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

Tracking Information
First Submitted Date ICMJE	June 10, 2004
First Posted Date ICMJE	June 11, 2004
Results First Submitted Date	November 4, 2013
Results First Posted Date	February 27, 2014
Last Update Posted Date	January 23, 2018
Study Start Date ICMJE	August 2003
Actual Primary Completion Date	December 2016 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: December 21, 2017)	Progression-Free Survival (PFS) in ERBB2-Negative Tumors Compared to ERBB2-Positive Tumors [ Time Frame: 2 years after tumor cell analysis in 122 participants ]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 ]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 3.5 years following completion of accrual ]The frequency of mutations for the main genes associated with SHH and WNT tumors identified via targeted sequencing based on formalin fixed paraffin embedded material is provided.
Original Primary Outcome Measures ICMJE	Not Provided
Change History	Complete list of historical versions of study NCT00085202 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: January 17, 2017)	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 10 years ]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 ]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 ]To correlate radiation dosimetry of target and normal tissues with rate and patterns of failure and longitudinal measures of audiometric, endocrine and cognitive effects.
Original Secondary Outcome Measures ICMJE	Not Provided
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Treatment of Patients With Newly Diagnosed Medulloblastoma, Supratentorial Primitive Neuroectodermal Tumor, or Atypical Teratoid Rhabdoid Tumor
Official Title ICMJE	Treatment of Patients With Newly Diagnosed Medulloblastoma, Supratentorial Primitive Neuroectodermal Tumor, or Atypical Teratoid Rhabdoid Tumor
Brief Summary	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).
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.
Study Type ICMJE	Interventional
Study Phase	Phase 3
Study Design ICMJE	Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Brain and Central Nervous System Tumors
Intervention ICMJE	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
Study Arms	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 Interventions: Biological: filgrastim Drug: cisplatin Drug: cyclophosphamide Drug: vincristine Procedure: autologous hematopoietic stem cell transplantation Radiation: radiation therapy; 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 Interventions: Biological: filgrastim Drug: cisplatin Drug: cyclophosphamide Drug: vincristine Procedure: autologous hematopoietic stem cell transplantation Radiation: radiation therapy
Publications *	Xu H, Robinson GW, Huang J, Lim JY, Zhang H, Bass JK, Broniscer A, Chintagumpala M, Bartels U, Gururangan S, Hassall T, Fisher M, Cohn R, Yamashita T, Teitz T, Zuo J, Onar-Thomas A, Gajjar A, Stewart CF, Yang JJ. Common variants in ACYP2 influence susceptibility to cisplatin-induced hearing loss. Nat Genet. 2015 Mar;47(3):263-6. doi: 10.1038/ng.3217. Epub 2015 Feb 9. Erratum in: Nat Genet. 2015 Apr;47(4):423.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Active, not recruiting
Actual Enrollment ICMJE; (submitted: January 9, 2014)	416
Original Enrollment ICMJE	Not Provided
Estimated Study Completion Date	January 2023
Actual Primary Completion Date	December 2016 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: All
Ages	3 Years to 21 Years (Child, Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Australia, Canada, United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00085202
Other Study ID Numbers ICMJE	SJMB03; NCI-2011-01185 ( Registry Identifier: NCI Clinical Trial Registration Program )
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	Studies a U.S. FDA-regulated Drug Product: Yes Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement	Not Provided
Responsible Party	St. Jude Children's Research Hospital
Study Sponsor ICMJE	St. Jude Children's Research Hospital
Collaborators ICMJE	Not Provided
Investigators ICMJE	Principal Investigator: Amar Gajjar, MD St. Jude Children's Research Hospital
PRS Account	St. Jude Children's Research Hospital
Verification Date	December 2017
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP