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


Phase 3
N/A
50 Years
Open (Enrolling)
Both
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

Thank you

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.


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)

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Event-free survival (EFS)

Outcome 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 10 years

Safety Issue:

No

Principal Investigator

Mason Bond

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group

Authority:

United States: Institutional Review Board

Study ID:

AEWS1031

NCT ID:

NCT01231906

Start Date:

November 2010

Completion Date:

Related Keywords:

  • 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
  • Kidney Neoplasms
  • Neuroectodermal Tumors
  • Neuroectodermal Tumors, Primitive
  • Sarcoma, Ewing's
  • Neuroectodermal Tumors, Primitive, Peripheral
  • Sarcoma
  • Osteosarcoma

Name

Location

Baylor College of MedicineHouston, Texas  77030
Johns Hopkins UniversityBaltimore, Maryland  21205
Cleveland Clinic FoundationCleveland, Ohio  44195
Roswell Park Cancer InstituteBuffalo, New York  14263
Mayo ClinicRochester, Minnesota  55905
University of Iowa Hospitals and ClinicsIowa City, Iowa  52242
University of Mississippi Medical CenterJackson, Mississippi  39216-4505
Washington University School of MedicineSaint Louis, Missouri  63110
Fox Chase Cancer CenterPhiladelphia, Pennsylvania  19111
Medical University of South CarolinaCharleston, South Carolina  29425-0721
Tripler Army Medical CenterHonolulu, Hawaii  96859-5000
Hurley Medical CenterFlint, Michigan  48503
Rhode Island HospitalProvidence, Rhode Island  02903
Medical City Dallas HospitalDallas, Texas  75230
University of Texas Health Science Center at San AntonioSan Antonio, Texas  78284-7811
Midwest Children's Cancer CenterMilwaukee, Wisconsin  53226
Sinai Hospital of BaltimoreBaltimore, Maryland  21225
Bronson Methodist HospitalKalamazoo, Michigan  49007
Geisinger Medical CenterDanville, Pennsylvania  17822-0001
Vanderbilt-Ingram Cancer CenterNashville, Tennessee  37232-6838
Loyola University Medical CenterMaywood, Illinois  60153
Massachusetts General Hospital Cancer CenterBoston, Massachusetts  02114
Morristown Memorial HospitalMorristown, New Jersey  07962-1956
Marshfield ClinicMarshfield, Wisconsin  54449
Loma Linda University Medical CenterLoma Linda, California  92354
Baptist Hospital of MiamiMiami, Florida  33176-2197
Newark Beth Israel Medical CenterNewark, New Jersey  07112
New York Medical CollegeValhalla, New York  10595
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
Cedars-Sinai Medical CenterLos Angeles, California  90048
University of Arkansas for Medical SciencesLittle Rock, Arkansas  72205
Brooke Army Medical CenterFort Sam Houston, Texas  78234-6200
Madigan Army Medical CenterTacoma, Washington  98431-5048
Eastern Maine Medical CenterBangor, Maine  04401
University of Nebraska Medical CenterOmaha, Nebraska  68198-3330
Hackensack University Medical CenterHackensack, New Jersey  07601
Children's Hospital Los AngelesLos Angeles, California  90027-0700
Children's National Medical CenterWashington, District of Columbia  20010-2970
All Children's HospitalSt. Petersburg, Florida  33701
Advocate Hope Children's HospitalOak Lawn, Illinois  60453
Saint Jude Midwest AffiliatePeoria, Illinois  61637
Ochsner Clinic FoundationNew Orleans, Louisiana  70121
Carolinas Medical CenterCharlotte, North Carolina  28232-2861
University of Oklahoma Health Sciences CenterOklahoma City, Oklahoma  73104
Legacy Emanuel Hospital and Health CenterPortland, Oregon  97227
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
Driscoll Children's HospitalCorpus Christi, Texas  78466
Scott and White Memorial HospitalTemple, Texas  76508
Inova Fairfax HospitalFalls Church, Virginia  22042-3300
Southern California Permanente Medical GroupDowney, California  90242
Children's Hospital Central CaliforniaMadera, California  93638-8762
Kosair Children's HospitalLouisville, Kentucky  40202-3830
Children's Hospital Medical Center of AkronAkron, Ohio  44308
University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001
Overlook HospitalSummit, New Jersey  07902-0220
Mount Sinai Medical CenterNew York, New York  10029
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Primary Children's Medical CenterSalt Lake City, Utah  84113-1100
Montefiore Medical CenterBronx, New York  10467-2490
Saint Peter's University HospitalNew Brunswick, New Jersey  08901-1780
Rady Children's Hospital - San DiegoSan Diego, California  92123-4282
Children's Hospitals and Clinics of Minnesota - MinneapolisMinneapolis, Minnesota  55404
University of New Mexico Cancer CenterAlbuquerque, New Mexico  87131-5636
Nationwide Children's HospitalColumbus, Ohio  43205-2696
Children's Hospital of Pittsburgh of UPMCPittsburgh, Pennsylvania  15213
Dell Children's Medical Center of Central TexasAustin, Texas  78723
Children's Hospital and Research Center at OaklandOakland, California  94609-1809
Mary Bridge Children's Hospital and Health CenterTacoma, Washington  98415-0299
Lehigh Valley Hospital - MuhlenbergBethlehem, Pennsylvania  18017
Presbyterian HospitalCharlotte, North Carolina  28233-3549
Memorial Medical CenterSpringfield, Illinois  62781
Lee Memorial Health SystemFort Myers, Florida  33902
University of VirginiaCharlottesville, Virginia  22908
University of Alabama at BirminghamBirmingham, Alabama  35294-3300
Children's Hospital of AlabamaBirmingham, Alabama  35233
Connecticut Children's Medical CenterHartford, Connecticut  06106
University of North CarolinaChapel Hill, North Carolina  27599
Duke University Medical CenterDurham, North Carolina  27710
University of FloridaGainesville, Florida  32610-0277
University of RochesterRochester, New York  14642
Nemours Children's Clinic - PensacolaPensacola, Florida  32504
Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, Michigan  49503
Yale UniversityNew Haven, Connecticut  06520
Wayne State UniversityDetroit, Michigan  48202
Mercy Children's HospitalToledo, Ohio  43608
Legacy Emanuel Children's HospitalPortland, Oregon  97227
BI-LO Charities Children's Cancer CenterGreenville, South Carolina  29605
University of Arizona Health Sciences CenterTucson, Arizona  85724
University of Massachusetts Medical SchoolWorcester, Massachusetts  01605
Dartmouth Hitchcock Medical CenterLebanon, New Hampshire  03756
Indiana University Medical CenterIndianapolis, Indiana  46202
University Of VermontBurlington,, Vermont  05403
Albany Medical CenterAlbany, New York  12208
University of Texas Southwestern Medical CenterDallas, Texas  
University of KentuckyLexington, Kentucky  40536-0098
UC Davis Comprehensive Cancer CenterSacramento, California  95817
Oregon Health and Science UniversityPortland, Oregon  97201
Virginia Commonwealth UniversityRichmond, Virginia  
David Geffen School of Medicine at UCLALos Angeles, California  90095
Florida HospitalOrlando, Florida  32803
Memorial Health University Medical CenterSavannah, Georgia  31404
University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470
M D Anderson Cancer CenterHouston, Texas  77030
Seattle Children's HospitalSeattle, Washington  98105
Froedtert and the Medical College of WisconsinMilwaukee, Wisconsin  53226
Wake Forest University Health SciencesWinston-Salem, North Carolina  27157
Childrens Memorial HospitalChicago, Illinois  60614
Kaiser Permanente-OaklandOakland, California  94611
Lombardi Comprehensive Cancer Center at Georgetown UniversityWashington, District of Columbia  20057
M D Anderson Cancer Center- OrlandoOrlando, Florida  32806
University of HawaiiHonolulu, Hawaii  96813
Saint Luke's Mountain States Tumor InstituteBoise, Idaho  83712
Saint Vincent Hospital and Health ServicesIndianapolis, Indiana  46260
Mercy Medical Center-Sioux CitySioux City, Iowa  51104
Saint Luke's Regional Medical CenterSioux City, Iowa  51104
Saint John Hospital and Medical CenterDetroit, Michigan  48236
Michigan State University - Breslin Cancer CenterEast Lansing, Michigan  48824-1313
Saint John's Mercy Medical CenterSaint Louis, Missouri  63141
Nevada Cancer Research Foundation CCOPLas Vegas, Nevada  89106
Saint Barnabas Medical CenterLivingston, New Jersey  07039
New York University Langone Medical CenterNew York, New York  10016
Columbia University Medical CenterNew York, New York  10032
State University of New York Upstate Medical UniversitySyracuse, New York  13210
Mission Hospitals IncAsheville, North Carolina  28801
Natalie W Bryant Cancer CenterTulsa, Oklahoma  74136
University of California Medical Center At Irvine-Orange CampusOrange, California  92868
University of South AlabamaMobile, Alabama  36693
University of IllinoisChicago, Illinois  60612
Stony Brook University Medical CenterStony Brook, New York  11794
Cook Children's Medical CenterFort Worth, Texas  76104
Memorial Healthcare System - Joe DiMaggio Children's HospitalHollywood, Florida  33021
West Virginia University CharlestonCharleston, West Virginia  25304
The Children's Medical Center of DaytonDayton, Ohio  45404
Advocate Lutheran General HospitalPark Ridge, Illinois  60068
University of Miami Miller School of Medicine-Sylvester Cancer CenterMiami, Florida  33136
University of Minnesota Medical Center-FairviewMinneapolis, Minnesota  55455
C S Mott Children's HospitalAnn Arbor, Michigan  48109
Southern Illinois UniversitySpringfield, Illinois  62702
University Of Missouri-ColumbiaColumbia, Missouri  65212
Siouxland Hematology Oncology AssociatesSioux City, Iowa  51101
Riley Hospital for ChildrenIndianapolis, Indiana  46202
UMDNJ - Robert Wood Johnson University HospitalNew Brunswick, New Jersey  08903
Phoenix Childrens HospitalPhoenix, Arizona  85016
Miller Children's HospitalLong Beach, California  90806
Childrens Hospital of Orange CountyOrange, California  92868-3874
Alfred I duPont Hospital for ChildrenWilmington, Delaware  19803
Nemours Children's Clinic - JacksonvilleJacksonville, Florida  32207-8426
Nemours Childrens Clinic - OrlandoOrlando, Florida  32806
Saint Joseph Children's Hospital of TampaTampa, Florida  33607
Children's Healthcare of Atlanta - EglestonAtlanta, Georgia  30322
The Childrens Mercy HospitalKansas City, Missouri  64108
Rainbow Babies and Childrens HospitalCleveland, Ohio  44106
Penn State Hershey Children's HospitalHershey, Pennsylvania  17033
Palmetto Health RichlandColumbia, South Carolina  29203
East Tennessee Childrens HospitalKnoxville, Tennessee  37916
Children's Hospital and Medical Center of OmahaOmaha, Nebraska  68114
Saint Joseph's Regional Medical CenterPaterson, New Jersey  07503
Childrens Hospital-King's DaughtersNorfolk, Virginia  23507
Sanford Medical Center-FargoFargo, North Dakota  58122
Children's Hospital ColoradoAurora, Colorado  80045
Lucile Packard Children's Hospital Stanford UniversityPalo Alto, California  94304
University of California San Francisco Medical Center-ParnassusSan Francisco, California  94143
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical CenterDenver, Colorado  80218
Raymond Blank Children's HospitalDes Moines, Iowa  50309
Children's Hospital-Main CampusNew Orleans, Louisiana  70118
The Toledo Hospital/Toledo Children's HospitalToledo, Ohio  43606
Saint Christopher's Hospital for ChildrenPhiladelphia, Pennsylvania  19134
Greenville Cancer Treatment CenterGreenville, South Carolina  29605
Sanford USD Medical Center - Sioux FallsSioux Falls, South Dakota  57117-5134
T C Thompson Children's HospitalChattanooga, Tennessee  37403
Providence Sacred Heart Medical Center and Children's HospitalSpokane, Washington  99204
Broward Health Medical CenterFort Lauderdale, Florida  33316
The Steven and Alexandra Cohen Children's Medical Center of New YorkNew Hyde Park, New York  11040
Mattel Children's Hospital UCLALos Angeles, California  90095
Georgia Regents UniversityAugusta, Georgia  30912
Saint John's HospitalSpringfield, Illinois  62702