Clinical Trials /

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

NCT02875314

Description:

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.

Related Conditions:
  • Central Nervous System Embryonal Neoplasm
  • Central Nervous System Ganglioneuroblastoma
  • Medulloblastoma
Recruiting Status:

Recruiting

Phase:

Phase 4

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: IRB15-00399
  • NCT ID: NCT02875314

Conditions

  • Medulloblastoma
  • Central Nervous System Embryonal Tumors

Interventions

DrugSynonymsArms
Inductionvincristine, cisplatin, cyclophosphamide, etoposide, high-dose methotrexateInduction
Single Cycle Intensive ChemotherapyCarboplatin, thiotepa, etoposideSingle Cycle Intensive Chemotherapy
Tandem 3 Cycle Intensive ChemotherapyCarboplatin, thiotepaTandem 3 Cycle Intensive Chemotherapy

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
InductionExperimentalThe 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.
  • Induction
Single Cycle Intensive ChemotherapyExperimentalThe 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
  • Single Cycle Intensive Chemotherapy
Tandem 3 Cycle Intensive ChemotherapyExperimentalThe 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.
  • Tandem 3 Cycle Intensive Chemotherapy

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
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Compare tandem consolidation vs. single cycle consolidation A
Time Frame:5 years
Safety Issue:
Description: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.

Secondary Outcome Measures

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

Details

Phase:Phase 4
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Nationwide Children's Hospital

Last Updated