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Treatment of Atypical Teratoid/Rhabdoid Tumors (AT/RT) of the Central Nervous System With Surgery, Intensive Chemotherapy, and 3-D Conformal Radiation


Phase 3
N/A
21 Years
Open (Enrolling)
Both
Childhood Atypical Teratoid/Rhabdoid Tumor

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Trial Information

Treatment of Atypical Teratoid/Rhabdoid Tumors (AT/RT) of the Central Nervous System With Surgery, Intensive Chemotherapy, and 3-D Conformal Radiation


PRIMARY OBJECTIVES:

I. To determine the 6-, 12-, and 24-month event-free survival and overall survival of
children (birth to 21 years of age) with atypical teratoid/rhabdoid CNS tumors (AT/RT),
diagnosed based on histology, immunophenotyping, and modern molecular and
immunohistochemical analysis of INI1, treated with surgery, intensive chemotherapy combined
with stem cell rescue, and radiation therapy.

II. To compare the outcome of very young patients (under 3 years old) on this study whose
histologic diagnosis is AT/RT with infants identified as having AT/RT on POG-9233 and
CCG-9921.

SECONDARY OBJECTIVES:

I. To determine the feasibility and toxicity of the proposed chemotherapy regimen in
combination with radiation therapy.

II. To contribute tumor samples from which biologic and gene expression data can be
developed to yield prognostic indicators and provide direction for future treatment
strategies.

III. To develop a clinical and biologic database on which future studies can be based.

OUTLINE: This is a multicenter study. Patients are stratified according to age and tumor
histology (infants [< 36 months of age] with tumor histology and immunohistochemical [IH]
analysis diagnostic of atypical teratoid/rhabdoid CNS tumors [AT/RT] [stratum 1] vs infants
with INI1 mutation only-based diagnosis [i.e., histology is not consistent with AT/RT] vs
older children [≥ 36 months of age] with tumor histology and IH analysis diagnostic of AT/RT
vs older children with INI1 mutation only-based diagnosis).

INDUCTION THERAPY AND STEM CELL HARVEST: Patients receive vincristine IV on days 1, 8, and
15 and high-dose methotrexate IV over 4 hours on day 1. Beginning 24 hours after the start
of methotrexate, patients receive leucovorin calcium orally or IV every 6 hours until the
serum methotrexate level is < 0.1 micromoles. 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
filgrastim (G-CSF) IV or subcutaneously (SC) once daily beginning on day 7 and continuing
until ANC recovers. When ANC is > 1,000/μL post nadir, patients receive G-CSF twice daily
for stem cell mobilization. Approximately 2-4 days, later peripheral blood stem cells are
harvested once daily, as needed, after each course of induction therapy until a total of 6 x
10^6 CD34+ cells/kg have been collected.

Treatment repeats every 21 days for 2 courses. After completion of induction therapy,
patients are re-evaluated. Patients with progressive disease are removed from study.
Patients with radiographic evidence of residual tumor are encouraged to undergo second-look
surgery prior to proceeding to radiotherapy or consolidation therapy; patients with complete
response, partial response, or stable disease proceed to radiation therapy or consolidation
therapy depending on age, location of the tumor, and initial diagnosis (whether or not
disease is disseminated).**

CONSOLIDATION THERAPY AND STEM CELL RESCUE: Within 2-6 weeks after completion of induction
therapy or radiation therapy, patients begin consolidation therapy. Patients receive
high-dose carboplatin IV over 4 hours and high-dose thiotepa IV over 2 hours on days 1 and 2
and undergo autologous peripheral blood stem cell (PBSC) rescue on approximately day 4.
Patients also receive G-CSF IV or SC once daily beginning 24 hours after stem cell infusion
and continuing until ANC recovers. Treatment with consolidation therapy followed by stem
cell rescue repeats every 28 days for 3 courses in the absence of disease progression or
unacceptable toxicity.

RADIATION THERAPY: *Before (but after induction therapy) or after consolidation therapy and
stem cell rescue, patients undergo 3-dimensional conformal radiotherapy (3D-CRT) to the
brain (and the spine if needed) 5 days a week for 5-6 weeks.

NOTE: *The administration of etoposide, cyclophosphamide, and cisplatin are dependant on the
prior clearance of methotrexate to a level of < 0.1 micromoles.

NOTE: **Patients with localized posterior fossa tumors and ≥ 6 months of age at the end of
induction therapy OR with localized supratentorial tumors at diagnosis and ≥ 12 months of
age at the end of induction therapy proceed to radiotherapy followed by consolidation
therapy; patients with disseminated disease at diagnosis, patients with localized posterior
fossa tumors at diagnosis and < 6 months of age at the end of induction therapy, or patients
with localized supratentorial tumors at diagnosis and < 12 months of age at the end of
induction therapy proceed to consolidation therapy followed by radiotherapy. Previously
collected tumor tissue is analyzed for a mutation in the INI1 rhabdoid tumor suppressor gene
and stained for INI1 antibody.

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


Inclusion Criteria:



- Diagnosis of CNS atypical teratoid/rhabdoid tumor (AT/RT) or tumors that have a
mutation of the INI1 gene (even if the tumor does not have the usual histologic
characteristics of AT/RT)

- Patients with extra neural metastasis (M4) or renal rhabdoid tumors are not
eligible

- Patients with MRI evidence of spinal disease are eligible

- Must have undergone definitive surgery in the past 31 days

- Cranial MRI (with and without gadolinium) must be done pre-operatively

- Post-operatively, cranial MRI (with and without gadolinium) must be done,
preferably within 48 hours of surgery or 10-28days after surgery

- Entire spinal MRI must be obtained either pre-operatively (with gadolinium) or
post-operatively (10-28 days after surgery), prior to study enrollment (with and
without gadolinium)

- Life expectancy > 8 weeks

- ANC > 1,000/μL

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

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

- Creatinine clearance (minimum of 12-24 hour urine collection) or radioisotope GFR ≥
60mL/min

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age

- AST and ALT < 2 times ULN for age

- Shortening fraction of ≥ 27% by echocardiogram OR ejection fraction of ≥ 47% by
radionuclide angiogram

- No evidence of dyspnea at rest

- Pulse oximetry > 94% on room air

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No prior radiotherapy or chemotherapy except for the following:

- Patients enrolled on protocol ACNS0334 whose tumors demonstrate the INI1 gene
mutation are eligible to transfer to this study even if they have received one
course of induction therapy (these patients must be re-consented to treatment
and restaged)

- Prior corticosteroids allowed

Type of Study:

Interventional

Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Event-free survival

Outcome Description:

For statistical evaluation and data reporting, the study cohort can be regarded as comprising four different strata. A one-sided log-rank test with 5% Type I error rate will be used for stratum I. For patients in strata II through IV, Kaplan-Meier estimates of disease control (event-free survival) and overall survival will be computed and compared to that in stratum I. The comparison with Stratum I will be largely descriptive.

Outcome Time Frame:

Time to disease progression, disease relapse, occurrence of a second malignant neoplasm, or death from any cause, assessed up to 4 years

Safety Issue:

No

Principal Investigator

Alyssa Reddy

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

ACNS0333

NCT ID:

NCT00653068

Start Date:

December 2008

Completion Date:

Related Keywords:

  • Childhood Atypical Teratoid/Rhabdoid Tumor
  • Central Nervous System Neoplasms
  • Rhabdoid Tumor

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 Mississippi Medical CenterJackson, Mississippi  39216-4505
Washington University School of MedicineSaint Louis, Missouri  63110
Medical University of South CarolinaCharleston, South Carolina  29425-0721
Rhode Island HospitalProvidence, Rhode Island  02903
University of Texas Health Science Center at San AntonioSan Antonio, Texas  78284-7811
Midwest Children's Cancer CenterMilwaukee, Wisconsin  53226
Loyola University Medical CenterMaywood, Illinois  60153
Morristown Memorial HospitalMorristown, New Jersey  07962-1956
Marshfield ClinicMarshfield, Wisconsin  54449
New York Medical CollegeValhalla, New York  10595
University of Arkansas for Medical SciencesLittle Rock, Arkansas  72205
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
Carolinas Medical CenterCharlotte, North Carolina  28232-2861
University of Oklahoma Health Sciences CenterOklahoma City, Oklahoma  73104
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
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
Nationwide Children's HospitalColumbus, Ohio  43205-2696
Children's Hospital and Research Center at OaklandOakland, California  94609-1809
Lee Memorial Health SystemFort Myers, Florida  33902
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
Wayne State UniversityDetroit, Michigan  48202
Mercy Children's HospitalToledo, Ohio  43608
BI-LO Charities Children's Cancer CenterGreenville, South Carolina  29605
University of KentuckyLexington, Kentucky  40536-0098
University of New MexicoAlbuquerque, New Mexico  87131
Tulane University Health Sciences CenterNew Orleans, Louisiana  70112
Florida HospitalOrlando, Florida  32803
University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470
Seattle Children's HospitalSeattle, Washington  98105
Childrens Memorial HospitalChicago, Illinois  60614
M D Anderson Cancer Center- OrlandoOrlando, Florida  32806
University of HawaiiHonolulu, Hawaii  96813
New York University Langone Medical CenterNew York, New York  10016
Columbia University Medical CenterNew York, New York  10032
Mission Hospitals IncAsheville, North Carolina  28801
Cook Children's Medical CenterFort Worth, Texas  76104
West Virginia University CharlestonCharleston, West Virginia  25304
The Children's Medical Center of DaytonDayton, Ohio  45404
University of Miami Miller School of Medicine-Sylvester Cancer CenterMiami, Florida  33136
Walter Reed National Military Medical CenterBethesda, Maryland  20889
Riley Hospital for ChildrenIndianapolis, Indiana  46202
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
University of California San Francisco Medical Center-ParnassusSan Francisco, California  94143
Children's Hospital-Main CampusNew Orleans, Louisiana  70118