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

Children's Oncology Group91 enrolled

Overview

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.

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.

Interventions

Autologous Hematopoietic Stem Cell TransplantationPROCEDURE

Undergo autologous PBSC resuce

CarboplatinDRUG

Given IV

CisplatinDRUG

Given IV

CyclophosphamideDRUG

Given IV

EtoposideDRUG

Given IV

FilgrastimBIOLOGICAL

Given IV or SC

Laboratory Biomarker AnalysisOTHER

Correlative studies

Leucovorin CalciumDRUG

Given IV or orally

MethotrexateDRUG

Given IV

Quality-of-Life AssessmentOTHER

Ancillary studies

ThiotepaDRUG

Given IV

Vincristine SulfateDRUG

Given IV

Eligibility

Sex: ALLMax age: 2 Years

Medical Language ↔ Plain English

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

Locations (145)

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

Outcomes

Primary Outcomes

Number of Patients Who Have Either a Complete Response (CR) Rate or No Complete Response Rate

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.

Time frame: At the end of consolidation treatment

Secondary Outcomes

Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort

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

Time frame: At baseline

Percentage of Participants With Event Free Survival (EFS)

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 80% 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.

Time frame: Baseline to up to 5 years

Patterns of Failure

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.

Time frame: Baseline to up to 5 years

Percentage of Participants With Any Acute Adverse Events

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.

Time frame: Beginning of treatment to the end of consolidation

Number of Participants With Acute Hearing Loss and No Acute Hearing Loss

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.

Time frame: Beginning of treatment to the end of consolidation

Number of Participants With Chronic Primary Hypothyroidism/Subclinical Compensatory HypothyroidismHypothyroidism/Subclinical Compensatory Hypothyroidism

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.