HeadStart4: Newly Diagnosed Children (<10 y/o) With Medulloblastoma and Other CNS Embryonal Tumors
- Conditions
- Central Nervous System Embryonal TumorsMedulloblastoma
- Interventions
- Registration Number
- NCT02875314
- Lead Sponsor
- Parth Patel
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 250
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Patients 10 years of age at the time of definitive confirmatory eligible histologic or cytologic diagnosis of eligible CNS tumor (brain or spinal cord)
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Patients may not have received irradiation or chemotherapy (except corticosteroids)
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Have histologically proven diagnosis of medulloblastoma or CNS embryonal tumors of the brain or spinal cord
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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.
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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
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Patients must have adequate organ functions at the time of registration:
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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.
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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.
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Bone Marrow Function:
- 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).
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- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Tandem 3 Cycle Intensive Chemotherapy 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. Induction 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. Single Cycle Intensive Chemotherapy 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
- Primary Outcome Measures
Name Time Method Compare tandem consolidation vs. single cycle consolidation A 5 years Dose-intensive tandem Consolidation will be compared with single cycle consolidation via randomization. The randomized consolidations will provide an event-free survival (EFS) analysis after completing "Head Start 4" Induction.
Compare tandem consolidation vs. single cycle consolidation B 5 years Dose-intensive tandem Consolidation will be compared with single cycle consolidation via randomization. The randomized consolidations will provide an overall survival (OS) analysis after completing "Head Start 4" Induction.
- Secondary Outcome Measures
Name Time Method Induction Cycle Reduction 5 years Induction chemotherapy cycles will be reduced in number 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. Outcome will be analyzed irrespective of Consolidation assignment (Primary Aim) and compared to historical controls.
Endocrine studies will be conducted using Serum-free T4, TSH, Cortisol, IGF and IGFBP3 laboratory tests. 5 years The long-term endocrine functions effect will be evaluated.
Uniform Treatment Regimen 5 years Assess the rate of response of 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.
Therapy-Related Hearing Loss Evaluation A 5 years The prevalence and severity of therapy-related hearing loss as a function of cumulative dosing of cisplatin (three versus five cycles during Induction) will be evaluated. Distortion-Product Oto-acoustic Emissions (DPOAE) will be used as an early predictor of hearing loss to identify at-risk patients.
Neuropsychological effects will be evaluated using age based tests and questionnaires. 5 years The long-term neuropsychological effects will be evaluated.
Physical growth will be evaluated by collecting patient's height, weight and BSA. 5 years The long-term physical growth effect will be evaluated.
The development of second neoplasms will be monitored. 5 years The long-term development of second neoplasms will be evaluated.
Therapy-Related Hearing Loss Evaluation B 5 years The prevalence and severity of therapy-related hearing loss as a function of AuHPCR (one versus three tandem transplants in Consolidation) will be evaluated. Distortion-Product Oto-acoustic Emissions (DPOAE) will be used as an early predictor of hearing loss to identify at-risk patients.
Neuropathology Biorepository and Clinical Database 5 years The study will 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.
Trial Locations
- Locations (61)
Memorial Care Health Services
🇺🇸Fountain Valley, California, United States
Mattel Children's Hospital (UCLA)
🇺🇸Los Angeles, California, United States
UCSF Oakland Benioff
🇺🇸Oakland, California, United States
Akron Children's Hospital
🇺🇸Akron, Ohio, United States
Dayton Children's Hospital
🇺🇸Dayton, Ohio, United States
University of Iowa Hospital and Clinics
🇺🇸Iowa City, Iowa, United States
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, 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
Penn State Hershey Children's Hospital
🇺🇸Hershey, Pennsylvania, United States
Columbia Presbyterian Children's Hospital
🇺🇸New York, New York, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
NYU Langone Medical Center
🇺🇸New York, New York, United States
John's Hopkins All Children's Hospital
🇺🇸Saint Petersburg, Florida, United States
Children's Hospital of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Stollery Children's Hospital
🇨🇦Edmonton, Canada
Northwell Health
🇺🇸Hempstead, New York, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
The Hospital of Sick Children
🇨🇦Toronto, Canada
Starship Children's Hospital
🇳🇿Auckland, New Zealand
Hamilton Health/McMasters Children's Hospital, Hamilton, Canada
🇨🇦Hamilton, Canada
Rainbow Babies & Children's Hospital
🇺🇸Cleveland, Ohio, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Loma Linda University Medical Center
🇺🇸Loma Linda, California, United States
Children's Hospital Orange County
🇺🇸Orange, California, United States
Shands Children's Hospital/ University of FL
🇺🇸Gainesville, Florida, United States
John's Hopkins University School of Medicine
🇺🇸Baltimore, Maryland, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
American Family Children's Hospital/University of Wisconsin
🇺🇸Madison, Wisconsin, United States
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Alberta Children's Hospital
🇨🇦Calgary, Canada
Christchurch Children's Hospital
🇳🇿Christchurch, New Zealand
Nicklaus Children's Hospital
🇺🇸Miami, Florida, United States
Riley Children's Hospital/University of Indiana
🇺🇸Indianapolis, Indiana, United States
Masonic Children's Hospital/University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Children's Specialty Care of Nevada
🇺🇸Las Vegas, Nevada, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Vanderbilt-Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States
Primary Children's Hospital
🇺🇸Salt Lake City, Utah, United States
New York Medical College
🇺🇸Hawthorne, New York, United States
Children's of Alabama
🇺🇸Birmingham, Alabama, United States
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
Central Michigan University
🇺🇸Detroit, Michigan, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Joseph Sanzari Children's Hospital/ Hackensack University
🇺🇸Hackensack, New Jersey, United States
Helen DeVos Children's Hospital
🇺🇸Grand Rapids, Michigan, United States
Phoenix Children's Hospital
🇺🇸Phoenix, Arizona, United States
Children's Healthcare of Atlanta
🇺🇸Atlanta, Georgia, United States
Nemours Center for Cancer and Blood Disorders
🇺🇸Jacksonville, Florida, United States
Morristown Medical Center, Atlantic Health System
🇺🇸Morristown, New Jersey, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Arkansas Children's Hospital
🇺🇸Little Rock, Arkansas, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
B.C. Children's Hospital
🇨🇦Vancouver, British Columbia, Canada
Orlando Health
🇺🇸Orlando, Florida, United States
University of Louisville School of Medicine
🇺🇸Louisville, Kentucky, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Virginia Commonwealth University
🇺🇸Richmond, Virginia, United States