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A Phase III Randomized Trial for the Treatment of Newly Diagnosed Supratentorial PNET and High Risk Medulloblastoma in Children <36 Months Old With Intensive Induction Chemotherapy With Methotrexate Followed by Consolidation With Stem Cell Rescue Versus the Same Therapy Without Methotrexate


Phase 3
N/A
2 Years
Open (Enrolling)
Both
Untreated Childhood Medulloblastoma, Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor

Thank you

Trial Information

A Phase III Randomized Trial for the Treatment of Newly Diagnosed Supratentorial PNET and High Risk Medulloblastoma in Children <36 Months Old With Intensive Induction Chemotherapy With Methotrexate Followed by Consolidation With Stem Cell Rescue Versus the Same Therapy Without Methotrexate


PRIMARY OBJECTIVES:

I. Determine if treatment of pediatric patients with newly diagnosed supratentorial
primitive neuroectodermal CNS tumors or high-risk medulloblastoma with intensive induction
chemotherapy comprising vincristine, etoposide, cyclophosphamide, and cisplatin in
combination with high-dose methotrexate and leucovorin calcium followed by consolidation
chemotherapy comprising carboplatin and thiotepa and peripheral blood stem cell rescue
results in a higher complete response rate then in patients treated with the same regimen
without high-dose methotrexate and leucovorin calcium.

SECONDARY OBJECTIVES:

I. Determine whether biologic characterization of these tumors will refine therapeutic
stratification separating atypical teratoid rhabdoid tumors from primitive neuroectodermal
tumors (PNETs) and possibly identifying other markers of value for stratification within the
group of PNETs.

II. Compare event-free survival and patterns of failure in patients treated with these
regimens.

III. Compare the acute, chronic, and late effects of these regimens, particularly in terms
of tolerance to the same consolidation regimen after treatment with 2 different induction
regimens, in these patients.

IV. Compare the gastrointestinal and nutritional toxicities of these regimens in these
patients.

V. Compare the quality of life outcomes in patients treated with these regimens.

VI. Compare the neuropsychological effects of these regimens in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to
diagnosis* (M0 medulloblastoma with ≥ 1.5 cm² residual tumor vs M1 medulloblastoma [positive
lumbar CSF cytology] vs M2, M3, or M4 medulloblastoma vs supratentorial PNET [any M-stage]
vs M0 medulloblastoma < 8 months without residual disease or with < 1.5 cm² radiographic
measurable residual tumor vs anaplastic M0 medulloblastoma without residual disease or with
< 1.5 cm² radiographic measurable residual vs classic M0 (nondesmoplastic) medulloblastoma
with < 1.5 cm² radiographic measurable residual tumor).

NOTE: *All diagnoses are for children < 36 months unless otherwise noted.

INDUCTION THERAPY: Patients are randomized to 1 of 2 induction treatment arms.

ARM I: Patients receive vincristine IV on days 1, 8, and 15; etoposide IV over 1 hour on
days 1-3; cyclophosphamide IV over 1 hour on days 1 and 2; cisplatin IV over 6 hours on day
3; and filgrastim (G-CSF) IV or subcutaneously (SC) beginning on day 4 and continuing until
blood counts recover. Treatment repeats every 3 weeks for 3 courses in the absence of
disease progression or unacceptable toxicity.

ARM II: Patients receive vincristine IV on days 1, 8, and 15; high-dose methotrexate IV over
4 hours on day 1; and leucovorin calcium IV or orally every 6 hours beginning on day 2 and
continuing until methotrexate levels are in a safe range. Once methotrexate levels are in a
safe range, patients then receive etoposide IV over 1 hour on approximately days 4, 5, and
6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6
hours on approximately day 6. Patients also receive G-CSF IV or SC beginning 24 hours after
the completion of chemotherapy and continuing until blood counts recover. Treatment repeats
every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

In both arms, patients with stable disease or partial response after induction therapy
proceed to second-look surgery followed by consolidation therapy. Patients with a complete
response after induction therapy proceed directly to consolidation therapy.

CONSOLIDATION THERAPY: Beginning no more than 6 weeks after completion of induction therapy,
patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa
IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 54 and continuing until
blood counts recover. Patients also receive autologous peripheral blood stem cells (PBSC) IV
on day 4. Treatment repeats every 3 weeks for 3 courses in the absence of disease
progression or unacceptable toxicity.

Blood and tissue samples are collected at baseline for correlative studies, including gene
expression profiling, biological marker analysis (i.e., cMyc, ErbB2/ErbB4), comparative
genome analysis, and mutation analysis.

After completion of study therapy, patients are followed up periodically for 4 years and
then annually thereafter.


Inclusion Criteria:



- Diagnosis of 1 of the following:

- High-risk medulloblastoma defined by any of the following:

- Residual disease > 1.5 cm²

- Lumbar cerebral spinal fluid cytology positive for tumor cells by analysis
of fluid collected either before definitive surgery or ≥ 10 days after
definitive surgery unless contraindicated

- M0 disease in children < 8 months of age at diagnosis

- M2 or M3 metastatic disease by MRI

- M4 disease

- Supratentorial primitive neuroectodermal tumor (PNET)(any M-stage)

- Anaplastic medulloblastoma regardless of M-stage or residual tumor

- M0 classic, non-desmoplastic medulloblastoma (R1) with radiographically
measurable residual disease < 1.5 cm^2

- MRI evidence of spinal disease

- Tumor must be negative for INI1 gene

- Has undergone definitive surgery within the past 31 days

- No atypical teratoid rhabdoid tumors

- Biological specimens must be available for correlative laboratory studies

- Life expectancy > 8 weeks

- Creatinine clearance or radioisotope glomerular filtration rate ≥ 60 mL/min

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

- AST and ALT < 2 times ULN

- Shortening fraction ≥ 27% by echocardiogram

- Ejection fraction ≥ 47% by radionuclide angiogram

- No evidence of dyspnea at rest

- Pulse oximetry > 94% on room air

- Absolute neutrophil count > 1,000/mm³

- Platelet count > 100,000/mm³ (transfusion independent)

- Hemoglobin > 8 g/dL (RBC transfusions allowed)

- Prior corticosteroids allowed

- No prior radiation therapy or chemotherapy

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Complete response (CR) rate

Outcome Description:

The analysis of response will be based on a one-sided, two-sample test of proportions, with Type I error of 10%. Tumor response criteria are determined by changes in size using all 3 dimensional measurements: width (W), transverse (T), and length (L) measurements.

Outcome Time Frame:

From baseline to up to 4 years

Safety Issue:

No

Principal Investigator

Claire Mazewski

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

ACNS0334

NCT ID:

NCT00336024

Start Date:

August 2007

Completion Date:

Related Keywords:

  • Untreated Childhood Medulloblastoma
  • Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor
  • Medulloblastoma
  • 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
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
Miami Children's HospitalMiami, Florida  33155-4069
All Children's HospitalSt. Petersburg, Florida  33701
Advocate Hope Children's HospitalOak Lawn, Illinois  60453
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
Southern California Permanente Medical GroupDowney, California  90242
Children's Hospital Central CaliforniaMadera, California  93638-8762
Kosair Children's HospitalLouisville, Kentucky  40202-3830
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
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
Mary Bridge Children's Hospital and Health CenterTacoma, Washington  98415-0299
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
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
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 VermontBurlington,, Vermont  05403
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
Seattle Children's HospitalSeattle, Washington  98105
Childrens Memorial HospitalChicago, Illinois  60614
Sutter General HospitalSacramento, California  95816
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
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
New York University Langone Medical CenterNew York, New York  10016
Columbia University Medical CenterNew York, New York  10032
Cook Children's Medical CenterFort Worth, Texas  76104
Memorial Healthcare System - Joe DiMaggio Children's HospitalHollywood, Florida  33021
The Children's Medical Center of DaytonDayton, Ohio  45404
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
Walter Reed National Military Medical CenterBethesda, Maryland  20889
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
Palmetto Health RichlandColumbia, South Carolina  29203
East Tennessee Childrens HospitalKnoxville, Tennessee  37916
Saint Mary's HospitalWest Palm Beach, Florida  33407
Saint Joseph's Regional Medical CenterPaterson, New Jersey  07503
Texas Tech University Health Science Center-AmarilloAmarillo, Texas  79106
Children's Hospital ColoradoAurora, Colorado  80045
Floating Hospital for Children at Tufts Medical CenterBoston, Massachusetts  02111
University of California San Francisco Medical Center-ParnassusSan Francisco, California  94143
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
Providence Sacred Heart Medical Center and Children's HospitalSpokane, Washington  99204
Broward Health Medical CenterFort Lauderdale, Florida  33316