evaluable for this outcome measure.
measure
Histological Response, in Terms of Event Free Survival After Local Control in Patients Who Received Local Control Therapy
time Frame
At the end of INDUCTION THERAPY (84 days)
description
Patients will be classified into two groups according to SUVmax as: (1) study population median or greater; and (2) less than the study population median.
measure
SUVmax as Determined by Positron Emission Tomography (PET)-Determined Response at Enrollment
time Frame
At study enrollment
description
Patients will be classified into two groups according to SUVmax as: (1) study population median or greater; and (2) less than the study population median. Patients who receive radiation therapy to the primary tumor prior to the completion of 2 cycles of induction or who do not receive 2 cycles of induction chemotherapy are not evaluable for this outcome measure.
measure
SUVmax as Determined by Positron Emission Tomography (PET)-Determined Response After Induction
time Frame
At the end of INDUCTION THERAPY (84 days)
description
Patients will be classified into two groups: (1) tumor volume 200 ml or greater and (2) tumor volume less than 200 ml.
measure
Tumor Volume in Milliliters (ml) at Enrollment
time Frame
At study enrollment
description
Patients will be classified into two groups: (1) complete resolution of soft tissue mass; and (2) soft tissue mass present after induction chemotherapy. Patients who receive radiation therapy to the primary tumor prior to the completion of 2 cycles of induction, who do not receive 2 cycles of induction chemotherapy or who do not have soft tissue involvement detected at enrollment or at any time prior to the end of induction chemotherapy are not evaluable for this outcome measure.
measure
Radiological Response of Soft Tissue Component of Mass by Radiological Evaluation at the End of Induction Chemotherapy
time Frame
At the end of INDUCTION THERAPY (84 days)
description
Patients will be categorized into the following groups: (1) surgery as the local control modality; (2) radiation therapy as the local control modality; (3) surgery and radiation therapy as the local control modality; and (4) no local control modality administered to the primary tumor site. Patients who do not complete induction chemotherapy will not be evaluable for this outcome measure.
measure
Type of Local Control Modality Used for Removal of Primary Tumor Site at Any Time up to the End of the First 6 Cycles of Consolidation Chemotherapy
time Frame
126 days after enrollment
description
Any National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 ME of grade 2 or greater or ME of any grade where surgery is required to treat a complication of local therapy. Patients who do not complete induction chemotherapy or do not have any local control modality administered to the primary tumor site will not be evaluable for this outcome measure.
measure
Occurrence of Grade 2 or Higher Musculoskeletal Event (ME), or Surgery Required to Treat a Complication of Local Therapy
time Frame
132 days after enrollment
description
Patients will be categorized into the following groups: (1) tumor present at the margin of resection; and (2) no tumor present at the margin of resection. Patients who are not classified as having surgery as the only local control modality will not be evaluable for this outcome measure.
measure
Presence of Tumor at the Margin of Resection for Patients Who Have Surgery as the Only Local Control Modality
time Frame
126 days after enrollment

primary Outcomes

description
Estimated 5-year EFS where EFS is calculated as the time from study enrollment to disease progression, disease relapse, occurrence of a second malignant neoplasm, death from any cause or last follow-up whichever occurs first. Kaplan-Meier method is used for estimation. Patients without an event are censored at last contact.
measure
Event-Free Survival
time Frame
5 years after enrollment

Full study description

brief Summary: This trial examined the outcome benefit to patients of adding a new chemotherapy drug combination to the established treatment approach for patients with extracranial Ewing sarcoma, that had not spread from the primary site to other places in the body. The trial randomly assigned patients at the time of study entry to receive established standard treatment with the following 5-drugs: vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, ifosfamide and etoposide. The outcome for patients receiving the standard 5-drug combination was compared to the outcome for patients who received the same 5-drugs with an additional drug, topotecan hydrochloride delivered in a novel combination with vincristine sulfate and cyclophosphamide.
detailed Description: 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 interval-compressed chemotherapy backbone on event-free and overall survival of children and young adults with Ewing sarcoma. CORRELATIVE SCIENCE 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 fluorodeoxyglucose (18F-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 A: INDUCTION THERAPY: Patients receive vincristine sulfate intravenously (IV) on day 1 in weeks 1, 2, 5, 6, 9, and 10; doxorubicin hydrochloride IV over 1-15 minutes (or as per institutional policies up to 60-minutes) 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. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 1 and 9. ARM B: 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 15-30 minutes on days 1-5 in weeks 1 and 9, and over 30-60 minutes on day 1 of weeks 5 and 11; ifosfamide and etoposide as in arm A; 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 over 30-60 minutes 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 received Dexrazoxane with doxorubicin hydrochloride in weeks 13 and 19. Patients could undergo surgery alone after recovery from week 12 chemotherapy if the primary tumor could be completely resected with negative margins and with reasonable functional result. Patients with inadequate margins after surgery were to receive radiotherapy in addition. Patients with 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 were recommended to receive radiation and not surgery. Radiotherapy was to be administered during weeks 1-7 of consolidation therapy or after recovery from surgery for patients with positive margins. Patients who received planned pre-operative radiation and had positive surgical margins were to 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.

Source references

avail Ipds

comment
Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive
type
Individual Participant Data Set
url
https://nctn-data-archive.nci.nih.gov/

references

citation
Leavey PJ, Laack NN, Krailo MD, Buxton A, Randall RL, DuBois SG, Reed DR, Grier HE, Hawkins DS, Pawel B, Nadel H, Womer RB, Letson GD, Bernstein M, Brown K, Maciej A, Chuba P, Ahmed AA, Indelicato DJ, Wang D, Marina N, Gorlick R, Janeway KA, Mascarenhas L. Phase III Trial Adding Vincristine-Topotecan-Cyclophosphamide to the Initial Treatment of Patients With Nonmetastatic Ewing Sarcoma: A Children's Oncology Group Report. J Clin Oncol. 2021 Dec 20;39(36):4029-4038. doi: 10.1200/JCO.21.00358. Epub 2021 Oct 15.
pmid
34652968
type
DERIVED