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Efficacy of Carboplatin Administered Concomitantly With Radiation and Isotretinoin as a Pro-Apoptotic Agent in Other Than Average Risk Medulloblastoma/PNET Patients


Phase 3
3 Years
21 Years
Open (Enrolling)
Both
Untreated Childhood Medulloblastoma, Untreated Childhood Pineoblastoma, Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor

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Trial Information

Efficacy of Carboplatin Administered Concomitantly With Radiation and Isotretinoin as a Pro-Apoptotic Agent in Other Than Average Risk Medulloblastoma/PNET Patients


PRIMARY OBJECTIVES:

I. Determine whether carboplatin radiosensitization increases long-term, event-free survival
of pediatric patients with newly diagnosed, previously untreated, high-risk medulloblastoma
or supratentorial primitive neuroectodermal tumors.

II. Determine whether isotretinoin increases long-term, event-free survival of these
patients.

SECONDARY OBJECTIVES:

I. Compare residual disease response to radiotherapy alone versus radiotherapy and
carboplatin in these patients.

II. Identify molecular prognostic indicators suitable for patient stratification in future
trials.

OUTLINE: This is a randomized, open-label, factorial-designed, multicenter study. Patients
are stratified according to location of disease and dissemination status (M0 medulloblastoma
with > 1.5 cm² residual tumor vs M+ medulloblastoma vs M0 supratentorial primitive
neuroectodermal tumor [SPNET] with < 1.5 cm² residual tumor vs M0 SPNET with > 1.5 cm²
residual tumor vs M+ SPNET vs M0 diffusely anaplastic medulloblastoma). Patients are
randomized to 1 of 4 treatment arms.

ARM I (standard chemoradiotherapy and standard maintenance therapy):

CHEMOTHERAPY: Patients undergo radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26,
29-33, and 36-40 and receive vincristine IV over 1 minute on days 1, 8, 15, 22, 29, and 36.
Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy.

MAINTENANCE THERAPY: Patients receive cisplatin IV over 6 hours on day 1, vincristine IV
over 1 minute on days 1 and 8, and cyclophosphamide IV over 1 hour on days 2 and 3. Patients
also receive filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 4 and continuing
until blood counts recover (at least 10 days).

Treatment repeats every 28 days for a total of 6 courses in the absence of disease
progression or unacceptable toxicity.

ARM II (standard chemoradiotherapy plus carboplatin and standard maintenance therapy):

CHEMORADIOTHERAPY: Patients receive carboplatin IV over 15 minutes once daily on days 1-5,
8-12, 15-19, 22-26, 29-33, and 36-40 and undergo radiotherapy and receive vincristine as in
arm I. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance
therapy.

MAINTENANCE THERAPY: Patients receive maintenance therapy as in arm I.

ARM III (standard chemoradiotherapy, standard maintenance therapy plus isotretinoin, and
continuation therapy with isotretinoin):

CHEMORADIOTHERAPY: Patients undergo chemoradiotherapy as in arm I. Six weeks after
completion of chemoradiotherapy, patients proceed to maintenance therapy.

MAINTENANCE THERAPY: Patients receive oral isotretinoin twice daily on day 1 and days 16-28
and cisplatin, vincristine, cyclophosphamide, and G-CSF as in arm I maintenance therapy.

Treatment repeats every 28 days for a total of 6 courses in the absence of disease
progression or unacceptable toxicity.

Patients then proceed to continuation therapy.

CONTINUATION THERAPY: Patients receive oral isotretinoin twice daily on days 15-28.

Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or
unacceptable toxicity.

ARM IV (standard chemoradiotherapy plus carboplatin, standard maintenance therapy plus
isotretinoin, and continuation therapy with isotretinoin):

CHEMORADIOTHERAPY: Patients undergo chemoradiotherapy as in arm II. Six weeks after
completion of chemoradiotherapy, patients proceed to maintenance therapy.

MAINTENANCE THERAPY: Patients receive maintenance therapy as in arm III. Patients then
proceed to continuation therapy.

CONTINUATION THERAPY: Patients receive continuation therapy as in arm III.

After completion of study treatment, patients are followed up periodically for up to 10
years.


Inclusion Criteria:



- Histologically confirmed diagnosis of medulloblastoma or supratentorial primitive
neuroectodermal tumor (PNET)

- Newly diagnosed disease

- Previously untreated disease

- Meets 1 of the following criteria:

- M0 medulloblastoma with > 1.5 cm² residual tumor

- M+ medulloblastoma

- M0 or M+ supratentorial PNET (including pineoblastoma)

- Diffusely anaplastic medulloblastoma with any M-stage or residual tumor

- Must have undergone stereotactic biopsy or attempted neurosurgical resection of the
tumor within the past 31 days

- The following procedures are required:

- Pre-operative MRI of the brain with and without contrast

- Post-operative (preferably within 72 hours after surgery) MRI of the brain with
and without contrast**

- Spinal MRI with and without contrast within 10 days before surgery or 28 days
after surgery

- Lumbar cerebrospinal fluid (CSF) cytological examination obtained
pre-operatively or within 31 days after surgery***

- No M4 disease

- Karnofsky performance status (PS) 30-100% (for patients > 16 years of age) OR Lansky
PS 30-100% (for patients ≤ 16 years of age)

- Life expectancy > 8 weeks

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use 2 effective forms of contraception

- Creatinine normal OR creatinine clearance or radioisotope glomerular filtration rate
≥ 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 to < 2 years of age)

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

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

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

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

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

- Bilirubin < 1.5 times upper limit of normal (ULN)

- AST and ALT < 2.5 times ULN (5 times ULN for patients on antiseizure medications)

- Absolute neutrophil count ≥ 1,000/mm³

- Platelet count ≥ 100,000/mm³ (transfusions not allowed)

- Hemoglobin ≥ 8 g/dL (transfusions allowed)

- No concurrent corticosteroids as an antiemetic during chemotherapy

- No prior chemotherapy or radiotherapy

- No other concurrent experimental therapy

- No concurrent isotretinoin for acne treatment

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) percentage

Outcome Description:

Based on stratified logrank test, with stratification on all randomization stratifiers as well as on the factorial treatment group not the subject of the analysis. Good approximation to the power of these test are obtained using the methods of Sposto and Sather. Monitoring for differences in long-term EFS will be based on the same one-sided likelihood ratio test

Outcome Time Frame:

Time from disease progression or recurrence, occurrence of a second malignant neoplasm, or death from any cause, assessed up to 5 years

Safety Issue:

No

Principal Investigator

James Olson

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group

Authority:

United States: Institutional Review Board

Study ID:

ACNS0332

NCT ID:

NCT00392327

Start Date:

March 2007

Completion Date:

Related Keywords:

  • Untreated Childhood Medulloblastoma
  • Untreated Childhood Pineoblastoma
  • Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor
  • Medulloblastoma
  • Pinealoma
  • Neuroectodermal Tumors
  • Neuroectodermal Tumors, Primitive

Name

Location

Baylor College of MedicineHouston, Texas  77030
Johns Hopkins UniversityBaltimore, Maryland  21205
Memorial Sloan Kettering Cancer CenterNew York, New York  10021
Cleveland Clinic FoundationCleveland, Ohio  44195
Roswell Park Cancer InstituteBuffalo, New York  14263
Mayo ClinicRochester, Minnesota  55905
Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
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
Medical University of South CarolinaCharleston, South Carolina  29425-0721
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
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
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
Eastern Maine Medical CenterBangor, Maine  04401
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
Carolinas Medical CenterCharlotte, North Carolina  28232-2861
University of Oklahoma Health Sciences CenterOklahoma City, Oklahoma  73104
Legacy Emanuel Hospital and Health CenterPortland, Oregon  97227
Driscoll Children's HospitalCorpus Christi, Texas  78466
Scott and White Memorial HospitalTemple, Texas  76508
Inova Fairfax HospitalFalls Church, Virginia  22042-3300
Children's Hospital Central CaliforniaMadera, California  93638-8762
Kosair Children's HospitalLouisville, Kentucky  40202-3830
Children's Hospital Medical Center of AkronAkron, Ohio  44308
Covenant Children's HospitalLubbock, Texas  79410
Overlook HospitalSummit, New Jersey  07902-0220
Winthrop University HospitalMineola, New York  11501
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Methodist Children's Hospital of South TexasSan Antonio, Texas  78229-3993
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
Lee Memorial Health SystemFort Myers, Florida  33902
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 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
Dartmouth Hitchcock Medical CenterLebanon, New Hampshire  03756
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
Tulane University Health Sciences CenterNew Orleans, Louisiana  70112
Virginia Commonwealth UniversityRichmond, Virginia  
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
Wake Forest University Health SciencesWinston-Salem, North Carolina  27157
Childrens Memorial HospitalChicago, Illinois  60614
Kaiser Permanente-OaklandOakland, California  94611
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
Saint John Hospital and Medical CenterDetroit, Michigan  48236
Michigan State University - Breslin Cancer CenterEast Lansing, Michigan  48824-1313
Kalamazoo Center for Medical StudiesKalamazoo, Michigan  49008
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
Saint Vincent HospitalGreen Bay, Wisconsin  54301
University of Maryland Greenebaum Cancer CenterBaltimore, Maryland  21201
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
Children's Oncology GroupArcadia, California  91006-3776
C S Mott Children's HospitalAnn Arbor, Michigan  48109
Southern Illinois UniversitySpringfield, Illinois  62702
Walter Reed National Military Medical CenterBethesda, Maryland  20889
Riley Hospital for ChildrenIndianapolis, Indiana  46202
Cardinal Glennon Children's Medical CenterSt. Louis, Missouri  63104
UMDNJ - Robert Wood Johnson University HospitalNew Brunswick, New Jersey  08903
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
Saint Mary's HospitalWest Palm Beach, Florida  33407
Children's Hospital and Medical Center of OmahaOmaha, Nebraska  68114
Saint Joseph's Regional Medical CenterPaterson, New Jersey  07503
Texas Tech University Health Science Center-AmarilloAmarillo, Texas  79106
Childrens Hospital-King's DaughtersNorfolk, Virginia  23507
Sanford Medical Center-FargoFargo, North Dakota  58122
Floating Hospital for Children at Tufts Medical CenterBoston, Massachusetts  02111
Lucile Packard Children's Hospital Stanford UniversityPalo Alto, California  94304
University of California San Francisco Medical Center-ParnassusSan Francisco, California  94143
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
Carilion Clinic Children's HospitalRoanoke, Virginia  24014
Providence Sacred Heart Medical Center and Children's HospitalSpokane, Washington  99204