Treatment of Patients With Newly Diagnosed Medulloblastoma, Supratentorial Primitive Neuroectodermal Tumor, or Atypical Teratoid Rhabdoid Tumor
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT00085202 |
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Recruitment Status :
Active, not recruiting
First Posted : June 11, 2004
Results First Posted : February 27, 2014
Last Update Posted : January 6, 2022
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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 or disease | Intervention/treatment | 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 |
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.
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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.
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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 : | Interventional (Clinical Trial) |
| Actual Enrollment : | 416 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Treatment of Patients With Newly Diagnosed Medulloblastoma, Supratentorial Primitive Neuroectodermal Tumor, or Atypical Teratoid Rhabdoid Tumor |
| Study Start Date : | August 2003 |
| Actual Primary Completion Date : | December 2016 |
| Estimated Study Completion Date : | January 2023 |
| Arm | Intervention/treatment |
|---|---|
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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:
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:
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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:
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:
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- 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.
- 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 up to 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.
- Longitudinal Change in Functional Outcomes by Mean RT Dose to Specified Target Tissues [ 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.
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| Ages Eligible for Study: | 3 Years to 21 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
DISEASE CHARACTERISTICS:
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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
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Meets one of the following risk criteria:
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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
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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)
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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
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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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00085202
| 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 | |
| Lady Cilento Children's Hospital, Brisbane | |
| 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 | |
| Principal Investigator: | Amar Gajjar, MD | St. Jude Children's Research Hospital |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | St. Jude Children's Research Hospital |
| ClinicalTrials.gov Identifier: | NCT00085202 |
| Other Study ID Numbers: |
SJMB03 NCI-2011-01185 ( Registry Identifier: NCI Clinical Trial Registration Program ) |
| First Posted: | June 11, 2004 Key Record Dates |
| Results First Posted: | February 27, 2014 |
| Last Update Posted: | January 6, 2022 |
| Last Verified: | December 2021 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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untreated childhood medulloblastoma untreated childhood supratentorial primitive neuroectodermal tumor childhood atypical teratoid/rhabdoid tumor untreated childhood pineoblastoma |
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Nervous System Neoplasms Central Nervous System Neoplasms Medulloblastoma Neuroectodermal Tumors Neuroectodermal Tumors, Primitive Rhabdoid Tumor Neoplasms Neoplasms by Site Nervous System Diseases Glioma Neoplasms, Neuroepithelial Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms, Glandular and Epithelial Neoplasms, Nerve Tissue |
Neoplasms, Complex and Mixed Cyclophosphamide Vincristine Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Myeloablative Agonists Antineoplastic Agents, Phytogenic Tubulin Modulators Antimitotic Agents |