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Standard Chemotherapy in Treating Young Patients with Medulloblastoma or Other Central Nervous System Primitive Neuro-ectodermal Tumors

Trial Status: Active

This phase IV trial studies how well standard chemotherapy works in treating young patients with medulloblastoma or other central nervous system primitive neuro-ectodermal 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.

Inclusion Criteria

  • Children with 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
  • 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 primitive neuro-ectodermal tumors (PNET) of the brain or spinal cord
  • Medulloblastoma: * Posterior fossa classic, desmoplastic or extensive nodular or anaplastic/large cell medulloblastoma with appropriate and sufficient tumor material (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
  • All children less than 120 months (10years) of age, irrespective of clinical stage, with a diagnosis of any of the following CNS PNET are eligible: pineoblastoma, all primary CNS-PNET, including CNS/cerebral neuroblastoma, CNS/cerebral ganglioneuroblastoma, medulloepithelioma, ependymoblastoma, embryonal tumor with abundant neuropil and true rosettes (ETANTR; more recently designated as "embryonal tumor with multilayered rosettes" or "ETMR"), melanotic medulloblastoma and/or medullomyoblastoma, CNS supratentorial PNET, spinal cord PNET, brainstem PNET are all eligible, regardless of patterns of (divergent) differentiation
  • 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
  • Children must commence Induction chemotherapy within 28 days of the most recent definitive 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 cerebrospinal fluid (CSF) cytological examination; the required eligibility observations must be done within 21 days of the start date of treatment; the date protocol therapy is projected to start must be no later than 7 calendar days after the date of study enrollment
  • Bilirubin less than 1.5 mg/dL (except for patients with Gilbert’s Syndrome of indirect hyperbilirubinemia)
  • 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
  • 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
  • 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)

Exclusion Criteria

  • All diagnoses other than medulloblastoma and CNS PNET - these include: CNS atypical teratoid/rhabdoid tumor (AT/RT); all ependymomas including anaplastic ependymomas of the brain or spinal cord.; All choroid plexus carcinomas; all high-grade glial and glio-neuronal tumors; all primary CNS germ cell tumors; all primary CNS sarcomas; all primary or metastatic CNS lymphomas and solid leukemic lesions (i.e., chloromas, granulocytic sarcomas)
  • Patients with unbiopsied diffuse intrinsic pontine tumors will NOT be eligible for this study.


Children's Hospital of Alabama
Status: ACTIVE
Contact: Gregory Kane Friedman


Phoenix Childrens Hospital
Status: ACTIVE
Contact: Michael Matthew Etzl


Los Angeles
Children's Hospital Los Angeles
Status: ACTIVE
Contact: Girish Dhall
Phone: 323-361-8147
Children's Hospital and Research Center at Oakland
Status: ACTIVE
Contact: Joseph Charles Torkildson


Children's Hospital Colorado
Status: ACTIVE
Contact: Kathleen M. O'Toole Dorris
Phone: 720-777-8314


Alfred I duPont Hospital for Children
Status: ACTIVE
Contact: Emi H. Caywood
Nemours NCI Community Oncology Research Program
Status: ACTIVE
Contact: Andrew William Walter

District of Columbia

Children's National Medical Center
Status: ACTIVE
Contact: Eugene Hsu Huang


University of Florida Health Science Center - Gainesville
Status: ACTIVE
Contact: Sridharan Gururangan
Phone: 352-294-8347
Nemours Children's Clinic-Jacksonville
Status: ACTIVE
Contact: Michael John Joyce
Nicklaus Children's Hospital
Status: ACTIVE
Contact: Ziad Ahmad Khatib
Saint Petersburg
Johns Hopkins All Children's Hospital
Status: ACTIVE
Contact: Stacie Lynn Stapleton


Children's Healthcare of Atlanta - Egleston
Status: ACTIVE
Contact: Claire Marie Mazewski
Children's Healthcare of Atlanta - Scottish Rite
Status: ACTIVE
Contact: Claire Marie Mazewski


Riley Hospital for Children
Status: ACTIVE
Contact: Chie-Schin Shih


Dana-Farber Cancer Institute
Status: ACTIVE
Contact: Susan N. Chi


Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: ACTIVE
Contact: Carl Johannes Koschmann
Phone: 734-615-2736
Children's Hospital of Michigan
Status: ACTIVE
Contact: Maxim Yankelevich
Phone: 313-745-5515
Wayne State University / Karmanos Cancer Institute
Status: ACTIVE
Contact: Hamza Gorsi
Grand Rapids
Helen DeVos Children's Hospital at Spectrum Health
Status: ACTIVE
Contact: Albert S. Cornelius


University of Minnesota / Masonic Children's Hospital
Status: ACTIVE
Contact: Christopher Loren Moertel

New Jersey

Hackensack University Medical Center
Status: ACTIVE
Contact: Derek R. Hanson
Phone: 551-996-5437

New York

Bay Shore
Northwell Health Imbert Cancer Center
Status: ACTIVE
Contact: Julie I. Krystal
Phone: 718-470-3460
New York
Laura and Isaac Perlmutter Cancer Center at NYU Langone
Status: ACTIVE
Contact: Sharon Leigh Gardner
Phone: 212-263-9983
Memorial Sloan Kettering Cancer Center
Status: ACTIVE
Contact: Kim Kramer
Phone: 212-639-6410
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
Status: ACTIVE
Contact: James H. Garvin
Phone: 212-305-5872
State University of New York Upstate Medical University
Status: ACTIVE
Contact: Melanie A. Comito

North Carolina

Carolinas Medical Center / Levine Cancer Institute
Status: ACTIVE
Contact: Chad T. Jacobsen


Cleveland Clinic Foundation
Status: ACTIVE
Contact: Tanya Marie Tekautz
Phone: 216-444-9532
Nationwide Children's Hospital
Status: ACTIVE
Contact: Jonathan Lester Finlay
Phone: 614-722-3521
Ohio State University Comprehensive Cancer Center
Status: ACTIVE
Contact: Pierre Giglio


Penn State Children's Hospital
Status: ACTIVE
Contact: Robert J. Greiner
Children's Hospital of Philadelphia
Status: ACTIVE
Contact: Kristina Ann Cole
Phone: 267-426-2285


Vanderbilt University / Ingram Cancer Center
Status: ACTIVE
Contact: Adam John Esbenshade


Virginia Commonwealth University / Massey Cancer Center
Status: ACTIVE
Contact: Zhihong Joanne Wang


University of Wisconsin Hospital and Clinics
Status: ACTIVE
Contact: Neha J. Patel
Children's Hospital of Wisconsin
Status: ACTIVE
Contact: Ryuma Tanaka
Medical College of Wisconsin
Status: ACTIVE
Contact: Jeffrey Alan Knipstein
Phone: 414-955-4170

British Columbia

British Columbia Children's Hospital
Status: ACTIVE
Contact: Sylvia Shew-Wai Cheng
Phone: 604-875-2345ext2406


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) primitive neuro-ectodermal tumors (PNET) 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 PNET 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) 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 PNET 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; pineal region PNET or pineoblastoma, non-pineal region supratentorial-PNET and other CNS PNET) 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-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 eventfree 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 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients with no evidence of residual tumor following recovery from the third course 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 courses.

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

CONSOLIDATION PHASE SINGLE COURSE 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 COURSE 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 course, about 21-28 days, treatment repeats for up to 3 total courses 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.

Trial Phase Phase IV

Trial Type Treatment

Lead Organization
Nationwide Children's Hospital

Principal Investigator
Jonathan Lester Finlay

  • Primary ID NCH-15004
  • Secondary IDs NCI-2016-01993, IRB15-00399
  • ID NCT02875314