Active, not recruiting
Phase 2
Risk-Adapted Therapy for Young Children With Embryonal Brain Tumors, Choroid Plexus Carcinoma, High Grade Glioma or Ependymoma
Condition(s) studied
Brain and Central Nervous System Tumors
Investigational drug(s) / intervention(s)
Induction ChemotherapyLow-Risk TherapyHigh-Risk TherapyIntermediate-Risk Therapy
Induction Chemotherapy: All patients will receive 4 identical cycles of induction chemotherapy including highdose (5 g/m2 or 2.5g/m2 for patients less than or equal to 31 days of age at enrollment) intravenous methotrexate and standard dose vincristine, cisplatin, and cyclophosphamide.
Low-Risk Therapy: Induction will be followed by further conventional chemotherapy with carboplatin, cyclophosphamide, and etoposide. After consolidation, patients will receive 6 cycles of oral maintenance chemotherapy with cyclophosphamide, topotecan, and depending on the diagnosis, either erlotinib or etoposide (VP-16).
High-Risk Therapy: High risk patients will also receive vinblastine with each course of induction chemotherapy. Induction will be followed by either chemotherapy with targeted intravenous topotecan and cyclophosphamide or optional craniospinal irradiation (CSI). CSI will be offered only to patients who reach 3 years of age by the end of induction only. After consolidation, all patients will receive 6 cycles of oral maintenance chemotherapy with cyclophosphamide, topotecan, and depending on the diagnosis, either erlotinib or etoposide (VP-16).
Intermediate-Risk Therapy: Induction will be followed by consolidation focal radiotherapy (RT) to the tumor bed. Patients less than 12 months old upon completion of induction will receive low risk chemotherapy to delay RT until the age of 12 months. After consolidation, patients will receive 6 cycles of oral maintenance chemotherapy with cyclophosphamide, topotecan, and depending on the diagnosis, either erlotinib or etoposide (VP-16).
Note: The option to receive focal proton beam irradiation was suspended 10/29/2015. Focal photon beam irradiation continues as part of the treatment plan.
Study summary
RATIONALE: In this study a combination of anti-cancer drugs (chemotherapy) is used to treat brain tumors in young children. Using chemotherapy gives the brain more time to develop before radiation is given. The chemotherapy in this study includes the drug methotrexate. This drug was an important part of the two clinical trials which resulted in the best survival results for children less than 3 years of age with medulloblastoma. Most patients treated on this trial will also receive radiation which is carefully targeted to the area of the tumor. This type of radiation (focal conformal or proton beam radiotherapy) may result in fewer problems with thinking and learning than radiation to the whole brain and spinal cord.
PURPOSE: This clinical trial is studying how well giving combination chemotherapy together with radiation therapy works in treating young patients with newly diagnosed central nervous system tumors.
Eligibility
Histologically confirmed newly diagnosed CNS tumors of any of the following :
* Medulloblastoma (all histologic subtypes, including medullomyoblastoma and melanotic medulloblastoma)
* Supratentorial primitive neuroectodermal tumor (PNET) (including CNS neuroblastoma or ganglioneuroblastoma, medulloepithelioma, and ependymoblastoma)
* Pineoblastoma
* Atypical teratoid rhabdoid tumor (ATRT)
* Choroid plexus carcinoma
* High grade glioma (including anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic ganglioglioma, pleomorphic xanthoastrocytoma with anaplastic features, high-grade astroblastoma , anaplastic pilocytic astrocytoma, malignant glioneuronal tumor, glioblastoma multiforme), or gliosarcoma,
* Ependymoma (including all ependymoma histological variants)
* Age \< 3 years at time of diagnosis for all histological diagnosis. Medulloblastoma patients ≥ 3 and \< 5years old at diagnosis who have non-metastatic disease with no more than 1cm2 of residual tumor are also eligible.
* Meets criteria for 1 of the following risk groups:
* Low-risk group:
* Histologically confirmed nodular desmoplastic medulloblastoma, including medulloblastoma with extensive nodularity
* Focal areas of anaplasia or other atypical features suggesting more aggressive phenotype in a tumor otherwise considered nodular desmoplastic should be treated on the intermediate-risk group, with final risk stratification at the discretion of principal investigator and study pathologist
* No evidence of CNS metastasis 7 to 28 days after surgery by MRI and cytologic examination of lumbar cerebrospinal fluid (CSF)
* Ventricular CSF from a shunt or Ommaya reservoir may be used to rule out M1 disease when lumbar puncture is medically contraindicated
* Intermediate-risk group assignment when there is no other evidence of metastasis and CSF sampling is not possible
* Gross total resection, defined as residual tumor or imaging abnormality (not definitive for residual tumor) with a size of \< 1 cm2 confirmed on postoperative CT scan or MRI
* Brain stem invasion by the tumor in the absence of imaging evidence of residual tumor (tumor size \< 1 cm2) and otherwise meets criteria for the low-risk group, the patient will be classified as low-risk
* Desmoplastic medulloblastoma patients who are ≥3 -\<5 years of age will NOT be eligible for the low risk arm of the protocol.
* Intermediate-risk group:
* Histologically confirmed nodular desmoplastic medulloblastoma with less than gross total resection and no evidence of metastasis
* Any eligible histologic diagnosis other than desmoplastic medulloblastoma with no evidence of CNS metastasis
* Medulloblastoma patients who are ≥3 and \< 5 yrs of age irrespective of histology and with no evidence of CNS metastasis
* High-risk group:
* Any eligible histologic diagnosis with evidence of CNS metastasis
* Patients with extraneural metastasis are eligible for treatment on the high-risk group
PATIENT CHARACTERISTICS:
* Lansky performance status ≥ 30 (except for posterior fossa syndrome)
* WBC \> 2,000/mm3
* Platelets \> 50,000/mm3 (without support)
* Hemoglobin \> 8 g/dL (with or without support)
* ANC \> 500/mm3
* Serum creatinine \< 3 times upper limit of normal (ULN)
* ALT \< 5 times ULN
* Total bilirubin \< 3 times ULN
PRIOR CONCURRENT THERAPY:
* See Disease Characteristics
* No more than 31 days since prior definitive surgery
* No prior radiotherapy or chemotherapy other than corticosteroid therapy
Primary outcome measure(s)
- Percent Probability of Progression-free Survival (PFS) for Medulloblastoma Patients — From date on treatment until date of first progression or relapse or disease related death or date of last contact, estimated at 1 year after treatment
Progression was defined as 25% increase in the size of any measurable lesion; the appearance of a new lesion; or the conversion of negative cerebrospinal fluid (CSF) cytology to positive. Defined as the time interval from date on treatment until the date of first progression, medulloblastoma-related death or date of last contact for patients who have not experienced an event. All eligible medulloblastoma patients who received any methotrexate are included in this analysis.
- Percent Probability of Progression-free Survival (PFS) for Medulloblastoma Patients by DNA Methylation Subgroup — From date on treatment to date of first progression or relapse or disease related death or date of last contact, estimated at 1 year after treatment
Defined as the time interval from date on treatment until the date of first progression, medulloblastoma-related death or date of last contact for patients who have not experienced an event. Eligible medulloblastoma patients who received any methotrexate and had molecularly confirmed medulloblastoma are included in this analysis. Five patients were excluded as 3 had no archival tissue available and 2 were found to not be medulloblastoma by methylation profile.
- Percent Probability of Event-free Survival (EFS) for Medulloblastoma Patients — From date on treatment to date of first progression, relapse, second malignancy or death from any cause or to date of last contact, estimated at 1 year after
Defined as the time interval from date on treatment until the date of first progression, second malignancy or death due to any cause; or date of last contact for patients who have not experienced an event. All eligible medulloblastoma patients who received any methotrexate are included in this analysis.
Trial sites (6)
| Facility | City | Region | Status |
|---|
| Lucile Packard Children's Hospital at Stanford University Medical Center |
Palo Alto |
California |
|
| Rady Children's Hospital |
San Diego |
California |
|
| Children's Hospitals and Clinics of Minnesota - St. Paul |
Saint Paul |
Minnesota |
|
| St. Jude Children's Research Hospital |
Memphis |
Tennessee |
|
| University of Texas Southwestern Medical Center at Dallas |
Dallas |
Texas |
|
| Lady Cilento Children's Hospital, Brisbane |
Brisbane |
Queensland |
|
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