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Dose Intensive Chemotherapy for Children Less Than Ten Years of Age Newly-Diagnosed With Malignant Brain Tumors: A Pilot Study of Two Alternative Intensive Induction Chemotherapy Regimens, Followed by Consolidation With Myeloablative Chemotherapy (Thiotepa and Carboplatin, With or Without Etoposide) and Autologous Stem Cell Rescue [HEAD START III]


Phase 3
N/A
10 Years
Open (Enrolling)
Both
Brain and Central Nervous System Tumors

Thank you

Trial Information

Dose Intensive Chemotherapy for Children Less Than Ten Years of Age Newly-Diagnosed With Malignant Brain Tumors: A Pilot Study of Two Alternative Intensive Induction Chemotherapy Regimens, Followed by Consolidation With Myeloablative Chemotherapy (Thiotepa and Carboplatin, With or Without Etoposide) and Autologous Stem Cell Rescue [HEAD START III]


OBJECTIVES:

Primary

- Determine the 2-year event-free survival (EFS) and overall survival (OS) of pediatric
patients with previously untreated nondisseminated medulloblastoma (< 4 years of age),
disseminated medulloblastoma (< 10 years of age), or noncerebellar primitive
neuroectodermal tumors (PNET) (disseminated or non-disseminated) treated with induction
chemotherapy followed by consolidation with myeloablative chemotherapy and autologous
hematopoietic stem cell rescue.

- Determine the toxicity of this regimen in these patients.

- Determine the mortality of patients treated with this regimen.

Secondary

- Determine the complete and partial response rates after completion of induction
chemotherapy in these patients stratified according to pathology (medulloblastoma vs
noncerebellar PNET vs high-grade gliomas vs atypical teratoid/rhabdoid tumors vs
choroid plexus carcinomas and atypical papillomas vs ependymomas).

- Describe the EFS and OS of these patients stratified according to additional diagnoses
(atypical teratoid/rhabdoid tumors vs choroid plexus carcinomas and atypical choroid
plexus papillomas vs ependymomas vs high-grade gliomas).

- Describe the time to progression and patterns of relapse in these patients stratified
by diagnosis and radiotherapy received (< 6 years of age with evidence of no residual
tumor pre-transplant and no post-transplant consolidation radiotherapy vs < 6 years of
age with residual tumor present pre-transplant treated with post-transplant
consolidation radiotherapy vs > 6 years of age treated with post-transplant
consolidation radiotherapy).

- Determine the neuropsychometric function, endocrinologic function, and physical growth
in these patients stratified according to radiotherapy received (none vs reduced-volume
craniospinal radiotherapy vs focused local-field radiotherapy).

OUTLINE: This is a pilot study. Patients are stratified according to type of tumor (nonglial
vs glial and diffuse pontine).

- Regimen C (patients with glial tumors):

- Stem cell harvesting (bone marrow and/or peripheral blood): Patients undergo
leukapheresis or bone marrow aspiration to collect bone marrow or peripheral blood
stem cells prior to beginning induction chemotherapy or after the first course of
induction chemotherapy.

- Induction chemotherapy: Patients receive vincristine IV on days 1, 8, and 15 of
courses 1-3, oral temozolomide once daily on days 1-5, and carboplatin IV over 4
hours on days 1 and 2. Patients also receive G-CSF SC beginning on day 6 and
continuing until blood counts recover. Treatment repeats every 28 days for 4
courses in the absence of disease progression or unacceptable toxicity.

Patients with unresectable bulky disease and corticosteroid dependence are removed from
study. All other patients proceed to consolidation chemotherapy.

- Consolidation chemotherapy: Patients receive carboplatin IV over 4 hours on days -8 to
-6 and thiotepa IV over 3 hours on days -5 to -3.

- Autologous bone marrow or peripheral blood stem cell transplantation: Patients undergo
reinfusion of bone marrow or peripheral blood stem cells on day 0. Patients also
receive G-CSF SC beginning on day 1 and continuing until blood counts recover.

- Radiotherapy: Beginning within 6 weeks after stem cell transplantation, patients > 6
years of age at diagnosis undergo radiotherapy once daily 5 days a week for 4-6 weeks
in the absence of disease progression or unacceptable toxicity. Patients ≤ 6 years of
age undergo radiotherapy if there is evidence of tumor remaining after completion of
induction chemotherapy.

- Regimen D2 (patients with nonglial tumors):

- Stem cell harvesting (bone marrow and/or peripheral blood): Patients undergo
leukapheresis or bone marrow aspiration to collect bone marrow or peripheral blood stem
cells prior to beginning induction chemotherapy or after the first course of induction
chemotherapy.

- Induction chemotherapy:

- Courses 1, 3, and 5 (28 days per course): Patients receive cisplatin IV over 6
hours on day 1, cyclophosphamide IV over 1 hour and etoposide IV over 2 hours on
days 2 and 3, high-dose methotrexate IV over 4 hours on day 4, and filgrastim
(G-CSF) subcutaneously (SC) beginning on day 5 and continuing until blood counts
recover. Patients also receive vincristine IV on days 1, 8, and 15 of courses 1
and 3.

- Courses 2 and 4 (28 days per course): Patients receive oral temozolomide once
daily on days 1-5, oral etoposide once daily on days 1-10, cyclophosphamide IV
over 1 hour on days 11 and 12, and G-CSF SC beginning on day 13 and continuing
until blood counts recover. Patients also receive vincristine IV on days 1, 8, and
15 of course 2.

Patients with unresectable bulky disease and corticosteroid dependence are removed from
study. All other patients proceed to consolidation chemotherapy.

- Consolidation chemotherapy: Patients receive carboplatin IV over 4 hours on days -8 to
-6 and thiotepa IV over 3 hours and etoposide IV over 3 hours on days -5 to -3.

- Autologous bone marrow or peripheral blood stem cell transplantation: Patients undergo
re-infusion of bone marrow or peripheral blood stem cells on day 0. Patients also
receive G-CSF SC beginning on day 1 and continuing until blood counts recover.

- Radiotherapy:Patients undergo radiotherapy as in regimen C. Patients in both regimens
undergo neuropsychological testing after induction chemotherapy but before
consolidation chemotherapy and then at 18, 36, and 54 months after completion of study
treatment. Neuropsychometric and neuroendocrine testing is performed before and after
radiotherapy. Quality of life is also assessed periodically.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 120 patients will be accrued for this study.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically confirmed malignant brain tumor, including any of the following:

- Posterior fossa medulloblastoma/primitive neuroectodermal tumor (PNET)*

- All stages allowed

- Must be < 4 years of age at diagnosis unless there is evidence of
postoperative residual tumor (> 1.5 cm² tumor area) or evidence of neuraxis
or extraneural dissemination (high-stage)

- Medulloblastoma, cerebral neuroblastoma, and ependymoblastoma allowed

- Low-stage (standard-risk) medulloblastoma not allowed in patients > 4
years of age

- Ependymoma*

- All stages and locations allowed

- Cellular and anaplastic subtypes allowed (no myxopapillary ependymomas of
the spinal cord)

- Must be < 36 months of age at diagnosis for posterior fossa tumor OR < 72
months of age for supratentorial tumor

- Evidence of neuraxis dissemination irrespective of primary site

- No cellular (low-grade) supratentorial ependymomas at any age with complete
resection of parenchymally based (i.e., not periventricular) supratentorial
tumors

- Brain stem tumor*

- All stages allowed irrespective of extent of resection

- No unbiopsied diffuse intrinsic pontine tumor

- Tumor pathologically confirmed to be either malignant glioma or PNET
allowed

- High-grade glioma**

- Primary atypical teratoid/rhabdoid tumor of the CNS*

- Choroid plexus carcinoma or atypical choroid plexus papilloma*

- All stages and locations allowed

- Anaplastic astrocytoma**

- Glioblastoma multiforme**

- Anaplastic oligodendroglioma**

- Anaplastic ganglioglioma**

- Other anaplastic mixed gliomas**

- Small-cell glioblastoma**

- Giant-cell glioblastoma**

- Gliosarcoma**

- The following diagnoses or subtypes are not allowed:

- Choroid plexus papilloma

- Pineocytoma

- Low-grade mixed glioma

- Primary CNS germ cell tumor

- Primary CNS lymphoma

- Solid leukemic lesions (i.e., chloromas, granulocytic sarcomas)

- Pleomorphic xanthoastrocytoma, low grade

- Desmoplastic ganglioglioma

- Low-grade astrocytoma

- Previously untreated disease

- Has undergone definitive surgery within the past 42 days NOTE: *Patients receive
treatment according to regimen D2

NOTE: **Patients receive treatment according to regimen C

PATIENT CHARACTERISTICS:

- Bilirubin < 1.5 mg/dL

- ALT and AST < 2.5 times upper limit of normal

- Creatinine clearance and/or glomerular filtration rate ≥ 60 mL/min

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- No prior radiotherapy or chemotherapy

- Prior corticosteroids allowed

- No concurrent corticosteroids for antiemesis only

- No concurrent brachytherapy or electron radiotherapy

- No concurrent dairy products or grapefruit juice with temozolomide administration

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Outcome Measure:

Time to tumor progression, disease recurrence, or death of any cause

Safety Issue:

No

Principal Investigator

Jonathan L. Finlay, MB, ChB

Investigator Role:

Study Chair

Investigator Affiliation:

Children's Hospital Los Angeles

Authority:

United States: Federal Government

Study ID:

CDR0000503990

NCT ID:

NCT00392886

Start Date:

March 2004

Completion Date:

Related Keywords:

  • Brain and Central Nervous System Tumors
  • untreated childhood medulloblastoma
  • untreated childhood supratentorial primitive neuroectodermal tumor
  • childhood infratentorial ependymoma
  • childhood supratentorial ependymoma
  • newly diagnosed childhood ependymoma
  • childhood high-grade cerebral astrocytoma
  • childhood oligodendroglioma
  • childhood atypical teratoid/rhabdoid tumor
  • childhood choroid plexus tumor
  • untreated childhood cerebellar astrocytoma
  • untreated childhood visual pathway and hypothalamic glioma
  • untreated childhood pineoblastoma
  • Brain Neoplasms
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms

Name

Location

Cleveland Clinic Taussig Cancer CenterCleveland, Ohio  44195
Children's Hospital of Orange CountyOrange, California  92668
Children's Mercy HospitalKansas City, Missouri  64108
Nemours Children's ClinicJacksonville, Florida  32207
Children's Memorial Hospital - ChicagoChicago, Illinois  60614
Schneider Children's HospitalNew Hyde Park, New York  11042
Kosair Children's HospitalLouisville, Kentucky  40202-3830
St. Vincent Mercy Medical CenterToledo, Ohio  43608
Toledo Children's HospitalToledo, Ohio  43601
Loma Linda University Cancer Institute at Loma Linda University Medical CenterLoma Linda, California  92354
Jonathan Jaques Children's Cancer Center at Miller Children's HospitalLong Beach, California  90801
Albert Einstein Cancer Center at Albert Einstein College of MedicineBronx, New York  10461
NYU Cancer Institute at New York University Medical CenterNew York, New York  10016
SUNY Upstate Medical University HospitalSyracuse, New York  13210
Rainbow Babies and Children's HospitalCleveland, Ohio  44106-5000
Childrens Hospital Los AngelesLos Angeles, California  90027
Children's Hospital and Research Center OaklandOakland, California  94609
Alfred I. duPont Hospital for ChildrenWilmington, Delaware  19803
Masonic Cancer Center at University of MinnesotaMinneapolis, Minnesota  55455
Herbert Irving Comprehensive Cancer Center at Columbia University Medical CenterNew York, New York  10032
Nationwide Children's HospitalColumbus, Ohio  43205-2696
Penn State Children's HospitalHershey, Pennsylvania  17033-0850
M. D. Anderson Cancer Center at University of TexasHouston, Texas  77030-4009
Riley's Children Cancer Center at Riley Hospital for ChildrenIndianapolis, Indiana  46202-5225
University of Chicago Comer Children's HospitalChicago, Illinois  60637
Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, Michigan  49503
Tomorrows Children's Institute at Hackensack University Medical CenterHackensack, New Jersey  07601
Mattel Children's Hospital at UCLALos Angeles, California  90095
Phoenix Children's Hospital Outpatient CenterPhoenix, Arizona  85016