Clinical trial NCT00085202: Treatment of Patients With Newly Diagnosed Medulloblastoma, Supratentorial Primitive Neuroectodermal Tumor, or Atypical Teratoid Rhabdoid Tumor
Official title: Treatment of Patients With Newly Diagnosed Medulloblastoma, Supratentorial Primitive Neuroectodermal Tumor, or Atypical Teratoid Rhabdoid Tumor
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
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
Lead sponsor: St. Jude Children's Research Hospital
Sponsor class: OTHER
First posted: 2004-06-11
Enrollment: 416
Sex: ALL
Minimum age (years): 3
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Progression-Free Survival (PFS) in ERBB2-Negative Tumors Compared to ERBB2-Positive Tumors
timeFrame: 2 years after tumor cell analysis in 122 participants
measure: Progression-Free Survival (PFS) Compared Between ERBB2 Assessment and Risk Group.
timeFrame: 2 years after tumor cell analysis in 122 participants
measure: Frequency of Mutations Associated With SHH and WNT Tumors
timeFrame: within 3.5 years following completion of accrual
Secondary outcomes:
measure: Reading Decoding Composite Scores in the Intervention and Standard of Care Groups
timeFrame: 5 years postdiagnosis
measure: Number of Average Risk Patients Whose Treatment Failure Included the Posterior Fossa
timeFrame: Annually for 6 years post irradiation
measure: Associative Memory for Two Risk Group at Enrollment
timeFrame: At enrollment
measure: Associative Memory for Two Risk Group at 5 Years After Enrollment
timeFrame: At 5 years after enrollment
measure: Processing Speed for Two Risk Group at Enrollment
timeFrame: At enrollment
measure: Processing Speed for Two Risk Group at 5 Years After Enrollment
timeFrame: At 5 years after enrollment
measure: Perceptual Speed for Two Risk Group at Enrollment
timeFrame: At enrollment
measure: Perceptual Speed for Two Risk Group at 5 Years After Enrollment
timeFrame: At 5 years after enrollment
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital
state: Texas
city: Randwick
country: Australia
facility: Sydney Children's Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Children's Hospital at Westmead
state: New South Wales
city: Brisbane
country: Australia
facility: Lady Cilento Children's Hospital, Brisbane
state: Queensland
city: Parkville
country: Australia
facility: Royal Children's Hospital
state: Victoria
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
Study officials:
affiliation: St. Jude Children's Research Hospital
name: Amar Gajjar, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.