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

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 embryonal tumors 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 (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
  • 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
  • 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 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
  • 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 embryonal tumors - 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.

Alabama

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

Arizona

Phoenix
Phoenix Childrens Hospital
Status: ACTIVE
Contact: Michael Matthew Etzl

Arkansas

Little Rock
Arkansas Children's Hospital
Status: ACTIVE
Contact: Kevin James Bielamowicz

California

Loma Linda
Loma Linda University Medical Center
Status: ACTIVE
Contact: Albert Kheradpour
Phone: 909-558-4076
Long Beach
Miller Children's and Women's Hospital Long Beach
Status: ACTIVE
Contact: Ramesh Patel
Phone: 562-933-8626
Los Angeles
Children's Hospital Los Angeles
Status: ACTIVE
Contact: Girish Dhall
Phone: 323-361-8147
Mattel Children's Hospital UCLA
Status: ACTIVE
Contact: Theodore B. Moore
Phone: 310-825-6708
Oakland
UCSF Benioff Children's Hospital Oakland
Status: ACTIVE
Contact: Joseph Charles Torkildson
Orange
Children's Hospital of Orange County
Status: ACTIVE
Contact: Chenue Abongwa
Phone: 714-509-8636

Colorado

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

Delaware

Wilmington
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

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

Florida

Gainesville
University of Florida Health Science Center - Gainesville
Status: ACTIVE
Contact: Sridharan Gururangan
Phone: 352-294-8347
Jacksonville
Nemours Children's Clinic-Jacksonville
Status: ACTIVE
Contact: Michael John Joyce
Miami
Nicklaus Children's Hospital
Status: ACTIVE
Contact: Ziad Ahmad Khatib
Orlando
Orlando Health Cancer Institute
Status: ACTIVE
Contact: Amy Amundson Smith

Georgia

Atlanta
Children's Healthcare of Atlanta - Egleston
Status: ACTIVE
Contact: Claire Marie Mazewski
Emory University Hospital / Winship Cancer Institute
Status: ACTIVE
Contact: Claire Marie Mazewski

Indiana

Indianapolis
Riley Hospital for Children
Status: ACTIVE
Contact: Scott L. Coven
Email: scoven@iu.edu

Iowa

Iowa City
University of Iowa / Holden Comprehensive Cancer Center
Status: ACTIVE
Contact: Mariko Sato

Kentucky

Louisville
Norton Children's Hospital
Status: ACTIVE
Contact: Michael Angelo Cacdac Huang

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: ACTIVE
Contact: Stacie Lynn Stapleton

Massachusetts

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

Michigan

Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: ACTIVE
Contact: Carl Johannes Koschmann
Phone: 734-615-2736
Detroit
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

Minnesota

Minneapolis
Children's Hospitals and Clinics of Minnesota - Minneapolis
Status: ACTIVE
Contact: Anne Elizabeth Bendel
Phone: 612-813-6835
University of Minnesota / Masonic Cancer Center
Status: ACTIVE
Contact: Christopher Loren Moertel
Phone: 612-626-2778
University of Minnesota / Masonic Children's Hospital
Status: ACTIVE
Contact: Christopher Loren Moertel

Missouri

Saint Louis
Washington University School of Medicine
Status: ACTIVE
Contact: Andrew Stephen Cluster

Nevada

Las Vegas
Alliance for Childhood Diseases / Cure 4 the Kids Foundation
Status: ACTIVE
Contact: Joseph L. Lasky
Phone: 702-732-1493

New Jersey

Hackensack
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
Syracuse
State University of New York Upstate Medical University
Status: ACTIVE
Contact: Melanie A. Comito
Valhalla
New York Medical College
Status: APPROVED
Contact: Jeremy Rosenblum

North Carolina

Charlotte
Carolinas Medical Center / Levine Cancer Institute
Status: ACTIVE
Contact: Chad T. Jacobsen
Durham
Duke University Medical Center
Status: ACTIVE
Contact: David Michael Ashley

Ohio

Cleveland
Cleveland Clinic Foundation
Status: ACTIVE
Contact: Tanya Marie Tekautz
Phone: 216-444-9532
Rainbow Babies and Childrens Hospital
Status: ACTIVE
Contact: Duncan Scott Stearns
Columbus
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
Dayton
Dayton Children's Hospital
Status: ACTIVE
Contact: Lionel Mu-Lo Chow

Pennsylvania

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

South Carolina

Charleston
Medical University of South Carolina
Status: ACTIVE
Contact: Sandeepkumar Babudin Kuril

Tennessee

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

Texas

Houston
M D Anderson Cancer Center
Status: ACTIVE
Contact: Wafik T. Zaky

Utah

Salt Lake City
Primary Children's Hospital
Status: ACTIVE
Contact: Carol S. Bruggers

Virginia

Richmond
Virginia Commonwealth University / Massey Cancer Center
Status: ACTIVE
Contact: Zhihong Joanne Wang
Phone: 804-828-9605

Wisconsin

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

Alberta

Calgary
Alberta Children's Hospital
Status: ACTIVE
Contact: Lucie E. Lafay-Cousin
Phone: 403-955-2554
Edmonton
Stollery Children's Hospital
Status: ACTIVE
Contact: Beverly J Wilson

British Columbia

Vancouver
University of British Columbia Hospital
Status: ACTIVE
Contact: Sylvia Shew-Wai Cheng

Ontario

Toronto
Hospital for Sick Children
Status: ACTIVE
Contact: Annie Huang
Phone: 416-813-7360

New Zealand

Christchurch
Christchurch Hospital
Status: ACTIVE
Contact: Andrew John Dodgshun
Phone: 64 33640 640
Grafton
Starship Children's Hospital
Status: ACTIVE
Contact: Karen D Tsuchiya

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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) 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.

OUTLINE:

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.

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
  • Clinicaltrials.gov ID NCT02875314