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

NCT00085202 | Completed Phase 3 Results FDA Drug

• 2 other identifiers: SJMB03NCI-2011-01185
• Study Type: interventional
• Target: 416
• Locations: 3 countries
• Sites: 9

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).

Conditions

Brain and Central Nervous System Tumors

Keywords

untreated childhood medulloblastoma; untreated childhood supratentorial primitive neuroectodermal tumor; childhood atypical teratoid/rhabdoid tumor; untreated childhood pineoblastoma

Outcome Measures

Primary Outcomes (3)

• Progression-Free Survival (PFS) in ERBB2-Negative Tumors Compared to ERBB2-Positive Tumors

  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.

  2 years after tumor cell analysis in 122 participants

• Progression-Free Survival (PFS) Compared Between ERBB2 Assessment and Risk Group.

  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.

  2 years after tumor cell analysis in 122 participants

• Frequency of Mutations Associated With SHH and WNT Tumors

  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.

  within 3.5 years following completion of accrual

Secondary Outcomes (8)

• Reading Decoding Composite Scores in the Intervention and Standard of Care Groups

  5 years postdiagnosis

• Number of Average Risk Patients Whose Treatment Failure Included the Posterior Fossa

  Annually for 6 years post irradiation

• Associative Memory for Two Risk Group at Enrollment

  At enrollment

• Associative Memory for Two Risk Group at 5 Years After Enrollment

  At 5 years after enrollment

• Processing Speed for Two Risk Group at Enrollment

  At enrollment

Study Arms (2)

Stratum 1 (high-risk group)

EXPERIMENTAL

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; Drug: cisplatin; Drug: cyclophosphamide; Drug: vincristine; Procedure: autologous hematopoietic stem cell transplantation; Radiation: radiation therapy

Stratum 2 (average-risk group)

EXPERIMENTAL

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; Drug: cisplatin; Drug: cyclophosphamide; Drug: vincristine; Procedure: autologous hematopoietic stem cell transplantation; Radiation: radiation therapy

Interventions

filgrastim BIOLOGICAL

Given subcutaneously

Also known as: Neupogen(R), G-CSF

Stratum 1 (high-risk group); Stratum 2 (average-risk group)

cisplatin DRUG

Given IV

Also known as: Platinol-AQ(R)

Stratum 1 (high-risk group); Stratum 2 (average-risk group)

cyclophosphamide DRUG

Given IV

Also known as: Cytoxan(R)

Stratum 1 (high-risk group); Stratum 2 (average-risk group)

vincristine DRUG

Given IV

Also known as: Oncovin(R)

Stratum 1 (high-risk group); Stratum 2 (average-risk group)

autologous hematopoietic stem cell transplantation PROCEDURE

Patients undergo autologous stem cell transplantation

Also known as: autologous HSCT

Stratum 1 (high-risk group); Stratum 2 (average-risk group)

radiation therapy RADIATION

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

Also known as: RT, Craniospinal radiotherapy

Stratum 1 (high-risk group); Stratum 2 (average-risk group)

Eligibility Criteria

• Age: 3 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

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

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead

Study Sites (9)

Duke Comprehensive Cancer Center

Durham, North Carolina, 27710, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

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

Houston, Texas, 77030-2399, United States

Location

Sydney Children's Hospital

Randwick, New South Wales, 2031, Australia

Location

Children's Hospital at Westmead

Westmead, New South Wales, 2145, Australia

Location

Lady Cilento Children's Hospital, Brisbane

Brisbane, Queensland, 4029, Australia

Location

Royal Children's Hospital

Parkville, Victoria, 3052, Australia

Location

Hospital for Sick Children

Toronto, Ontario, M5S 0A4, Canada

Location

Related Publications (5)

• 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.

  PMID: 34714708 DERIVED

• 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.

  PMID: 33743477 DERIVED

• 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.

  PMID: 33502920 DERIVED

• 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.

  PMID: 33405951 DERIVED

• 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.

  PMID: 25665007 DERIVED

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

MeSH Terms

Conditions

Central Nervous System Neoplasms; Rhabdoid Tumor

Interventions

Filgrastim; Granulocyte Colony-Stimulating Factor; Cisplatin; Cyclophosphamide; Vincristine; Radiotherapy

Condition Hierarchy (Ancestors)

Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Nervous System Diseases; Neoplasms, Complex and Mixed; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Therapeutics

Limitations and Caveats

The study participants for Secondary Outcome Measure #4 were randomized to standard-of-care group vs. reading intervention after medical treatment. The participants were a subset of patients who contributed to the primary aim and who signed a separate consent form distinct from the main medical treatment consent. They were then randomly assigned to either the standard-of-care group (SOC) or to the reading intervention (RI) group.

Results Point of Contact

• Title: Amar Gajjar, MD
• Organization: St. Jude Children's Research Hospital

info@stjude.org

866-278-5833

Study Officials

• Amar Gajjar, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 10, 2004
• First Posted: June 11, 2004
• Study Start: August 1, 2003
• Primary Completion: December 1, 2016
• Study Completion: December 31, 2023
• Last Updated: February 8, 2024
• Results First Posted: February 27, 2014

Record last verified: 2024-01

Locations

CA (1); US (4); AU (4)