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Standard Chemotherapy in Treating Young Patients with Medulloblastoma or Other Central Nervous System Embryonal Tumors

Cancer Type
Brain & Spinal Cord Tumor
Brain Tumor
Neurologocal Tumor
Trial Phase
Phase IV
0 - 9 Years, Male and Female
Study Type
Protocol IDs
NCH-15004 (primary)
Study Sponsor
Nationwide Children's Hospital


This phase IV trial studies how well standard chemotherapy works in treating young patients with medulloblastoma or other central nervous system embryonal tumors. Drugs used in standard chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.


I. To determine, in a prospective randomized clinical trial, whether dose-intensive tandem consolidation, in a randomized comparison with single cycle consolidation, provides an event-free survival (EFS) and overall survival (OS) benefit for high-risk patients (non-Wnt and non-Shh subgroups) with medulloblastoma, and for all patients with central nervous system (CNS) embryonal tumors completing “Head Start 4” induction.
II. To further determine whether the additional labor-intensity (duration of hospitalizations and short-term and long-term morbidities) associated with the tandem treatment is justified by the improvement in outcome.

I. To determine if reduction in the number of induction chemotherapy cycles from five to three for molecularly high-risk medulloblastoma (non-Shh/non-Wnt) and CNS embryonal tumors who achieve a complete response (CR) after three cycles of induction therapy results in equivalent 3-year EFS.
II. To determine molecular subtypes of medulloblastoma at diagnosis.
III. Determine whether dose-intensive and dose-compressed induction chemotherapy, risk-adapted based upon the absence of detectable residual disease (after 3 induction chemotherapy cycles) and low risk medulloblastoma biology (Shh or Wnt sub-groups, with the exception of anaplastic/large cell Shh) results in equivalent patient outcomes (3-year EFS and OS) with subsequent single cycle marrow-ablative chemotherapy consolidation regimen (compared to historical controls from “Head Start II” and “Head Start III” and other studies).
IV. To assess the rate of response to sequential dose-intensive and dose-compressed induction chemotherapy followed by marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHPCR) for children with medulloblastoma and other CNS embryonal tumors enrolled on the “Head Start 4” study utilizing a uniform treatment regimen.
V. To determine the proportion of patients with each histopathological disease type of CNS embryonal tumor (desmoplastic/nodular medulloblastoma, classic medulloblastoma, anaplastic/large cell medulloblastoma; pineoblastoma and non-pineal region supratentorial embryonal tumors) cured without the need of CNS irradiation.
VI. To determine the prevalence and severity of therapy-related hearing loss between study arms as a function of cumulative dosing of cisplatin (three versus five cycles during Induction) and AuHPCR (one versus three tandem transplants in Consolidation) and to evaluate Distortion Product Oto-acoustic Emissions (DPOAE) as an early predictor of hearing loss to identified at-risk patients.
VII. To determine the long-term endocrine functions and physical growth, as well as incidence of development of second neoplasms, in children treated on this protocol.
VIII. To compare the toxicity and quality of life (QoL) effects of single versus tandem HDCx cycles.
IX. To establish a “Head Start 4” repository of clinical, radiographic and biologic specimens, including nucleic acids derived from these specimens, for future genomic, biologic, and pharmacologic research.
X. To determine if prognostic biomarkers of irradiation-free progression-free survival can be identified from deoxyribonucleic acid (DNA) copy number profiling (Oncoscan), gene expression profiling (e.g. MBL31 gene, MBL nanostring-22 gene assay and whole exome sequencing and methylation profiling) collected in “Head Start 4”.
XI. To determine if the 5-gene detection signature (MBL5-cerebrospinal fluid [CSF]) assay performed on cerebrospinal fluid (CSF) samples will improve prediction of outcome in the context of imaging, patho-biologic and clinical variables for patients enrolled in “Head Start 4”.
XII. To identify exosomal microRNAs in the CSF specific for medulloblastoma at diagnosis and to determine if decrease/disappearance of such CSF MiRNAs correlates with radiographic documentation of response to induction and consolidation therapies, and correlates with event-free survival.
XIII. To prospectively evaluate neurocognitive functioning, adjustment, and quality of life in children with brain tumors receiving treatment with “Head Start 4”.
XIV. To assess CNS myelin load, gray and white matter volumes and structural integrity with brain imaging techniques, and include the impact of socioeconomic status, home environment, parenting, and parent distress as factors that may directly affect or moderate risk.

INDUCTION PHASE: Patients undergo molecular testing for risk stratification. Patients receive cisplatin intravenously (IV) over 6 hours on day 1, vincristine sulfate IV on days 1, 8, and 15, etoposide IV over 2 hours and cyclophopsphamide IV over 1 hour on days 2 and 3, and methotrexate IV over 4 hours on day 4. Treatment repeats every 21-28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients with no evidence of residual tumor following recovery from the third cycle of induction chemotherapy proceed directly to the consolidation phase of treatment. Patients with positive lumbar cerebral spinal fluid (CSF) cytology or unresectable residual viable tumor or residual radiographic abnormalities consistent with residual tumor but not deemed able to be biopsied, receive up to 2 additional induction cycles.

CONSOLIDATION PHASE: Low risk patients (determined by molecular testing) undergo a single cycle chemotherapy. High risk patients are randomized to 1 of 2 arms.

CONSOLIDATION PHASE SINGLE CYCLE CHEMOTHERAPY: Patients receive carboplatin IV over 4 hours on days -8 to -6, and thiotepa IV over 3 hours and etoposide IV over 3 hours on days -5 to -3. Patients undergo stem cell transplant on day 0.

CONSOLIDATION PHASE TANDEM 3 CYCLE CHEMOTHERAPY: Patients receive carboplatin IV over 4 hours and thiotepa IV over 3 hours on days -4 to -3. Patients undergo stem cell transplant on day 0. Following recovery from the first cycle, about 21-28 days, treatment repeats for up to 3 total cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 6 weeks and once a month in the first year, every 3 months in the second and third years, every 4-6 months in the fourth year, and annually after 5 years.


  1. Children less than 120 months (10 years) of age at the time of definitive confirmatory eligible histologic or cytological diagnosis of eligible CNS tumor within the brain or spinal cord, who have not previously received either irradiation or chemotherapy (except corticosteroids) will be eligible for study entry
  2. Children who have histologically proven diagnoses of the following types of CNS tumor are eligible for entry onto this protocol; the exclusive focus is on medulloblastoma and other CNS embryonal tumors of the brain or spinal cord
  3. Medulloblastoma: * Posterior fossa classic, desmoplastic or extensive nodular or anaplastic/large cell medulloblastoma with appropriate and sufficient tumor material (formalin-fixed, parrafin-embedded [FFPE] or snap frozen) for proposed assays: all stages, age less than 6 years at diagnosis * Posterior fossa classic or anaplastic/large cell medulloblastoma with sufficient tumor material (FFPE or snap frozen) for proposed assays: clinically high-stage (neuraxis or extra-neural dissemination, M1-4), age greater than 6 years to less than 10 years at diagnosis * Posterior fossa medulloblastoma, those 6 years of age and above at diagnosis, will only be eligible if they have evidence of neuraxis or extraneural dissemination. Patients 6 years of age and above with low-stage (standard-risk, M0) medulloblastoma will NOT be eligible for this study, irrespective of molecular subgroup and extend of local resection
  4. All children less than 120 months (10 years) of age, irrespective of clinical stage, with a diagnosis of any of the following CNS embryonal are eligible: pineoblastoma, pineal anlage tumor, CNS neuroblastoma, CNS ganglioneuroblastoma, embryonal tumor with multi-layered rosettes (ETMR, including embryonal tumor with abundant neuropil and true rosettes [ETANTR]), ependymoblastoma and ETMR not otherwise specified), medulloepithelioma, CNS embryonal tumor with rhabdoid features (INI1 intact) and CNS embryonal tumor, not otherwise specified
  5. Histologic diagnosis is mandatory for all patients prior to study entry; study eligibility will be based on institutional pathology; however, performance (and ultimate submission for Central Pathology review) of immunohistochemically (IHC) stained slides for INI11 (to rule out CNS AT/RT), GFAP, EMA, neuronal markers (synaptophysin) for all tumors, as well as a reticulin stain for medulloblastomas displaying any degree of desmoplasia on conventional microscopy, is required; in addition, requested, but not required, are IHC slides for P53 and MIB-1/Ki-67 for all tumors
  6. Children must be enrolled on study within 28 days of the most recent definitive tumor biopsy/resection surgical procedure and within 21 days of the most recent neuro-imaging studies (magnetic resonance imaging [MRI] of brain, performed with and without gadolinium contrast, and MRI of total spine, performed with gadolinium contrast) and lumbar CSF cytological examination; if a lumbar puncture (LP) is medically contraindicated, please contact the study chair for waiver of LP for eligibility and additional guidance; please note, day 1 begins the day after surgery and/or scans; example: Patient had tumor resection surgery on June 1, 2017, therefore the last day the patient could be enrolled is June 29, 2017 (28 days from surgery); the date protocol therapy is projected to start must be no later than 4 calendar days after the date of study enrollment
  7. Bilirubin less than 1.5 mg/dL (except for patients with Gilbert’s Syndrome of indirect hyperbilirubinemia)
  8. Transaminases (serum glutamic pyruvic transaminase [SGPT] or alanine aminotransferase [ALT], and serum glutamic oxaloacetic transaminase [SGOT] or aspartate aminotransferase [AST]) less than 2.5 (two and a half) times the upper limits of institutional normal
  9. Creatinine clearance and/or glomerular filtration rate (GFR) greater than or equal to 60 mL/min/1.73m^2 within 21 days of protocol therapy; kidney function cannot be estimated by other means
  10. Adequate Bone Marrow Function defined as: * Peripheral absolute phagocyte count (APC) > 1000/ µL; APC = numbers of banded neutrophils + segmented neutrophils + metamyelocytes + monocytes + eosinophils Please note, if institution reports differential as a percentage, then APC = [percentage of banded neutrophils + segmented neutrophils+ metamyelocytes+monocytes+eosinophils] x total white cell count. * Platelet Count > 100,000/µL (transfusion independent) * Hemoglobin > 8 gm/dL (may have received RBC transfusions)

Treatment Sites in Georgia

Aflac Cancer and Blood Disorders Center of Children’s at Egleston

1405 Clifton Road NE
3rd Floor
Atlanta, GA 30322

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