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

Medulloblastoma Clinical Trial

Official title:

HeadStart4: Newly Diagnosed Children (<10 y/o) With Medulloblastoma and Other CNS Embryonal Tumors Clinical and Molecular Risk-Tailored Intensive and Compressed Induction Chemotherapy Followed by Consolidation With Randomization to Either Single Cycle or to Three Tandem Cycles of Marrow-Ablative Chemotherapy With Autologous Hematopoietic Progenitor Cell Rescue

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02875314
• Other study ID #: IRB15-00399
• Status: Active, not recruiting
• Phase: Phase 4
• 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
• 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.

Related Conditions & MeSH terms

• Central Nervous System Embryonal Tumors
• Medulloblastoma
• Neoplasms, Germ Cell and Embryonal

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