Risk-Adapted Therapy in Treating Young Children with Brain Tumors
This phase II trial studies how well combination chemotherapy and radiation therapy work in treating younger patients with newly diagnosed central nervous system tumors. Drugs used in chemotherapy, such as methotrexate, vincristine sulfate, cisplatin, cyclophosphamide, vinblastine sulfate, carboplatin, etoposide, topotecan hydrochloride, and erlotinib hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x rays to kill tumor cells. Giving combination chemotherapy and radiation therapy may kill more tumor cells.
Inclusion Criteria
- Newly diagnosed tumor of the CNS, to include patients with: * Medulloblastoma (all histologic subtypes) * Supratentorial primitive neuro-ectodermal tumors (PNET) (including CNS neuroblastoma or ganglioneuroblastoma, medulloepithelioma, and ependymoblastoma) * Pineoblastoma * Atypical teratoid rhabdoid tumor (ATRT) * Choroid plexus carcinoma * High-grade glioma, including anaplastic astrocytoma (World Health Organization [WHO] grade III), anaplastic oligodendroglioma (WHO grade III), anaplastic oligoastrocytoma (WHO grade III), anaplastic ganglioglioma (WHO grade III), pleomorphic xanthoastrocytoma with anaplastic features (WHO grade III), high-grade astroblastoma, anaplastic pilocytic astrocytoma (WHO grade III), malignant glioneuronal tumor, glioblastoma multiforme (WHO grade IV) or gliosarcoma (WHO grade IV) * Patients with ependymoma (including all ependymoma histological variants)
- Histologic diagnosis has been verified by institutional pathologist and classified according to the WHO (2007) system
- Age < 3 years at time of diagnosis for all histological diagnosis
- Medulloblastoma patients >= 3 and < 5 years old at diagnosis who have non-metastatic disease with no more than 1 cm^2 of residual tumor are also eligible; medulloblastoma patients in the >= 3 and < 5 years old age group with anaplastic or large cell histology or with v-myc avian myelocytomatosis viral oncogene homolog (MYC) or v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) amplification are excluded; pathology from collaborating institutions must be centrally reviewed prior to enrollment for confirmation
- No previous radiotherapy or chemotherapy other than corticosteroid therapy
- Patients must begin treatment as outlined in the protocol within 31 days of definitive surgery
- Serum creatinine concentration < 3 X the institutional upper limit of normal (ULN)
- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) concentration < 5 X the institutional ULN
- Total bilirubin concentration < 3 X the institutional ULN
- Hemoglobin concentration > 8 g/dL (with or without support)
- White blood cell (WBC) > 2000/mm^3
- Absolute neutrophil count (ANC) > 500/mm^3
- Platelets > 50,000/mm^3 (without support)
- Adequate performance status as defined by Lansky Score >= 30 (except for Posterior Fossa Syndrome)
- CRITERIA FOR ASSIGNMENT TO THE LOW-RISK ARM OF THE PROTOCOL:
- LOW RISK MEDULLOBLASTOMA (patients must meet all of the following criteria):
- Histologic diagnosis of nodular desmoplastic medulloblastoma (includes medulloblastoma with extensive nodularity); patients with focal areas of anaplasia or other atypical features suggesting a more aggressive phenotype in a tumor which would otherwise be considered nodular desmoplastic should be treated on the intermediate risk arm; in such unusual cases, final risk stratification will be at the discretion of the principal investigator and study pathologist
- No evidence of CNS metastasis as indicated by MR images of the brain and spine and by cytologic examination of lumbar CSF 7 to 28 days after surgery; if lumbar puncture is medically contraindicated, ventricular CSF from a shunt or Ommaya reservoir may be used to rule out M1 disease; if CSF sampling is not possible and the patient has no other evidence of metastasis, the patient should be assigned to the intermediate risk arm
- Gross total resection as determined by the intraoperative observations of the neurosurgeon of record and confirmed by postoperative MR imaging; gross total resection is defined as residual tumor or imaging abnormality (not definitive for residual tumor) whose size is < 1 cm^2 on postoperative computed tomography (CT) or MR images
- If there is brain stem invasion by the tumor in the absence of imaging evidence of residual tumor (tumor size < 1 cm^2) and the patient otherwise meets criteria for enrollment on the low-risk arm, the patient will be classified as low-risk
- Desmoplastic medulloblastoma patients who are >= 3 to < 5 years of age will NOT be eligible for the low risk arm of the protocol
- LOW RISK HIGH-GRADE GLIOMA (patients must meet all of the following criteria):
- Histologic diagnosis of high-grade glioma, including anaplastic astrocytoma (WHO grade III), anaplastic oligodendroglioma (WHO grade III), anaplastic oligoastrocytoma (WHO grade III), anaplastic ganglioglioma (WHO grade III), pleomorphic xanthoastrocytoma with anaplastic features (WHO grade III), high grade astroblastoma (WHO grade III), anaplastic pilocytic astrocytoma (WHO grade III), malignant glioneuronal tumor, glioblastoma multiforme (WHO grade IV) or gliosarcoma (WHO grade IV)
- No evidence of CNS metastasis as indicated by MR images of the brain and spine and by cytologic examination of lumbar CSF 7 to 28 days after surgery; if lumbar puncture is medically contraindicated, ventricular CSF from a shunt or Ommaya reservoir may be used to rule out M1 disease; if CSF sampling is not possible and the patient has no other evidence of metastasis, the patient will be assigned to the low risk arm
- CRITERIA FOR ASSIGNMENT TO THE INTERMEDIATE-RISK ARM OF THE PROTOCOL
- Patients less than 3 years of age at diagnosis must meet one of the two following criteria:
- Histologic diagnosis of nodular desmoplastic medulloblastoma with less than gross total resection, but with 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 years of age with no more than 1cm^2 of residual tumor and with no evidence of CNS metastasis; medulloblastoma patients in the >= 3 and < 5 years old age group with anaplastic histology, large cell histology, melanotic differentiation, or myogenic differentiation or tumors with MYC or MYCN gain or amplification are excluded; pathology from collaborating institutions’ patients must be centrally reviewed prior to enrollment for confirmation
- CRITERIA FOR ASSIGNMENT TO THE HIGH-RISK ARM OF THE PROTOCOL
- Any eligible histologic diagnosis, with evidence of CNS metastasis
- Patients with extraneural metastasis are eligible for treatment on the high-risk arm
- Testing for extraneural metastasis by bone scan or bone marrow biopsy will not be performed routinely on this protocol; in the unlikely event that extraneural metastasis is detected on an evaluation performed at an outside institution prior to referral or because of clinical suspicion, such M4 patients will be eligible for protocol treatment on the high-risk arm
Additional locations may be listed on ClinicalTrials.gov for NCT00602667.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVES:
I. To identify patterns of methylation profiling that are associated with progression-free survival among young patients with medulloblastoma treated with risk-adapted therapy. (Biology)
II. To estimate the event free survival distribution of young medulloblastoma patients treated with risk-adapted therapy. (Therapeutic)
SECONDARY OBJECTIVES:
I. To perform high resolution genome-wide analyses of chromosomal abnormalities and gene expression patterns, and evaluate the relationship of these to other clinicopathological variables. (Biology)
II. To evaluate specific tumor types for molecular abnormalities with suspected prognostic or therapeutic significance. (Biology)
III. To evaluate the feasibility of collecting frozen and fixed tumor samples for analysis using high-resolution molecular biology tools. (Biology)
IV. To estimate the event free and overall survival of patients treated with the proposed risk-adapted therapy regimen, and to descriptively compare these survival rates to historical controls. (Therapeutic)
V. To estimate the rates of local and distant disease progression in patients treated with focal radiotherapy (RT) to the post-operative tumor bed using a 5 mm clinical target volume margin. (Therapeutic)
VI. To estimate the objective response rate (sustained for 8 weeks) to induction chemotherapy including high-dose intravenous methotrexate for patients with residual or metastatic disease. (Therapeutic)
VII. To evaluate the feasibility and toxicity of administering low dose intravenous vinblastine (vinblastine sulfate) in conjunction with induction chemotherapy to patients with metastatic disease. (Therapeutic)
VIII. To evaluate the feasibility and toxicity of administering consolidation therapy including cyclophosphamide and pharmacokinetically targeted topotecan (topotecan hydrochloride) to patients with metastatic disease, and to estimate the sustained (for 8 weeks) objective response rate (complete response and partial response) to such therapy in patients with measurable residual disease after induction. (Therapeutic)
IX. To evaluate the feasibility and toxicity of administering oral maintenance therapy in young children. (Therapeutic)
X. To use quantitative magnetic resonance (MR) measures (volumetric, diffusion, and perfusion) of young brain tumor patients receiving chemotherapy including high-dose intravenous methotrexate to assess impact of treatment on developing brain. (Therapeutic)
XI. Investigate the feasibility of using positron emission tomography (PET) as an in-vivo dosimetric and distal edge verification system for patients treated with proton beam therapy (for participants enrolled at St Jude only). (Therapeutic)
XII. To develop a population pharmacokinetic model containing covariates which explain inter- and intra-patient pharmacokinetic variability for high-dose methotrexate in young children with brain tumors, and to explore the relationship between clinical effect (toxicity and antitumor efficacy) and methotrexate pharmacokinetics. (Pharmacologic)
XIII. To assess the extent of inter-patient variability in the pharmacokinetics of intravenous and oral cyclophosphamide and metabolites in young children with brain tumors, and to explore possible associations between cyclophosphamide pharmacokinetic parameters and patient specific covariates (e.g., age, sex, race, weight). (Pharmacologic)
XIV. To assess the ability to achieve the target systemic exposure of intravenous topotecan in young patients with metastatic brain tumors. (Pharmacologic)
XV. To assess the extent of inter-patient variability in the pharmacokinetics of intravenous and oral topotecan in young children with brain tumors, and explore possible associations between topotecan systemic exposure and patient specific covariates (e.g., age, sex, race, weight). (Pharmacologic)
XVI. To assess the extent of inter-patient variability in the pharmacokinetics of oral erlotinib (erlotinib hydrochloride) in young children with medulloblastoma and ependymoma, and explore possible associations between erlotinib pharmacokinetic parameters and patient specific covariates (e.g., age, sex, race, weight). (Pharmacologic)
XVII. For St. Jude patients enrolled on the personal genomic (PGEN5) protocol, to assess the relation between pharmacogenetic variation in drug metabolizing enzymes and drug transporters, and the pharmacokinetics of methotrexate, cyclophosphamide, topotecan, and erlotinib in young children with brain tumors. (Pharmacologic)
XVIII. To explore possible associations between cerebrospinal fluid (CSF) neurotransmitter concentrations, with emphasis placed upon concentrations of dopamine and its metabolites, and the development of neurocognitive deficits as identified by standardized tests. (Cancer control aims)
XIX. To explore the association between genetic polymorphisms affecting central dopaminergic transmission and specific phenotypes, including central nervous system (CNS) neurotransmitter and neurocognitive performance phenotypes. (Cancer control aims)
XX. To investigate changes in neuropsychological performance among patients enrolled in the study, and examine the impact of the proposed treatment regimen and other disease related factors (e.g., hydrocephalus) on neuropsychological performance. (Cancer control aims)
XXI. To assess the impact of changes in quantitative MR measures in the frontal lobe on neurocognitive performance in attention, working memory, and fluency. (Cancer control aims)
XXII. To assess the impact of changes in quantitative MR measures in the right frontal-parietal regions on neurocognitive performance on visual-spatial reasoning and processing speed. (Cancer control aims)
XXIII. To assess the incidence of endocrinopathy after radiation therapy using photons or protons (for participants enrolled at St Jude only). (Cancer control aims)
XXIV. To estimate the rate of longitudinal change in growth hormone secretion after conformal, intensity-modulated and proton beam radiation therapy (for participants enrolled at St Jude only). (Cancer control aims)
OUTLINE:
INDUCTION THERAPY: Patients receive methotrexate intravenously (IV) over 24 hours on day 1, leucovorin calcium IV or orally (PO) every 6 hours (beginning at 42 hours) for 5 doses, vincristine sulfate IV on days 8 and 15, cisplatin IV over 6 hours on day 8, and cyclophosphamide IV over 1 hour on day 9. High-risk patients also receive vinblastine sulfate on days 17, 19, 22, 24, and 26. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION TREATMENT: Patients are assigned to 1 of 3 treatment groups.
GROUP I (low-risk): Patients receive cyclophosphamide IV over 1 hour on day 1, carboplatin IV over 1 hour on day 2, and etoposide IV over 1 hour on days 1 and 2. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity.
GROUP II (intermediate-risk): Patients undergo focal radiation therapy.
GROUP III (high-risk): Patients < 3 years of age receive topotecan hydrochloride IV over 4 hours on days 1-5 and cyclophosphamide IV over 1 hour on days 4 and 5. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients >= 3 years of age at end of induction will be offered craniospinal irradiation.
MAINTENANCE TREATMENT: Patients receive cyclophosphamide PO on days 1-21 and topotecan hydrochloride PO on days 1-10 of courses 1, 3 and 5. Patients with medulloblastoma, high-grade glioma, or ependymoma receive erlotinib hydrochloride PO on days 1-28 of courses 2, 4, and 6. Patients with all other diagnoses receive etoposide PO daily on days 1-21 of courses 2, 4, and 6. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 3, 6, 9, 12, 16, 20, 24, 30, and 36 months and then every 6-12 months for up to 60 months.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationSaint Jude Children's Research Hospital
Principal InvestigatorAmar Gajjar
- Primary IDSJYC07
- Secondary IDsNCI-2011-01193
- ClinicalTrials.gov IDNCT00602667