Treatment of Patients With Newly Diagnosed Medulloblastoma, Supratentorial Primitive Neuroectodermal Tumor, or Atypical Teratoid Rhabdoid Tumor

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier:
NCT00085202
First received: June 10, 2004
Last updated: January 9, 2014
Last verified: January 2013
  Purpose

Drugs used in chemotherapy, such as vincristine, cisplatin, and cyclophosphamide, work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining radiation therapy with chemotherapy may kill more tumor cells. Autologous stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy or radiation therapy. It is not yet known which radiation therapy regimen combined with chemotherapy and donor stem cell transplant is more effective in treating medulloblastoma, supratentorial primitive neuroectodermal tumor, or atypical teratoid rhabdoid tumor.

This phase III trial is studying two different regimens of radiation therapy when given together with chemotherapy and autologous stem cell transplant to see how well they work in treating patients with newly diagnosed medulloblastoma, supratentorial primitive neuroectodermal tumor, or atypical teratoid rhabdoid tumor.

PRIMARY OBJECTIVE:

  • To assess the relationship between ERBB2 protein expression in tumors and progression-free survival probability for patients with medulloblastoma.
  • To estimate the frequency of mutations associated with SHH and WNT tumors (as defined by gene expression profiling) via targeted sequencing performed in an independent cohort of WNT and SHH tumors (also defined by gene expression profiling).

Condition Intervention Phase
Brain and Central Nervous System Tumors
Biological: filgrastim
Drug: cisplatin
Drug: cyclophosphamide
Drug: vincristine
Procedure: autologous hematopoietic stem cell transplantation
Radiation: radiation therapy
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Treatment of Patients With Newly Diagnosed Medulloblastoma, Supratentorial Primitive Neuroectodermal Tumor, or Atypical Teratoid Rhabdoid Tumor

Resource links provided by NLM:


Further study details as provided by St. Jude Children's Research Hospital:

Primary Outcome Measures:
  • Progression-Free Survival (PFS) in ERBB2-Negative Tumors Compared to ERBB2-Positive Tumors [ Time Frame: 2 years after tumor cell analysis in 122 participants ] [ Designated as safety issue: No ]
    The relationship between ERBB2 protein expression in tumors and progression-free survival was assessed in 122 participants with a diagnosis of medulloblastoma and with ERBB2 protein assessments. If the ERBB2 value was greater than zero, the ERBB2 was defined as positive for the participant. If the ERBB2 value was zero, the ERBB2 was defined as negative. Progression-free survival was calculated from the date of diagnosis to the date of disease progression/relapse, the date of death, or the date of last contact. The log-rank test was used to compare the PFS distributions of ERBB2 groups.

  • Progression-Free Survival (PFS) Compared Between ERBB2 Assessment and Risk Group. [ Time Frame: 2 years after tumor cell analysis in 122 participants ] [ Designated as safety issue: No ]
    122 participants with a diagnosis of medulloblastoma were grouped by ERBB2 positive/negative assessment and risk group into 4 groups. Progression-free survival was calculated from the date of diagnosis to the date of disease progression/relapse, the date of death, or the date of last contact. The log-rank test was used to compare the PFS distributions of ERBB2 groups.

  • Frequency of Mutations Associated With SHH and WNT Tumors [ Time Frame: within 18 months following completion of accrual ] [ Designated as safety issue: No ]
    To estimate the frequency of mutations associated with SHH and WNT tumors via targeted sequencing


Secondary Outcome Measures:
  • Reading Decoding Composite Scores in the Intervention and Standard of Care Groups [ Time Frame: Measurements will be made at time of randomization, at 3 months from initiation of treatment, and yearly thereafter for 5 years ] [ Designated as safety issue: No ]
    To compare the effects of a computer-based training system specifically targeting language, reading, and learning skills (Fast ForWord, Scientific Learning Corporation) with the current standard of care on reading decoding skills as measured by individual academic testing.

  • Number of Average Risk Patients Whose Treatment Failure Included the Posterior Fossa [ Time Frame: Annually for 6 years post irradiation ] [ Designated as safety issue: No ]
    To monitor for treatment failure in the posterior fossa of patients whose tumor bed receives a reduced volume of radiation.

  • Mean RT Dose to Specified Target Tissue Volume by Rate and Pattern of Failure, e.g. Local Failure, Distant Failure, Etc. [ Time Frame: Once all patients have been followed for 2 years ] [ Designated as safety issue: No ]
    To correlate radiation dosimetry of target and normal tissues with rate and patterns of failure and longitudinal measures of audiometric, endocrine and cognitive effects.


Enrollment: 416
Study Start Date: August 2003
Estimated Study Completion Date: September 2018
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Stratum 1 (high-risk group)

Patients undergo craniospinal radiotherapy once daily 5 days a week for 6 weeks. Six weeks after the completion of radiotherapy, patients receive high-dose chemotherapy followed by autologous stem cell transplantation (SCT) and filgrastim (G-CSF) with post-transplantation vincristine. High-dose chemotherapy and autologous SCT repeat every 4 weeks for 3 additional courses in the absence of unacceptable toxicity.

Interventions: vincristine, cisplatin, cyclophosphamide, autologous hematopoietic stem cell transplantation, filgrastim, radiation therapy

Biological: filgrastim
Given subcutaneously
Other Names:
  • Neupogen(R)
  • G-CSF
Drug: cisplatin
Given IV
Other Name: Platinol-AQ(R)
Drug: cyclophosphamide
Given IV
Other Name: Cytoxan(R)
Drug: vincristine
Given IV
Other Name: Oncovin(R)
Procedure: autologous hematopoietic stem cell transplantation
Patients undergo autologous stem cell transplantation
Other Name: autologous HSCT
Radiation: radiation therapy
Patients undergo craniospinal radiotherapy once daily 5 days a week for 6 weeks.
Other Names:
  • RT
  • Craniospinal radiotherapy
Experimental: Stratum 2 (average-risk group)

Patients undergo craniospinal radiotherapy as in stratum 1, but at a lower dose. Patients receive high-dose chemotherapy, autologous SCT, G-CSF, and post-transplantation vincristine as in stratum 1.

Interventions: vincristine, cisplatin, cyclophosphamide, autologous hematopoietic stem cell transplantation, filgrastim, radiation therapy

Biological: filgrastim
Given subcutaneously
Other Names:
  • Neupogen(R)
  • G-CSF
Drug: cisplatin
Given IV
Other Name: Platinol-AQ(R)
Drug: cyclophosphamide
Given IV
Other Name: Cytoxan(R)
Drug: vincristine
Given IV
Other Name: Oncovin(R)
Procedure: autologous hematopoietic stem cell transplantation
Patients undergo autologous stem cell transplantation
Other Name: autologous HSCT
Radiation: radiation therapy
Patients undergo craniospinal radiotherapy once daily 5 days a week for 6 weeks.
Other Names:
  • RT
  • Craniospinal radiotherapy

Detailed Description:

SECONDARY OBJECTIVES:

  • To compare the effects of a computer-based training system specifically targeting language, reading, and learning skills (Fast ForWord, Scientific Learning Corporation) with the current standard of care on reading decoding skills as measured by individual academic testing.
  • To monitor for treatment failure in the posterior fossa of patients whose tumor bed receives a reduced volume of radiation.
  • To correlate radiation dosimetry of target and normal tissues with rate and patterns of failure and longitudinal measures of audiometric, endocrine and cognitive effects.

EXPLORATORY OBJECTIVES:

  • To estimate the change in neuropsychological performance from the neuropsychology assessment battery (intellect, academic achievement and cognitive ability) and examine the relationship of these changes to risk group, age at diagnosis, and parent measures.
  • To evaluate the differences between neurotoxicity in the average-risk patient group with that in the high-risk group through qMRI, and fMRI.
  • To develop or refine novel models relating impact of medulloblastoma therapy on neurocognitive performance to quantitative and functional neuroimaging measures.

OUTLINE: This is a multicenter study. Patients are stratified according to disease risk (high-risk disease vs average-risk disease).

Patients in both strata undergo peripheral blood stem cell or bone marrow harvest.

  • Stratum 1 (high-risk group):

    • Radiotherapy: Patients undergo craniospinal radiotherapy once daily 5 days a week for 6 weeks.
    • High-dose chemotherapy and autologous stem cell transplantation (SCT): Six weeks after the completion of radiotherapy, patients receive high-dose chemotherapy comprising vincristine IV followed by cisplatin IV over 6 hours on day -4 and cyclophosphamide IV over 1 hour on days -3 and -2. Patients undergo autologous SCT on day 0. Patients receive filgrastim (G-CSF) subcutaneously beginning on day 1 and continuing until blood counts recover. Patients receive vincristine IV on day 6. High-dose chemotherapy and autologous SCT repeat every 4 weeks for 3 additional courses in the absence of unacceptable toxicity.
  • Stratum 2 (average-risk group):

    • Radiotherapy: Patients undergo craniospinal radiotherapy as in stratum 1, but at a lower dose.
    • High-dose chemotherapy and autologous SCT: Patients receive high-dose chemotherapy, autologous SCT, G-CSF, and post-transplantation vincristine as in stratum 1.

Some patients undergo a neuropsychology assessment at baseline, before chemotherapy, and then annually for 5 years.

After completion of study therapy, patients are followed every 3 months until month 30 (2.5 years) after diagnosis and then every 6 months until month 72 (6 years) after diagnosis.

  Eligibility

Ages Eligible for Study:   3 Years to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically confirmed diagnosis of 1 of the following:

    • Medulloblastoma
    • Supratentorial primitive neuroectodermal tumor (PNET)
    • PNET variants (ependymoblastoma, pineoblastoma, CNS neuroblastoma)
    • Atypical teratoid rhabdoid tumor (ATRT)
  • Definitive surgery for CNS tumor within the past 31 days
  • Meets one of the following risk criteria:

    • Average-risk disease

      • Localized disease with no overt evidence of invasion beyond the posterior fossa (or supratentorial compartment for PNET or ATRT) by intraoperative observations of the neurosurgeon AND postoperative CT scan or MRI
      • T4 disease eligible if all of the following are true:

        • Gross total resection determined by intraoperative observations of the neurosurgeon AND postoperative CT scan or MRI
        • Residual tumor or imaging abnormality whose size is < 1.5 cm^2
        • No evidence of CNS or extraneural metastasis by MRI of the spine (with and without contrast agent) or CT-based myelogram AND by cytologic examination of the lumbar cerebral spinal fluid (CSF) 14-28 days after surgery
      • Brain stem invasion allowed in the absence of residual tumor (tumor < 1.5 cm^2 by imaging)
    • High-risk disease meeting one of the following criteria:

      • Metastatic disease within the neuraxis (i.e., evidence of subarachnoid dissemination by imaging and/or cytologic examination of CSF)
      • Presence of residual disease > 1.5 cm^2 at the primary site after surgery

PATIENT CHARACTERISTICS:

Age

  • 3 to 21 at diagnosis

Performance status

  • Lansky 30-100% (< 10 years old)
  • Karnofsky 30-100% (≥ 10 years old) (except for posterior fossa syndrome)

Life expectancy

  • Not specified

Hematopoietic

  • Hemoglobin > 8 g/dL
  • WBC > 2,000/mm^3
  • Absolute neutrophil count > 500/mm^3
  • Platelet count > 50,000/mm^3

Hepatic

  • ALT < 5 times normal
  • Bilirubin < 3.0 mg/dL

Renal

  • Creatinine < 2.0 mg/dL OR
  • Creatinine clearance > 70 mL/min

Other

  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

  • Not specified

Chemotherapy

  • No prior chemotherapy

Endocrine therapy

  • Prior corticosteroid therapy allowed

Radiotherapy

  • No prior radiotherapy

Surgery

  • See Disease Characteristics
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00085202

Locations
United States, North Carolina
Duke Comprehensive Cancer Center
Durham, North Carolina, United States, 27710
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
United States, Texas
Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital
Houston, Texas, United States, 77030-2399
Australia, New South Wales
Sydney Children's Hospital
Randwick, New South Wales, Australia, 2031
Children's Hospital at Westmead
Westmead, New South Wales, Australia, 2145
Australia, Queensland
Royal Children's Hospital
Brisbane, Queensland, Australia, 4029
Australia, Victoria
Royal Children's Hospital
Parkville, Victoria, Australia, 3052
Canada, Ontario
Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8
Sponsors and Collaborators
St. Jude Children's Research Hospital
Investigators
Principal Investigator: Amar Gajjar, MD St. Jude Children's Research Hospital
  More Information

Additional Information:
No publications provided

Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT00085202     History of Changes
Other Study ID Numbers: SJMB03
Study First Received: June 10, 2004
Results First Received: November 4, 2013
Last Updated: January 9, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by St. Jude Children's Research Hospital:
untreated childhood medulloblastoma
untreated childhood supratentorial primitive neuroectodermal tumor
childhood atypical teratoid/rhabdoid tumor
untreated childhood pineoblastoma

Additional relevant MeSH terms:
Central Nervous System Neoplasms
Medulloblastoma
Neoplasms
Nervous System Neoplasms
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Rhabdoid Tumor
Glioma
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Complex and Mixed
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Nervous System Diseases
Cisplatin
Cyclophosphamide
Lenograstim
Vincristine
Adjuvants, Immunologic
Alkylating Agents
Antimitotic Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antineoplastic Agents, Phytogenic
Antirheumatic Agents
Immunologic Factors
Immunosuppressive Agents
Mitosis Modulators

ClinicalTrials.gov processed this record on October 21, 2014