MedPath

Combination Chemotherapy Followed By Peripheral Stem Cell Transplant in Treating Young Patients With Newly Diagnosed Supratentorial Primitive Neuroectodermal Tumors or High-Risk Medulloblastoma

Phase 3
Active, not recruiting
Conditions
Medulloblastoma
Anaplastic Medulloblastoma
Supratentorial Embryonal Tumor, Not Otherwise Specified
Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor
Interventions
Procedure: Autologous Hematopoietic Stem Cell Transplantation
Drug: Carboplatin
Drug: Cisplatin
Drug: Cyclophosphamide
Drug: Etoposide
Biological: Filgrastim
Other: Laboratory Biomarker Analysis
Other: Quality-of-Life Assessment
Drug: Leucovorin Calcium
Drug: Thiotepa
Drug: Methotrexate
Drug: Vincristine Sulfate
Registration Number
NCT00336024
Lead Sponsor
Children's Oncology Group
Brief Summary

This randomized phase III trial is studying two different combination chemotherapy regimens to compare how well they work in treating young patients with newly diagnosed supratentorial primitive neuroectodermal tumors or high-risk medulloblastoma when given before additional intense chemotherapy followed by peripheral blood stem cell rescue. It is not yet known which combination chemotherapy regimen is more effective when given before a peripheral stem cell transplant in treating supratentorial primitive neuroectodermal tumors or medulloblastoma.

Detailed Description

PRIMARY OBJECTIVES:

I. To determine if treatment of infants with high risk primitive neuroectodermal tumors (PNET) central nervous system (CNS) tumors with intensive chemotherapy plus high-dose methotrexate and peripheral blood stem cell rescue results in a higher complete response rate then the same regimen without methotrexate.

SECONDARY OBJECTIVES:

I. To determine whether biologic characterization of these tumors will refine therapeutic stratification separating atypical teratoid rhabdoid tumors (AT/RT) from primitive neuroectodermal tumors (PNETs) and possibly identifying other markers of value for stratification within the group of PNETs.

II. To determine if event free survival (EFS) and patterns of failure differ between the methotrexate arm versus the arm without methotrexate.

III. To compare the acute, chronic and late effects of these two very intensive regimens, especially as to the tolerance of the same consolidation regimen following the differing induction regimens.

IV. To compare the gastrointestinal and nutritional toxicities of these intense regimens.

V. To describe and compare the quality of life outcomes and neuropsychological effects of these intense systemic therapies.

OUTLINE: Patients are randomized to 1 of 2 treatment arms

INDUCTION THERAPY:

ARM I: Patients receive vincristine IV over 1 minute on days 1, 8, and 15; etoposide IV over 1 hour on days 1-3; cyclophosphamide IV over 1 hour on days 1 and 2; cisplatin IV over 6 hours on day 3; and filgrastim (G-CSF) IV or subcutaneously (SC) beginning on day 4 and continuing until blood counts recover. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive vincristine IV over 1 minute on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or orally (PO) every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Once methotrexate levels are in a safe range, patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Patients also receive G-CSF IV or SC beginning 24 hours after the completion of chemotherapy and continuing until blood counts recover. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

In both arms, patients with stable disease or partial response after induction therapy proceed to second-look surgery followed by consolidation therapy. Patients with a complete response after induction therapy proceed directly to consolidation therapy.

CONSOLIDATION THERAPY: Beginning no more than 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous peripheral blood stem cells (PBSC) IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up periodically for 4 years and then annually thereafter.

Recruitment & Eligibility

Status
ACTIVE_NOT_RECRUITING
Sex
All
Target Recruitment
91
Inclusion Criteria

  • High-risk medulloblastoma defined by any of the following:

    • > 1.5 cm^2 residual disease for any medulloblastoma histology, or
    • Lumbar cerebral spinal fluid (CSF) cytology positive for tumor cells by analysis of fluid collected either before definitive surgery or at least 10 days after definitive surgery unless contraindicated, or
    • Magnetic resonance imaging (MRI) evidence of M2 or M3 metastatic disease, or
    • M4 disease

  • Supratentorial primitive neuroectodermal tumor (PNET) (any M-stage) will be eligible for study entry

  • Children less than 8 months of age at the time of definitive surgery with or without measurable radiographic residual tumor with M0 stage medulloblastoma will be eligible for study entry

  • Patients with anaplastic medulloblastoma are eligible regardless of M-stage or residual tumor

  • Patients with M0 classic, non-desmoplastic medulloblastoma (R1) with radiographically measurable residual disease < 1.5 cm^2 are eligible

  • Cranial MRI (with and without gadolinium) must be done pre-operatively; post-operatively, cranial MRI (with and without gadolinium) must be done, preferably within 48 hours of surgery; entire spinal MRI must be obtained either pre-operatively (with gadolinium) or post-operatively (at least 10 days following surgery) prior to study enrollment (with and without gadolinium); patients with MRI evidence of spinal disease are eligible for this study

  • Evaluation of lumbar CSF cytology (cytospin preparation for microscopic evaluation) must be performed either pre-operatively or at least 10 days after definitive surgery unless contraindicated

  • Patient must have a life expectancy > 8 weeks

  • Patient must have received no prior radiation therapy or chemotherapy other than corticosteroids; corticosteroids are allowable for all patients

  • Creatinine clearance or radioisotope glomerular filtration rate >= 60 mL/min

  • Total bilirubin =< 1.5 x upper limit of normal (ULN) for age, and

  • Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamic pyruvic transaminase (SGPT) (alanine transaminase [ALT]) < 2 x ULN for age

  • Shortening fraction >= 27% by echocardiogram, or

  • Ejection fraction >= 47% by radionuclide angiogram

  • No evidence of dyspnea at rest

  • Pulse oximetry > 94% on room air

  • Peripheral absolute neutrophil count (ANC) > 1,000/uL

  • Platelet count > 100,000/uL (transfusion independent)

  • Hemoglobin greater than 8 g/dL (may have received red blood cell [RBC] transfusions allowed)

  • Hold trimethoprim/sulfamethoxazole (Bactrim) on the day of high-dose methotrexate (HDMTX) infusion and continue to hold until the methotrexate level is less than 0.1 micromolar (1 x 10-7 M)

  • Avoid probenecid, penicillins, cephalosporins, aspirin, proton pump inhibitors and nonsteroidal anti-inflammatory drug (NSAIDS) on the day of methotrexate and continue until the methotrexate level is less than 0.1 micromolar (1 x 10-7 M) as renal excretion of methotrexate is inhibited by these agents

  • Avoid IV contrast media, urinary acidifiers, phenytoin, and fosphenytoin on the day of methotrexate and until the methotrexate level is less than 0.1 micromolar (1 x 10-7 M)

  • Concurrent use of enzyme inducing anticonvulsants (e.g. phenytoin, phenobarbital, and carbamazepine) should be avoided

  • Clinically significant drug interactions have been reported when using vincristine with strong cytochrome P450 (CYP450) family 3 subfamily A member 4 (3A4) inhibitors and inducers; selected strong inhibitors of cytochrome P450 3A4 include azole antifungals, such as fluconazole, voriconazole, itraconazole, ketoconazole, and strong inducers include drugs such as rifampin, phenytoin, phenobarbitol, carbamazepine, and St. John's wort; the use of these drugs should be avoided with vincristine

  • All patients and/or their parents or legal guardians must sign a written informed consent

  • All institutional, Food and Drug administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Read More
Exclusion Criteria

Not provided

Read More

Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
Arm I (induction+consolidation chemotherapy, autologous PBSC)Autologous Hematopoietic Stem Cell TransplantationPatients receive vincristine IV over 1 minute on days 1, 8, and 15; etoposide IV over 1 hour on days 1-3; cyclophosphamide IV over 1 hour on days 1 and 2; cisplatin IV over 6 hours on day 3. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm I (induction+consolidation chemotherapy, autologous PBSC)Laboratory Biomarker AnalysisPatients receive vincristine IV over 1 minute on days 1, 8, and 15; etoposide IV over 1 hour on days 1-3; cyclophosphamide IV over 1 hour on days 1 and 2; cisplatin IV over 6 hours on day 3. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm I (induction+consolidation chemotherapy, autologous PBSC)Quality-of-Life AssessmentPatients receive vincristine IV over 1 minute on days 1, 8, and 15; etoposide IV over 1 hour on days 1-3; cyclophosphamide IV over 1 hour on days 1 and 2; cisplatin IV over 6 hours on day 3. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm I (induction+consolidation chemotherapy, autologous PBSC)Vincristine SulfatePatients receive vincristine IV over 1 minute on days 1, 8, and 15; etoposide IV over 1 hour on days 1-3; cyclophosphamide IV over 1 hour on days 1 and 2; cisplatin IV over 6 hours on day 3. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm II (induction+consolidation chemotherapy, autologous PBSC)Autologous Hematopoietic Stem Cell TransplantationPatients receive vincristine IV over 1 minute on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or PO every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm II (induction+consolidation chemotherapy, autologous PBSC)Laboratory Biomarker AnalysisPatients receive vincristine IV over 1 minute on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or PO every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm II (induction+consolidation chemotherapy, autologous PBSC)Leucovorin CalciumPatients receive vincristine IV over 1 minute on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or PO every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm II (induction+consolidation chemotherapy, autologous PBSC)Quality-of-Life AssessmentPatients receive vincristine IV over 1 minute on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or PO every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm II (induction+consolidation chemotherapy, autologous PBSC)Vincristine SulfatePatients receive vincristine IV over 1 minute on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or PO every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm I (induction+consolidation chemotherapy, autologous PBSC)CarboplatinPatients receive vincristine IV over 1 minute on days 1, 8, and 15; etoposide IV over 1 hour on days 1-3; cyclophosphamide IV over 1 hour on days 1 and 2; cisplatin IV over 6 hours on day 3. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm I (induction+consolidation chemotherapy, autologous PBSC)CyclophosphamidePatients receive vincristine IV over 1 minute on days 1, 8, and 15; etoposide IV over 1 hour on days 1-3; cyclophosphamide IV over 1 hour on days 1 and 2; cisplatin IV over 6 hours on day 3. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm I (induction+consolidation chemotherapy, autologous PBSC)CisplatinPatients receive vincristine IV over 1 minute on days 1, 8, and 15; etoposide IV over 1 hour on days 1-3; cyclophosphamide IV over 1 hour on days 1 and 2; cisplatin IV over 6 hours on day 3. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm I (induction+consolidation chemotherapy, autologous PBSC)FilgrastimPatients receive vincristine IV over 1 minute on days 1, 8, and 15; etoposide IV over 1 hour on days 1-3; cyclophosphamide IV over 1 hour on days 1 and 2; cisplatin IV over 6 hours on day 3. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm I (induction+consolidation chemotherapy, autologous PBSC)EtoposidePatients receive vincristine IV over 1 minute on days 1, 8, and 15; etoposide IV over 1 hour on days 1-3; cyclophosphamide IV over 1 hour on days 1 and 2; cisplatin IV over 6 hours on day 3. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm I (induction+consolidation chemotherapy, autologous PBSC)ThiotepaPatients receive vincristine IV over 1 minute on days 1, 8, and 15; etoposide IV over 1 hour on days 1-3; cyclophosphamide IV over 1 hour on days 1 and 2; cisplatin IV over 6 hours on day 3. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm II (induction+consolidation chemotherapy, autologous PBSC)CisplatinPatients receive vincristine IV over 1 minute on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or PO every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm II (induction+consolidation chemotherapy, autologous PBSC)CarboplatinPatients receive vincristine IV over 1 minute on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or PO every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm II (induction+consolidation chemotherapy, autologous PBSC)EtoposidePatients receive vincristine IV over 1 minute on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or PO every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm II (induction+consolidation chemotherapy, autologous PBSC)FilgrastimPatients receive vincristine IV over 1 minute on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or PO every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm II (induction+consolidation chemotherapy, autologous PBSC)CyclophosphamidePatients receive vincristine IV over 1 minute on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or PO every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm II (induction+consolidation chemotherapy, autologous PBSC)MethotrexatePatients receive vincristine IV over 1 minute on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or PO every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Arm II (induction+consolidation chemotherapy, autologous PBSC)ThiotepaPatients receive vincristine IV over 1 minute on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or PO every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
Primary Outcome Measures
NameTimeMethod
Number of Patients Who Have Either a Complete Response (CR) Rate or No Complete Response RateAt the end of consolidation treatment

At the end of consolidation, the number of evaluable patients treated with intensive chemotherapy with methotrexate who achieved CR or not will be compared to those who achieved CR or not after treated with the same intensive chemotherapy without methotrexate. The CR rates between these two groups will be compared at a significance level of 0.1 using one-sided Chi-square test. Complete Response (CR) requires: CR for target lesions: disappearance of all target lesions, CR for non-target lesions: disappearance of all non-target lesions and no new lesions. No CR is any response not fitting the definition of CR.

Secondary Outcome Measures
NameTimeMethod
Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 CohortAt baseline

The number of patients will be reported for this analysis by Molecular Sub-types of MB, CNS-PNETs/EBTs

Percentage of Participants With Event Free Survival (EFS)Baseline to up to 5 years

EFS was defined as time from enrollment to the occurrence of first event (disease progression/relapse, secondary malignancy, death from any cause) or date of last contact for patients who are event-free. The percentage of participants with EFS and 90% confidence interval were provided. The difference in incidence for the two treatment regimens were compared using a one-sided log-rank test with a significance level of 0.1.

Patterns of FailureBaseline to up to 5 years

The patterns of failure for relapse/disease progression will be provided for patients treated with/without methotrexate drug in three categories, namely local, distant, and both local and distant. The number of patients with each type of failure will be listed per arm. The two groups will be compared to determine if the pattern of failure distribution is different between the two arms using Fisher exact test.

Percentage of Participants With Any Acute Adverse EventsBeginning of treatment to the end of consolidation

Event is defined as the first occurrence of any acute toxicity. Estimates will be obtained using life-table methods. Patients who have progression or recurrence of disease will be censored in this analysis. Difference in incidence for the two treatment regimens will be compared using log-rank test.

Number of Participants With Acute Hearing Loss and No Acute Hearing LossBeginning of treatment to the end of consolidation

Per protocol, hearing was assessed pretreatment and at regular specified intervals during treatment and off therapy, using DPOAE, audiogram or Brainstem Evoked Auditory. Per CTCAE V4.0 grade 3 Hearing impaired is defined as follows; Pediatric (on a 1,2,3,4, 6 and 8 kHz audiogram): hearing loss sufficient to indicate therapeutic intervention, including hearing aids, threshold shift \>20 dB at 3 kHz and above in at least one ear, additional speech-language related services as indicated. Per CTCAE V4.0 grade 4 Hearing impaired is defined as follows; Pediatric Audiologic indication for cochlear implant and additional speech-language related services as indicated.

Number of Participants With Chronic Primary Hypothyroidism/Subclinical Compensatory HypothyroidismHypothyroidism/Subclinical Compensatory HypothyroidismOff-treatment up to 9 years

Thyroid function was assessed as per ACNS0334 Endocrine Guidelines. "Normal" and "Abnormal" are defined at each institution by the laboratory standards where the blood tests are run. Primary Hypothyroidism/Subclinical Compensatory Hypothyroidism is defined as patients with Free T4 level less than "Institutional" Normal or equal to "Institutional" Normal with TSH level greater than "Institutional" Normal.

Number of Participants With Chronic Central HypothyroidismOff-treatment up to 9 years

Thyroid function was assessed as per ACNS0334 Endocrine Guidelines. "Normal" and "Abnormal" are defined at each institution by the laboratory standards where the blood tests are run. Central Hypothyroidism is defined as Free T4 level less than "Institutional" Normal with TSH less than or equal to "Institutional" Normal.

Number of Participants With Chronic Low Somatomedin COff-treatment up to 9 years

Low Somatomedin C is defined as patients with somatomedin C value less than institutional normal. As numbers are too small, descriptive statistics such as number will be reported for this analysis. Growth hormone function was assessed as per ACNS0334 Endocrine Guidelines. Low Somatomedin C levels are defined at each institution by the laboratory standards where the blood tests are run.

Number of Participants With Chronic Diabetes InsipidusBeginning of off-treatment to up to 9 years

The number of patients who had "Diabetes Insipidus" and on DDAVP will be reported for this analysis due to small numbers..

Number of Participants With Secondary MalignanciesOff-treatment up to 9 years

The number of patients who had secondary malignancy will be reported for this analysis due to small numbers.

Number of Participants With Chronic/Late Hearing Loss and No Chronic/Late Hearing LossOff-treatment up to 9 years

The number of patients who are reported to have abnormal hearing, graded according to CTCAE 4.0 or not, with onset while on therapy or when off therapy which persisted after off therapy will be reported and will be compared using Fisher exact test.

Rates of Gastrointestinal ToxicitiesBeginning of treatment to the end of consolidation

Rates of gastrointestinal toxicities reported as Adverse Events during therapy for each cycle will be summarized using standard descriptive methods (such as number of patients). The difference in number of patients with gastrointestinal toxicities between the two treatment regimens will be compared using a Chi-square test.

Rates of Nutritional ToxicitiesBeginning of treatment to the end of consolidation

Rates of nutritional toxicities reported as Adverse Events during therapy for each cycle will be summarized using standard descriptive methods (such as number of patients). The difference in number of patients with nutritional toxicities between the two treatment regimens will be compared using a Chi-square test.

Median/Range of Patients for Total Quality of Life (QOL) Score, Intelligence Quotient (IQ) and Processing Speed Index (PSI).60 months (+/- 3 months)

Three tools are used to assess intelligence (IQ) depending on age. The range of IQ scores is 40-160 (mean=100, SD=15); range for the Processing Speed Index (PSI)=45-155. Higher scores represent better functioning. (1) Wechsler Preschool and Primary Scale of Intelligence-4th Edition (WPPSI-IV) is used for ages 2.5 to 6 years. Bug Search and Cancellation subtests are summed to calculate PSI. (2) Wechsler Intelligence Scales for Children-5th Edition (WISC-V) is used for ages 6 - 16 years. Symbol Search and Coding subtests are summed to calculate PSI. (3) Wechsler Adult Intelligence Scales-4th Edition (WAIS-IV) is used for ages 16 and older. Symbol Search and Coding subtests are summed to calculate PSI.

The Pediatric Quality of Life Inventory Version 4 (PedsQL) measures health-related quality of life (QOL). Parents complete the measure for children ages 2-17, and patients \> 18 complete a self-report version. Total scores range from 0-100, with higher scores representing better QOL.

Trial Locations

Locations (145)

Tulane University School of Medicine

🇺🇸

New Orleans, Louisiana, United States

Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital

🇺🇸

Grand Rapids, Michigan, United States

NYU Langone Hospital - Long Island

🇺🇸

Mineola, New York, United States

CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)

🇨🇦

Quebec, Canada

Children's Hospital of Alabama

🇺🇸

Birmingham, Alabama, United States

University of Alabama at Birmingham Cancer Center

🇺🇸

Birmingham, Alabama, United States

Phoenix Childrens Hospital

🇺🇸

Phoenix, Arizona, United States

Arkansas Children's Hospital

🇺🇸

Little Rock, Arkansas, United States

University of Arkansas for Medical Sciences

🇺🇸

Little Rock, Arkansas, United States

Kaiser Permanente Downey Medical Center

🇺🇸

Downey, California, United States

Loma Linda University Medical Center

🇺🇸

Loma Linda, California, United States

Miller Children's and Women's Hospital Long Beach

🇺🇸

Long Beach, California, United States

Children's Hospital Los Angeles

🇺🇸

Los Angeles, California, United States

Cedars Sinai Medical Center

🇺🇸

Los Angeles, California, United States

Valley Children's Hospital

🇺🇸

Madera, California, United States

Children's Hospital of Orange County

🇺🇸

Orange, California, United States

Sutter Medical Center Sacramento

🇺🇸

Sacramento, California, United States

University of California Davis Comprehensive Cancer Center

🇺🇸

Sacramento, California, United States

Rady Children's Hospital - San Diego

🇺🇸

San Diego, California, United States

UCSF Medical Center-Parnassus

🇺🇸

San Francisco, California, United States

Children's Hospital Colorado

🇺🇸

Aurora, Colorado, United States

Connecticut Children's Medical Center

🇺🇸

Hartford, Connecticut, United States

Alfred I duPont Hospital for Children

🇺🇸

Wilmington, Delaware, United States

Children's National Medical Center

🇺🇸

Washington, District of Columbia, United States

Broward Health Medical Center

🇺🇸

Fort Lauderdale, Florida, United States

Lee Memorial Health System

🇺🇸

Fort Myers, Florida, United States

Golisano Children's Hospital of Southwest Florida

🇺🇸

Fort Myers, Florida, United States

University of Florida Health Science Center - Gainesville

🇺🇸

Gainesville, Florida, United States

Memorial Regional Hospital/Joe DiMaggio Children's Hospital

🇺🇸

Hollywood, Florida, United States

Nemours Children's Clinic-Jacksonville

🇺🇸

Jacksonville, Florida, United States

University of Miami Miller School of Medicine-Sylvester Cancer Center

🇺🇸

Miami, Florida, United States

Nicklaus Children's Hospital

🇺🇸

Miami, Florida, United States

AdventHealth Orlando

🇺🇸

Orlando, Florida, United States

Arnold Palmer Hospital for Children

🇺🇸

Orlando, Florida, United States

Nemours Children's Clinic - Orlando

🇺🇸

Orlando, Florida, United States

Orlando Health Cancer Institute

🇺🇸

Orlando, Florida, United States

Nemours Children's Hospital

🇺🇸

Orlando, Florida, United States

Nemours Children's Clinic - Pensacola

🇺🇸

Pensacola, Florida, United States

Johns Hopkins All Children's Hospital

🇺🇸

Saint Petersburg, Florida, United States

Saint Joseph's Hospital/Children's Hospital-Tampa

🇺🇸

Tampa, Florida, United States

Saint Mary's Hospital

🇺🇸

West Palm Beach, Florida, United States

Children's Healthcare of Atlanta - Egleston

🇺🇸

Atlanta, Georgia, United States

Memorial Health University Medical Center

🇺🇸

Savannah, Georgia, United States

University of Hawaii Cancer Center

🇺🇸

Honolulu, Hawaii, United States

Saint Luke's Cancer Institute - Boise

🇺🇸

Boise, Idaho, United States

Lurie Children's Hospital-Chicago

🇺🇸

Chicago, Illinois, United States

Loyola University Medical Center

🇺🇸

Maywood, Illinois, United States

Advocate Children's Hospital-Oak Lawn

🇺🇸

Oak Lawn, Illinois, United States

Ascension Saint Vincent Indianapolis Hospital

🇺🇸

Indianapolis, Indiana, United States

University of Iowa/Holden Comprehensive Cancer Center

🇺🇸

Iowa City, Iowa, United States

University of Kentucky/Markey Cancer Center

🇺🇸

Lexington, Kentucky, United States

Norton Children's Hospital

🇺🇸

Louisville, Kentucky, United States

Eastern Maine Medical Center

🇺🇸

Bangor, Maine, United States

Johns Hopkins University/Sidney Kimmel Cancer Center

🇺🇸

Baltimore, Maryland, United States

Walter Reed National Military Medical Center

🇺🇸

Bethesda, Maryland, United States

Tufts Children's Hospital

🇺🇸

Boston, Massachusetts, United States

Dana-Farber Cancer Institute

🇺🇸

Boston, Massachusetts, United States

C S Mott Children's Hospital

🇺🇸

Ann Arbor, Michigan, United States

Michigan State University Clinical Center

🇺🇸

East Lansing, Michigan, United States

Bronson Methodist Hospital

🇺🇸

Kalamazoo, Michigan, United States

Kalamazoo Center for Medical Studies

🇺🇸

Kalamazoo, Michigan, United States

Children's Hospitals and Clinics of Minnesota - Minneapolis

🇺🇸

Minneapolis, Minnesota, United States

University of Minnesota/Masonic Cancer Center

🇺🇸

Minneapolis, Minnesota, United States

Mayo Clinic in Rochester

🇺🇸

Rochester, Minnesota, United States

University of Mississippi Medical Center

🇺🇸

Jackson, Mississippi, United States

Children's Mercy Hospitals and Clinics

🇺🇸

Kansas City, Missouri, United States

Cardinal Glennon Children's Medical Center

🇺🇸

Saint Louis, Missouri, United States

Washington University School of Medicine

🇺🇸

Saint Louis, Missouri, United States

Mercy Hospital Saint Louis

🇺🇸

Saint Louis, Missouri, United States

Alliance for Childhood Diseases/Cure 4 the Kids Foundation

🇺🇸

Las Vegas, Nevada, United States

Nevada Cancer Research Foundation NCORP

🇺🇸

Las Vegas, Nevada, United States

Hackensack University Medical Center

🇺🇸

Hackensack, New Jersey, United States

Morristown Medical Center

🇺🇸

Morristown, New Jersey, United States

Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital

🇺🇸

New Brunswick, New Jersey, United States

Newark Beth Israel Medical Center

🇺🇸

Newark, New Jersey, United States

Saint Joseph's Regional Medical Center

🇺🇸

Paterson, New Jersey, United States

Overlook Hospital

🇺🇸

Summit, New Jersey, United States

University of New Mexico Cancer Center

🇺🇸

Albuquerque, New Mexico, United States

Montefiore Medical Center - Moses Campus

🇺🇸

Bronx, New York, United States

Roswell Park Cancer Institute

🇺🇸

Buffalo, New York, United States

Laura and Isaac Perlmutter Cancer Center at NYU Langone

🇺🇸

New York, New York, United States

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center

🇺🇸

New York, New York, United States

Memorial Sloan Kettering Cancer Center

🇺🇸

New York, New York, United States

University of Rochester

🇺🇸

Rochester, New York, United States

Stony Brook University Medical Center

🇺🇸

Stony Brook, New York, United States

New York Medical College

🇺🇸

Valhalla, New York, United States

UNC Lineberger Comprehensive Cancer Center

🇺🇸

Chapel Hill, North Carolina, United States

Carolinas Medical Center/Levine Cancer Institute

🇺🇸

Charlotte, North Carolina, United States

Novant Health Presbyterian Medical Center

🇺🇸

Charlotte, North Carolina, United States

Sanford Broadway Medical Center

🇺🇸

Fargo, North Dakota, United States

Cincinnati Children's Hospital Medical Center

🇺🇸

Cincinnati, Ohio, United States

Rainbow Babies and Childrens Hospital

🇺🇸

Cleveland, Ohio, United States

Cleveland Clinic Foundation

🇺🇸

Cleveland, Ohio, United States

Nationwide Children's Hospital

🇺🇸

Columbus, Ohio, United States

Dayton Children's Hospital

🇺🇸

Dayton, Ohio, United States

ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital

🇺🇸

Toledo, Ohio, United States

Mercy Children's Hospital

🇺🇸

Toledo, Ohio, United States

University of Oklahoma Health Sciences Center

🇺🇸

Oklahoma City, Oklahoma, United States

Legacy Emanuel Children's Hospital

🇺🇸

Portland, Oregon, United States

Legacy Emanuel Hospital and Health Center

🇺🇸

Portland, Oregon, United States

Oregon Health and Science University

🇺🇸

Portland, Oregon, United States

Geisinger Medical Center

🇺🇸

Danville, Pennsylvania, United States

Children's Hospital of Philadelphia

🇺🇸

Philadelphia, Pennsylvania, United States

Saint Christopher's Hospital for Children

🇺🇸

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh of UPMC

🇺🇸

Pittsburgh, Pennsylvania, United States

Medical University of South Carolina

🇺🇸

Charleston, South Carolina, United States

Prisma Health Richland Hospital

🇺🇸

Columbia, South Carolina, United States

BI-LO Charities Children's Cancer Center

🇺🇸

Greenville, South Carolina, United States

Greenville Cancer Treatment Center

🇺🇸

Greenville, South Carolina, United States

Sanford USD Medical Center - Sioux Falls

🇺🇸

Sioux Falls, South Dakota, United States

East Tennessee Childrens Hospital

🇺🇸

Knoxville, Tennessee, United States

Vanderbilt University/Ingram Cancer Center

🇺🇸

Nashville, Tennessee, United States

Texas Tech University Health Sciences Center-Amarillo

🇺🇸

Amarillo, Texas, United States

Driscoll Children's Hospital

🇺🇸

Corpus Christi, Texas, United States

Medical City Dallas Hospital

🇺🇸

Dallas, Texas, United States

Cook Children's Medical Center

🇺🇸

Fort Worth, Texas, United States

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center

🇺🇸

Houston, Texas, United States

Covenant Children's Hospital

🇺🇸

Lubbock, Texas, United States

Methodist Children's Hospital of South Texas

🇺🇸

San Antonio, Texas, United States

University of Texas Health Science Center at San Antonio

🇺🇸

San Antonio, Texas, United States

Primary Children's Hospital

🇺🇸

Salt Lake City, Utah, United States

University of Vermont and State Agricultural College

🇺🇸

Burlington, Vermont, United States

Inova Fairfax Hospital

🇺🇸

Falls Church, Virginia, United States

Naval Medical Center - Portsmouth

🇺🇸

Portsmouth, Virginia, United States

Virginia Commonwealth University/Massey Cancer Center

🇺🇸

Richmond, Virginia, United States

Seattle Children's Hospital

🇺🇸

Seattle, Washington, United States

Providence Sacred Heart Medical Center and Children's Hospital

🇺🇸

Spokane, Washington, United States

Mary Bridge Children's Hospital and Health Center

🇺🇸

Tacoma, Washington, United States

Marshfield Medical Center-Marshfield

🇺🇸

Marshfield, Wisconsin, United States

Children's Hospital of Wisconsin

🇺🇸

Milwaukee, Wisconsin, United States

Sydney Children's Hospital

🇦🇺

Randwick, New South Wales, Australia

The Children's Hospital at Westmead

🇦🇺

Westmead, New South Wales, Australia

Royal Children's Hospital

🇦🇺

Parkville, Victoria, Australia

Princess Margaret Hospital for Children

🇦🇺

Perth, Western Australia, Australia

Alberta Children's Hospital

🇨🇦

Calgary, Alberta, Canada

British Columbia Children's Hospital

🇨🇦

Vancouver, British Columbia, Canada

CancerCare Manitoba

🇨🇦

Winnipeg, Manitoba, Canada

IWK Health Centre

🇨🇦

Halifax, Nova Scotia, Canada

McMaster Children's Hospital at Hamilton Health Sciences

🇨🇦

Hamilton, Ontario, Canada

Kingston Health Sciences Centre

🇨🇦

Kingston, Ontario, Canada

Children's Hospital of Eastern Ontario

🇨🇦

Ottawa, Ontario, Canada

Hospital for Sick Children

🇨🇦

Toronto, Ontario, Canada

The Montreal Children's Hospital of the MUHC

🇨🇦

Montreal, Quebec, Canada

Centre Hospitalier Universitaire Sainte-Justine

🇨🇦

Montreal, Quebec, Canada

San Jorge Children's Hospital

🇵🇷

San Juan, Puerto Rico

© Copyright 2025. All Rights Reserved by MedPath
HomeTerms & ConditionsPrivacy Policy