HeadStart4: Newly Diagnosed Children (<10 y/o) With Medulloblastoma and Other CNS Embryonal Tumors

NCT ID: NCT02875314

Last Updated: 2025-08-24

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 250 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-09-30
• Study Completion Date: 2030-12-31

Brief Summary

This is a prospective randomized clinical trial, to determine whether dose-intensive tandem Consolidation, in a randomized comparison with single cycle Consolidation, provides an event-free survival (EFS) and overall survival (OS). The study population will be high-risk patients (non-Wnt and non-Shh sub-groups) with medulloblastoma, and for all patients with central nervous system (CNS) embryonal tumors completing "Head Start 4" Induction. This study will 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. It is expected that the tandem (3 cycles) Consolidation regimen will produce a superior outcome compared to the single cycle Consolidation, given the substantially higher dose intensity of the tandem regimen, without significant addition of either short-term or long-term morbidities.

Detailed Description

Due to the inferior response and event-free survival data of Regimens D and D2 on "Head Start III" for all children with supratentorial embryonal tumors, in comparison with the published data from "Head Start II" with Regimen A2 for metastatic patients, all such patients will receive the "Head Start II" Induction Regimen A2, on "Head Start 4", for either three or five cycles, depending upon whether or not they achieve complete remission by the end of Induction cycle #3. They will then undergo randomization to either single cycle or three tandem cycles of Consolidation marrow-ablative chemotherapy with AuHPCR.

Because of the unsatisfactory event-free survival for young children with non-desmoplastic/extensive nodular medulloblastoma (predominantly non-Shh and non-Wnt medulloblastoma subgroups) on Regimens D and D2 of "Head Start III", all these patients will receive the "Head Start II" Induction Regimen A2 on ""Head Start 4"", for either three or five cycles, depending upon whether or not they achieve complete remission by the end of Induction cycle #3. They will then undergo randomization to either single cycle or three tandem cycles of Consolidation marrow-ablative chemotherapy with AuHPCR.

Because of the excellent event-free and overall survival for young children with good risk medullo-blastoma (Shh or Wnt subgroups) treated with up-front "Head Start" chemotherapy strategies, such patients will undergo risk-tailored reduction of duration of Induction therapy from five cycles to three cycles of the "Head Start II" Induction Regimen A2 on "Head Start 4" for patients achieving a complete response to 3 cycles, followed, provided they are also without evidence of residual tumor following recovery from Induction cycle #3. They will NOT then undergo randomization, but will follow with a single cycle of Consolidation marrow-ablative chemotherapy as in "Head Start" studies.

Conditions

Medulloblastoma; Central Nervous System Embryonal Tumors

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Induction

The 5 chemotherapy drugs used in the Induction part of treatment are vincristine, cisplatin, cyclophosphamide, etoposide and high-dose methotrexate.

Three medications are also given to help reduce the side effects of the chemotherapy drugs. Filgrastim will be given through a vein or through a tiny needle into the tissue just under the skin to help blood counts recover after the chemotherapy. Mesna will be given through a vein with cyclophosphamide to help prevent bleeding in the bladder. Leucovorin will be given through a vein after the methotrexate to protect the body from the side effects of the methotrexate.

Group Type: EXPERIMENTAL

Induction

Intervention Type: DRUG

vincristine, cisplatin, cyclophosphamide, etoposide, high-dose methotrexate

Single Cycle Intensive Chemotherapy

The three drugs to be used in this research study are thiotepa, etoposide and carboplatin. These drugs will be given over 6 days to help kill the cancer cells. After 72 hours from getting these drugs, previously collected and frozen blood cells will be thawed and returned through the venous catheter.

Carboplatin is given by vein over 4 hours. Thiotepa is given by vein over 3 hours. Etoposide is given by vein over 3 hours. The schedule for these drugs is as follows:

Day -8: Carboplatin Day -7: Carboplatin Day -6: Carboplatin Day -5: Thiotepa, Etoposide Day -4: Thiotepa, Etoposide Day -3: Thiotepa, Etoposide Day -2: Rest Day -1: Rest Day 0: Re-infusion of blood cells

Group Type: EXPERIMENTAL

Single Cycle Intensive Chemotherapy

Intervention Type: DRUG

Carboplatin, thiotepa, etoposide

Tandem 3 Cycle Intensive Chemotherapy

The 2 drugs to be used in this treatment are thiotepa and carboplatin. These drugs will be given over 2 days to help kill the cancer cells. After 72 hours from getting these drugs, previously collected and frozen blood cells will be thawed and returned through the venous catheter.

Day -4: Thiotepa, Carboplatin Day -3: Thiotepa, Carboplatin Day -2: Rest Day -1: Rest Day 0: Re-infusion of blood cells.

Following recovery from the first cycle of this chemotherapy, about 28 days following the Day 0 reinfusion of blood cells, the same cycle will be repeated again. A total of 3 cycles of this therapy will be administered, over the course of 12 weeks.

Group Type: EXPERIMENTAL

Tandem 3 Cycle Intensive Chemotherapy

Intervention Type: DRUG

Carboplatin, thiotepa

Interventions

Induction

vincristine, cisplatin, cyclophosphamide, etoposide, high-dose methotrexate

Intervention Type: DRUG

Single Cycle Intensive Chemotherapy

Carboplatin, thiotepa, etoposide

Intervention Type: DRUG

Tandem 3 Cycle Intensive Chemotherapy

Carboplatin, thiotepa

Intervention Type: DRUG

Other Intervention Names

vincristine, cisplatin, cyclophosphamide, etoposide, high-dose methotrexate; Carboplatin, thiotepa, etoposide; Carboplatin, thiotepa

Eligibility Criteria

Inclusion Criteria

• Patients 10 years of age at the time of definitive confirmatory eligible histologic or cytologic diagnosis of eligible CNS tumor (brain or spinal cord)
• Patients may not have received irradiation or chemotherapy (except corticosteroids)
• Have histologically proven diagnosis of medulloblastoma or 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 (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
• CNS Embryonal Tumors:

• Pineoblastoma, 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.
• 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 (MRI of brain, performed with and without gadolinium contrast, and MRI of total spine, performed with gadolinium contrast) and lumbar CSF cytological examination
• Patients must have adequate organ functions at the time of registration:

• Liver: bilirubin less than 1.5 mg/dL (except for patients with Gilbert's Syndrome of indirect hyperbilirubinemia) and transaminases [SGPT or ALT, and SGOT or AST] less than 2.5 (two and a half) times the upper limits of institutional normal.
• Renal: Creatinine clearance and/or glomerular filtration rate (GFR) greater than or equal to 60 mL/min/1.73m² within 21 days of protocol therapy.
• Bone Marrow Function:

1. 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.

2. Platelet Count > 100,000/µL (transfusion independent)

3. Hemoglobin > 8 gm/dL (may have received RBC transfusions).

Exclusion Criteria

• Patients older than 10 years of age at time of diagnosis
• Following diagnoses are not eligible for study enrollment: 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.

• Maximum Eligible Age: 10 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Children's of Alabama

OTHER

Sponsor Role: collaborator

Parth Patel

OTHER

Sponsor Role: lead

Responsible Party

Parth Patel

Prinicipal Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Randal Olshefski, MD

Role: PRINCIPAL_INVESTIGATOR

Nationwide Children's Hospital

Jonathan Finlay, MD

Role: STUDY_CHAIR

Global Neuro-Oncology, Inc.

Girish Dhall, MD

Role: STUDY_CHAIR

Children's of Alabama at UAB

Locations

Children's of Alabama

Birmingham, Alabama, United States

Phoenix Children's Hospital

Phoenix, Arizona, United States

Arkansas Children's Hospital

Little Rock, Arkansas, United States

Loma Linda University Medical Center

Loma Linda, California, United States

Memorial Care Health Services

Long Beach, California, United States

Children's Hospital Los Angeles

Los Angeles, California, United States

Mattel Children's Hospital (UCLA)

Los Angeles, California, United States

UCSF Oakland Benioff

Oakland, California, United States

Children's Hospital Orange County

Orange, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Nemours Center for Cancer and Blood Disorders

Wilmington, Delaware, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

Shands Children's Hospital/ University of FL

Gainesville, Florida, United States

Nemours Center for Cancer and Blood Disorders

Jacksonville, Florida, United States

Nicklaus Children's Hospital

Miami, Florida, United States

Orlando Health

Orlando, Florida, United States

John's Hopkins All Children's Hospital

St. Petersburg, Florida, United States

Children's Healthcare of Atlanta

Atlanta, Georgia, United States

Riley Children's Hospital/University of Indiana

Indianapolis, Indiana, United States

University of Iowa Hospital and Clinics

Iowa City, Iowa, United States

University of Louisville School of Medicine

Louisville, Kentucky, United States

John's Hopkins University School of Medicine

Baltimore, Maryland, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

University of Michigan

Ann Arbor, Michigan, United States

Central Michigan University

Detroit, Michigan, United States

Helen DeVos Children's Hospital

Grand Rapids, Michigan, United States

Children's Hospital of Minnesota

Minneapolis, Minnesota, United States

Masonic Children's Hospital/University of Minnesota

Minneapolis, Minnesota, United States

Mayo Clinic

Rochester, Minnesota, United States

Washington University School of Medicine

St Louis, Missouri, United States

Children's Specialty Care of Nevada

Las Vegas, Nevada, United States

Joseph Sanzari Children's Hospital/ Hackensack University

Hackensack, New Jersey, United States

Morristown Medical Center, Atlantic Health System

Morristown, New Jersey, United States

New York Medical College

Hawthorne, New York, United States

Northwell Health

Hempstead, New York, United States

NYU Langone Medical Center

New York, New York, United States

Columbia Presbyterian Children's Hospital

New York, New York, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Upstate Golisano Children's Hospital/ SUNY Upstate Medical University

Syracuse, New York, United States

Carolina's HealthCare System/Levine Cancer Institute

Charlotte, North Carolina, United States

Duke University Medical Center

Durham, North Carolina, United States

Akron Children's Hospital

Akron, Ohio, United States

Rainbow Babies & Children's Hospital

Cleveland, Ohio, United States

Cleveland Clinic

Cleveland, Ohio, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

Dayton Children's Hospital

Dayton, Ohio, United States

Penn State Hershey Children's Hospital

Hershey, Pennsylvania, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, United States

MD Anderson Cancer Center

Houston, Texas, United States

Primary Children's Hospital

Salt Lake City, Utah, United States

Virginia Commonwealth University

Richmond, Virginia, United States

American Family Children's Hospital/University of Wisconsin

Madison, Wisconsin, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

B.C. Children's Hospital

Vancouver, British Columbia, Canada

Alberta Children's Hospital

Calgary, , Canada

Stollery Children's Hospital

Edmonton, , Canada

Hamilton Health/McMasters Children's Hospital, Hamilton, Canada

Hamilton, , Canada

The Hospital of Sick Children

Toronto, , Canada

Starship Children's Hospital

Auckland, , New Zealand

Christchurch Children's Hospital

Christchurch, , New Zealand

Countries

United States; Canada; New Zealand

Other Identifiers

IRB15-00399

Identifier Type: -

Identifier Source: org_study_id