Combination Chemotherapy in Treating Younger Patients With Newly Diagnosed, Non-metastatic Desmoplastic Medulloblastoma

Study Overview
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Brief Summary
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This phase II trial studies how well combination chemotherapy works in treating younger patients with newly diagnosed, non-metastatic desmoplastic medulloblastoma. Drugs used in chemotherapy, such as vincristine sulfate, cyclophosphamide, methotrexate, etoposide, and carboplatin, 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.

Detailed Description
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PRIMARY OBJECTIVES: I. Estimate of the progression free survival (PFS) distribution for patients 0-<4 years of age with M0 desmoplastic medulloblastoma (nodular desmoplastic or medulloblastoma with extensive nodularity) treated with the modified HIT SKK regimen (excluding the use of intraventricular methotrexate). OTHER PRE-SPECIFIED OBJECTIVES: I. Evaluate the feasibility of a rapid central pathology screening review for treatment allocation according to histology and assess agreement between institutional and central pathology review diagnoses as well as among central pathology review diagnoses. II. Prospectively evaluate the molecular profile of nodular desmoplastic (ND)/medulloblastoma with extensive nodularity (MBEN) medulloblastoma in young children. III. Monitor and describe the neurocognitive and adaptive functioning of young children with ND/MBEN medulloblastoma treated on this protocol using the ALTE07C1 protocol. OUTLINE: INDUCTION THERAPY: Patients receive vincristine sulfate intravenously (IV) over 1 minute or infused via minibag on days 1, 15, and 29; cyclophosphamide IV over 1 hour on days 1-3; methotrexate IV over 24 hours on days 15 and 29; etoposide IV over 60-120 minutes on days 43-45; and carboplatin IV over 1 hour on days 43-45. Treatment repeats every 63 days for 3 courses in the absence of disease progression or unacceptable toxicity. CONTINUATION THERAPY: Patients receive vincristine sulfate IV over 1 minute or infused via minibag on day 1, cyclophosphamide IV over 1 hour on days 1-3, etoposide IV over 60-120 minutes on days 21-23, and carboplatin IV over 1 hour on days 21-23. Treatment repeats every 42 days for 2 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, 36, 48, 60, and 72 months.

Official Title
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A Phase II Study for the Treatment of Non-metastatic Nodular Desmoplastic Medulloblastoma in Children Less Than 4 Years of Age

Conditions
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Desmoplastic/Nodular Medulloblastoma, Medulloblastoma, Medulloblastoma With Extensive Nodularity, Nevoid Basal Cell Carcinoma Syndrome

Intervention / Treatment
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* Drug: Carboplatin
* Other: Cognitive Assessment
* Drug: Cyclophosphamide
* Drug: Etoposide
* Other: Laboratory Biomarker Analysis
* Drug: Methotrexate
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be newly diagnosed and have a confirmed histologic diagnosis of nodular desmoplastic (ND) medulloblastoma or medulloblastoma with extensive nodularity (MBEN) from rapid central pathology screening review; please note: patients with Gorlin syndrome are eligible Patient must have negative lumbar cerebrospinal fluid (CSF) cytology (lumbar CSF must be obtained unless medically contraindicated); CSF cytology for staging should be performed preferably no sooner than 14 days post operatively to avoid false positive CSF, ideally, CSF should be obtained between day 14 and day 21 to allow for final staging status before enrollment onto the study; Note: patients with positive CSF cytology obtained prior to 14 days after surgery may have cytology repeated to determine eligibility and final CSF status Patients must have: Pre-operative cranial magnetic resonance imaging (MRI) (recommended with gadolinium) or pre-operative computed tomography (CT) (recommended with contrast) Post-operative cranial MRI with and without gadolinium within 72 hours of surgery Spinal MRI pre-op with and without gadolinium or post-op with and without gadolinium preferably within 72 hours of surgery Patients must be enrolled on study within 31 days of definitive surgical resection at which time tissue is acquired to determine a diagnosis; patients must be enrolled before treatment begins; the date protocol therapy is projected to start must be no later than five (5) calendar days after the date of study enrollment; patients who are started on protocol therapy on a Phase II study prior to study enrollment will be considered ineligible Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2; use Lansky for patients =< 16 years of age Patients must have a life expectancy of >= 8 weeks Patients who are receiving dexamethasone must be on a stable dose for at least 1 week prior to study entry Peripheral absolute neutrophil count (ANC) >= 1000/uL Platelet count >= 100,000/uL (transfusion independent) Hemoglobin >= 10.0 g/dL (may receive red blood cell [RBC] transfusions) Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows: 1 month to < 6 months: 0.4 mg/dL 6 months to < 1 year: 0.5 mg/dL 1 to < 2 years: 0.6 mg/dL 2 to < 6 years: 0.8 mg/dL Total bilirubin =< 1.5 x upper limit of normal (ULN) for age Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x upper limit of normal (ULN) for age Central nervous system function defined as: Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled Patients must not be in status, coma or assisted ventilation prior to study enrollment Exclusion Criteria: Patients with metastatic disease by either MRI evaluation (brain and spine) or lumbar CSF cytology are not eligible Patients must not have received any prior tumor-directed therapy other than surgical intervention and corticosteroids

Ages Eligible for Study
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Maximum Age: 47 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (combination chemotherapy)<br>INDUCTION THERAPY: Patients receive vincristine sulfate IV over 1 minute or infused via minibag on days 1, 15, and 29; cyclophosphamide IV over 1 hour on days 1-3; methotrexate IV over 24 hours on days 15 and 29; etoposide IV over 60-120 minutes on days 43-45; and carboplatin IV over 1 hour on days 43-45. Treatment repeats every 63 days for 3 courses in the absence of disease progression or unacceptable toxicity. CONTINUATION THERAPY: Patients receive vincristine sulfate IV over 1 minute or infused via minibag on day 1, cyclophosphamide IV over 1 hour on days 1-3, etoposide IV over 60-120 minutes on days 21-23, and carboplatin IV over 1 hour on days 21-23. Treatment repeats every 42 days for 2 courses in the absence of disease progression or unacceptable toxicity. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Other: Cognitive Assessment<br>* Optional ancillary studies<br>Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Methotrexate<br>* Given IV<br>* Other names: WR-19039;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Progression-free survival (PFS) is defined as the time interval from diagnosis to the earliest of disease progression/recurrence or death from any cause, or to the date of last follow-up for patients without events. PFS was estimated using the method of Kaplan and Meier. 2-year estimates are reported with 95% CI's. | 2 years from diagnosis | 
| Overall Survival (OS) | Overall Survival (OS) is defined as the time from diagnosis to death from any cause, or to the date of last follow-up for survivors. OS was estimated using the method of Kaplan and Meier. 2-year estimates are reported with 95% CI's, as the data are not mature to 72 months. | Assessed up to 72 months, reported at 2 years from diagnosis | 
| Event-free Survival (EFS) | Event-free survival (EFS) is defined as the time from diagnosis to the earliest of disease progression/recurrence, second malignancy or death from any cause, or to the date of last follow-up for patients without events. EFS was estimated using the method of Kaplan and Meier. 2-year estimates are reported with 95% CI's. | 2 years from diagnosis | 
| Percentage of Patients With Responses at 189 Days | The percentage of patients with complete response (CR) at the end of induction ( 189 days) was reported and presented with the associated exact 95% confidence interval. | 189 days from start of treatment | 
| Percentage of Patients With Responses at 273 Days | The percentage of patients with complete response (CR) at the end of therapy ( 273 days) was reported and presented with the associated exact 95% confidence interval. | 273 days from start of treatment |