Clinical trial NCT02875314: HeadStart4: Newly Diagnosed Children (<10 y/o) With Medulloblastoma and Other CNS Embryonal Tumors
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Medulloblastoma
Central Nervous System Embryonal Tumors
Lead sponsor: Nationwide Children's Hospital
Sponsor class: OTHER
Collaborators: name: Children's of Alabama
First posted: 2016-08-23
Enrollment: 250
Sex: ALL
Maximum age (years): 10
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Compare tandem consolidation vs. single cycle consolidation A
timeFrame: 5 years
measure: Compare tandem consolidation vs. single cycle consolidation B
timeFrame: 5 years
Secondary outcomes:
measure: Induction Cycle Reduction
timeFrame: 5 years
measure: Uniform Treatment Regimen
timeFrame: 5 years
measure: Therapy-Related Hearing Loss Evaluation A
timeFrame: 5 years
measure: Therapy-Related Hearing Loss Evaluation B
timeFrame: 5 years
measure: Neuropsychological effects will be evaluated using age based tests and questionnaires.
timeFrame: 5 years
measure: Endocrine studies will be conducted using Serum-free T4, TSH, Cortisol, IGF and IGFBP3 laboratory tests.
timeFrame: 5 years
measure: Physical growth will be evaluated by collecting patient's height, weight and BSA.
timeFrame: 5 years
measure: The development of second neoplasms will be monitored.
timeFrame: 5 years
measure: Neuropathology Biorepository and Clinical Database
timeFrame: 5 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's of Alabama
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center
state: California
city: Long Beach
country: United States
facility: Memorial Care Health Services
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: Mattel Children's Hospital (UCLA)
state: California
city: Oakland
country: United States
facility: UCSF Oakland Benioff
state: California
city: Orange
country: United States
facility: Children's Hospital Orange County
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Wilmington
country: United States
facility: Nemours Center for Cancer and Blood Disorders
state: Delaware
city: Washington DC
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: Shands Children's Hospital/ University of FL
state: Florida
city: Jacksonville
country: United States
facility: Nemours Center for Cancer and Blood Disorders
state: Florida
city: Miami
country: United States
facility: Nicklaus Children's Hospital
state: Florida
city: Orlando
country: United States
facility: Orlando Health
state: Florida
city: Saint Petersburg
country: United States
facility: John's Hopkins All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Indianapolis
country: United States
facility: Riley Children's Hospital/University of Indiana
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospital and Clinics
state: Iowa
city: Louisville
country: United States
facility: University of Louisville School of Medicine
state: Kentucky
city: Baltimore
country: United States
facility: John's Hopkins University School of Medicine
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Central Michigan University
state: Michigan
city: Grand Rapids
country: United States
facility: Helen DeVos Children's Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospital of Minnesota
state: Minnesota
city: Minneapolis
country: United States
facility: Masonic Children's Hospital/University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Las Vegas
country: United States
facility: Children's Specialty Care of Nevada
state: Nevada
city: Hackensack
country: United States
facility: Joseph Sanzari Children's Hospital/ Hackensack University
state: New Jersey
city: Morristown
country: United States
facility: Morristown Medical Center, Atlantic Health System
state: New Jersey
city: Hawthorne
country: United States
facility: New York Medical College
state: New York
city: Hempstead
country: United States
facility: Northwell Health
state: New York
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
city: New York
country: United States
facility: Columbia Presbyterian Children's Hospital
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Syracuse
country: United States
facility: Upstate Golisano Children's Hospital/ SUNY Upstate Medical University
state: New York
city: Charlotte
country: United States
facility: Carolina's HealthCare System/Levine Cancer Institute
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Akron
country: United States
facility: Akron Children's Hospital
state: Ohio
city: Cleveland
country: United States
facility: Rainbow Babies & Children's Hospital
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Dayton
country: United States
facility: Dayton Children's Hospital
state: Ohio
city: Hershey
country: United States
facility: Penn State Hershey Children's Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Madison
country: United States
facility: American Family Children's Hospital/University of Wisconsin
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Vancouver
country: Canada
facility: B.C. Children's Hospital
state: British Columbia
city: Calgary
country: Canada
facility: Alberta Children's Hospital
city: Edmonton
country: Canada
facility: Stollery Children's Hospital
city: Hamilton
country: Canada
facility: Hamilton Health/McMasters Children's Hospital, Hamilton, Canada
city: Toronto
country: Canada
facility: The Hospital of Sick Children
city: Auckland
country: New Zealand
facility: Starship Children's Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Children's Hospital
Study officials:
affiliation: Nationwide Children's Hospital
name: Randal Olshefski, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Global Neuro-Oncology, Inc.
name: Jonathan Finlay, MD
role: STUDY_CHAIR
affiliation: Children's of Alabama at UAB
name: Girish Dhall, MD
role: STUDY_CHAIR
References: