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

NCT ID: NCT00085202

Last Updated: 2024-02-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 416 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2003-08-31
• Study Completion Date: 2023-12-31

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.

Conditions

Brain and Central Nervous System Tumors

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

filgrastim

Intervention Type: BIOLOGICAL

Given subcutaneously

cisplatin

Intervention Type: DRUG

Given IV

cyclophosphamide

Intervention Type: DRUG

Given IV

vincristine

Intervention Type: DRUG

Given IV

autologous hematopoietic stem cell transplantation

Intervention Type: PROCEDURE

Patients undergo autologous stem cell transplantation

radiation therapy

Intervention Type: RADIATION

Patients undergo craniospinal radiotherapy once daily 5 days a week for 6 weeks.

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

Group Type: EXPERIMENTAL

filgrastim

Intervention Type: BIOLOGICAL

Given subcutaneously

cisplatin

Intervention Type: DRUG

Given IV

cyclophosphamide

Intervention Type: DRUG

Given IV

vincristine

Intervention Type: DRUG

Given IV

autologous hematopoietic stem cell transplantation

Intervention Type: PROCEDURE

Patients undergo autologous stem cell transplantation

radiation therapy

Intervention Type: RADIATION

Patients undergo craniospinal radiotherapy once daily 5 days a week for 6 weeks.

Interventions

filgrastim

Given subcutaneously

Intervention Type: BIOLOGICAL

cisplatin

Given IV

Intervention Type: DRUG

cyclophosphamide

Given IV

Intervention Type: DRUG

vincristine

Given IV

Intervention Type: DRUG

autologous hematopoietic stem cell transplantation

Patients undergo autologous stem cell transplantation

Intervention Type: PROCEDURE

radiation therapy

Patients undergo craniospinal radiotherapy once daily 5 days a week for 6 weeks.

Intervention Type: RADIATION

Other Intervention Names

Neupogen(R); G-CSF; Platinol-AQ(R); Cytoxan(R); Oncovin(R); autologous HSCT; RT; Craniospinal radiotherapy

Eligibility Criteria

Inclusion Criteria

• 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

• Minimum Eligible Age: 3 Years
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

St. Jude Children's Research Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Amar Gajjar, MD

Role: PRINCIPAL_INVESTIGATOR

St. Jude Children's Research Hospital

Locations

Duke Comprehensive Cancer Center

Durham, North Carolina, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

St. Jude Children's Research Hospital

Memphis, Tennessee, United States

Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital

Houston, Texas, United States

Sydney Children's Hospital

Randwick, New South Wales, Australia

Children's Hospital at Westmead

Westmead, New South Wales, Australia

Lady Cilento Children's Hospital, Brisbane

Brisbane, Queensland, Australia

Royal Children's Hospital

Parkville, Victoria, Australia

Hospital for Sick Children

Toronto, Ontario, Canada

Countries

United States; Australia; Canada

References

Acharya S, Guo Y, Patni T, Li Y, Wang C, Gargone M, Ashford JM, Wilson L, Faught A, Reddick WE, Patay Z, Gajjar A, Conklin HM, Merchant TE. Association Between Brain Substructure Dose and Cognitive Outcomes in Children With Medulloblastoma Treated on SJMB03: A Step Toward Substructure-Informed Planning. J Clin Oncol. 2022 Jan 1;40(1):83-95. doi: 10.1200/JCO.21.01480. Epub 2021 Oct 29.

Reference Type: DERIVED

PMID: 34714708 (View on PubMed)

Partanen M, Anghelescu DL, Hall L, Schreiber JE, Rossi M, Gajjar A, Jacola LM. Longitudinal associations between exposure to anesthesia and neurocognitive functioning in pediatric medulloblastoma. Eur J Cancer. 2021 May;148:103-111. doi: 10.1016/j.ejca.2021.02.010. Epub 2021 Mar 17.

Reference Type: DERIVED

PMID: 33743477 (View on PubMed)

Kumar R, Smith KS, Deng M, Terhune C, Robinson GW, Orr BA, Liu APY, Lin T, Billups CA, Chintagumpala M, Bowers DC, Hassall TE, Hansford JR, Khuong-Quang DA, Crawford JR, Bendel AE, Gururangan S, Schroeder K, Bouffet E, Bartels U, Fisher MJ, Cohn R, Partap S, Kellie SJ, McCowage G, Paulino AC, Rutkowski S, Fleischhack G, Dhall G, Klesse LJ, Leary S, Nazarian J, Kool M, Wesseling P, Ryzhova M, Zheludkova O, Golanov AV, McLendon RE, Packer RJ, Dunham C, Hukin J, Fouladi M, Faria CC, Pimentel J, Walter AW, Jabado N, Cho YJ, Perreault S, Croul SE, Zapotocky M, Hawkins C, Tabori U, Taylor MD, Pfister SM, Klimo P Jr, Boop FA, Ellison DW, Merchant TE, Onar-Thomas A, Korshunov A, Jones DTW, Gajjar A, Ramaswamy V, Northcott PA. Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma. J Clin Oncol. 2021 Mar 1;39(7):807-821. doi: 10.1200/JCO.20.01359. Epub 2021 Jan 27.

Reference Type: DERIVED

PMID: 33502920 (View on PubMed)

Gajjar A, Robinson GW, Smith KS, Lin T, Merchant TE, Chintagumpala M, Mahajan A, Su J, Bouffet E, Bartels U, Schechter T, Hassall T, Robertson T, Nicholls W, Gururangan S, Schroeder K, Sullivan M, Wheeler G, Hansford JR, Kellie SJ, McCowage G, Cohn R, Fisher MJ, Krasin MJ, Stewart CF, Broniscer A, Buchhalter I, Tatevossian RG, Orr BA, Neale G, Klimo P Jr, Boop F, Srinivasan A, Pfister SM, Gilbertson RJ, Onar-Thomas A, Ellison DW, Northcott PA. Outcomes by Clinical and Molecular Features in Children With Medulloblastoma Treated With Risk-Adapted Therapy: Results of an International Phase III Trial (SJMB03). J Clin Oncol. 2021 Mar 1;39(7):822-835. doi: 10.1200/JCO.20.01372. Epub 2021 Jan 6.

Reference Type: DERIVED

PMID: 33405951 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25665007 (View on PubMed)

Related Links

http://www.stjude.org

St. Jude Children's Research Hospital

http://www.stjude.org/protocols

Clinical Trials Open at St. Jude

Other Identifiers

NCI-2011-01185

Identifier Type: REGISTRY

Identifier Source: secondary_id

SJMB03

Identifier Type: -

Identifier Source: org_study_id