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Clinical Trial Details — Status: Active, not recruiting

Administrative data

NCT number NCT02875314
Other study ID # IRB15-00399
Secondary ID
Status Active, not recruiting
Phase Phase 4
First received
Last updated
Start date September 2015
Est. completion date December 2030

Study information

Verified date May 2024
Source Nationwide Children's Hospital
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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 information / eligibility

Status Active, not recruiting
Enrollment 250
Est. completion date December 2030
Est. primary completion date December 2024
Accepts healthy volunteers No
Gender All
Age group N/A to 10 Years
Eligibility 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.

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Induction
vincristine, cisplatin, cyclophosphamide, etoposide, high-dose methotrexate
Single Cycle Intensive Chemotherapy
Carboplatin, thiotepa, etoposide
Tandem 3 Cycle Intensive Chemotherapy
Carboplatin, thiotepa

Locations

Country Name City State
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 B.C. Children's Hospital Vancouver British Columbia
New Zealand Starship Children's Hospital Auckland
New Zealand Christchurch Children's Hospital Christchurch
United States Akron Children's Hospital Akron Ohio
United States University of Michigan Ann Arbor Michigan
United States Children's Healthcare of Atlanta Atlanta Georgia
United States Children's Hospital Colorado Aurora Colorado
United States John's Hopkins University School of Medicine Baltimore Maryland
United States Children's of Alabama Birmingham Alabama
United States Dana Farber Cancer Institute Boston Massachusetts
United States Medical University of South Carolina Charleston South Carolina
United States Carolina's HealthCare System/Levine Cancer Institute Charlotte North Carolina
United States Cleveland Clinic Cleveland Ohio
United States Rainbow Babies & Children's Hospital Cleveland Ohio
United States Nationwide Children's Hospital Columbus Ohio
United States Dayton Children's Hospital Dayton Ohio
United States Central Michigan University Detroit Michigan
United States Duke University Medical Center Durham North Carolina
United States Memorial Care Health Services Fountain Valley California
United States Shands Children's Hospital/ University of FL Gainesville Florida
United States Helen DeVos Children's Hospital Grand Rapids Michigan
United States Joseph Sanzari Children's Hospital/ Hackensack University Hackensack New Jersey
United States New York Medical College Hawthorne New York
United States Northwell Health Hempstead New York
United States Penn State Hershey Children's Hospital Hershey Pennsylvania
United States MD Anderson Cancer Center Houston Texas
United States Riley Children's Hospital/University of Indiana Indianapolis Indiana
United States University of Iowa Hospital and Clinics Iowa City Iowa
United States Nemours Center for Cancer and Blood Disorders Jacksonville Florida
United States Children's Specialty Care of Nevada Las Vegas Nevada
United States Arkansas Children's Hospital Little Rock Arkansas
United States Loma Linda University Medical Center Loma Linda California
United States Children's Hospital Los Angeles Los Angeles California
United States Mattel Children's Hospital (UCLA) Los Angeles California
United States University of Louisville School of Medicine Louisville Kentucky
United States American Family Children's Hospital/University of Wisconsin Madison Wisconsin
United States Nicklaus Children's Hospital Miami Florida
United States Medical College of Wisconsin Milwaukee Wisconsin
United States Children's Hospital of Minnesota Minneapolis Minnesota
United States Masonic Children's Hospital/University of Minnesota Minneapolis Minnesota
United States Morristown Medical Center, Atlantic Health System Morristown New Jersey
United States Vanderbilt-Ingram Cancer Center Nashville Tennessee
United States Columbia Presbyterian Children's Hospital New York New York
United States Memorial Sloan Kettering Cancer Center New York New York
United States NYU Langone Medical Center New York New York
United States UCSF Oakland Benioff Oakland California
United States Children's Hospital Orange County Orange California
United States Orlando Health Orlando Florida
United States Children's Hospital of Philadelphia Philadelphia Pennsylvania
United States Phoenix Children's Hospital Phoenix Arizona
United States Virginia Commonwealth University Richmond Virginia
United States Mayo Clinic Rochester Minnesota
United States Washington University School of Medicine Saint Louis Missouri
United States John's Hopkins All Children's Hospital Saint Petersburg Florida
United States Primary Children's Hospital Salt Lake City Utah
United States Upstate Golisano Children's Hospital/ SUNY Upstate Medical University Syracuse New York
United States Children's National Medical Center Washington District of Columbia
United States Nemours Center for Cancer and Blood Disorders Wilmington Delaware

Sponsors (2)

Lead Sponsor Collaborator
Parth Patel Children's of Alabama

Countries where clinical trial is conducted

United States,  Canada,  New Zealand, 

Outcome

Type Measure Description Time frame Safety issue
Primary Compare tandem consolidation vs. single cycle consolidation A 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. 5 years
Primary Compare tandem consolidation vs. single cycle consolidation B 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. 5 years
Secondary Induction Cycle Reduction 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. 5 years
Secondary Uniform Treatment Regimen 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. 5 years
Secondary Therapy-Related Hearing Loss Evaluation A 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. 5 years
Secondary Therapy-Related Hearing Loss Evaluation B 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. 5 years
Secondary Neuropsychological effects will be evaluated using age based tests and questionnaires. The long-term neuropsychological effects will be evaluated. 5 years
Secondary Endocrine studies will be conducted using Serum-free T4, TSH, Cortisol, IGF and IGFBP3 laboratory tests. The long-term endocrine functions effect will be evaluated. 5 years
Secondary Physical growth will be evaluated by collecting patient's height, weight and BSA. The long-term physical growth effect will be evaluated. 5 years
Secondary The development of second neoplasms will be monitored. The long-term development of second neoplasms will be evaluated. 5 years
Secondary Neuropathology Biorepository and Clinical Database 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. 5 years
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