Etoposide Plus Radiation Therapy Followed by Combination Chemotherapy in Treating Children With Newly Diagnosed Advanced Medulloblastoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining radiation therapy with chemotherapy may kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of etoposide plus radiation therapy followed by combination chemotherapy in treating children with newly diagnosed advanced medulloblastoma.

Detailed Description
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OBJECTIVES: Assess the response rate and toxicity of oral etoposide and radiotherapy in children with newly diagnosed high stage medulloblastoma. Compare the response rate and toxicity of these patients to historical control patients registered on POG #9031. Estimate the 2-year event-free survival and overall survival of these patients. Evaluate the toxicity of dose intensive chemotherapy with oral etoposide, cisplatin, cyclophosphamide, and vincristine following craniospinal irradiation in these patients. OUTLINE: Patients begin treatment within 1 month of surgery. Patients receive 6 weeks of radiotherapy to the head and spine, with boosts to the posterior fossa and to sites of metastasis. Patients also receive 2 courses of oral etoposide once daily for 3 weeks concurrent with and immediately following radiotherapy (weeks 1-3 and 5-7). Patients then receive adjuvant chemotherapy consisting of cisplatin IV once every 4 weeks for 3 courses beginning on week 11, oral etoposide daily for 21 days every 4 weeks for 3 courses (weeks 11, 15, and 19), cyclophosphamide IV on days 1 and 2 with filgrastim (G-CSF) SQ daily for at least 10 days every 4 weeks for 8 courses (weeks 23-51), and vincristine IV on days 1, 8, and 15 every 4 weeks for 8 courses (weeks 23-51). Patients are followed every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year, and annually thereafter. PROJECTED ACCRUAL: A total of 48 patients will be accrued for this study within about 2 years.

Official Title
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A Phase I/II Feasibility Study of Oral Etoposide Given Concurrently With Radiotherapy Followed With Dose Intensive Adjuvant Chemotherapy for Children With Newly Diagnosed High Stage Medulloblastoma

Conditions
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Brain Tumors, Central Nervous System Tumors

Intervention / Treatment
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* Biological: filgrastim
* Drug: cisplatin
* Drug: cyclophosphamide
* Drug: etoposide
* Drug: vincristine sulfate
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically diagnosed advanced (high grade) childhood medulloblastoma Residual disease of at least 1.5 cm2 in size on MRI or CT scan OR Evidence of CNS or extraneural metastases PATIENT CHARACTERISTICS: Age: 3 to 21 Performance status: Not specified Life expectancy: Not specified Hematopoietic: Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Hepatic: SGPT less than 5 times normal Bilirubin less than 1.5 mg/dL Renal: Creatinine less than 1.7 mg/dL OR Creatinine clearance greater than 70 mL/min Other: Not pregnant or nursing Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: No prior chemotherapy Endocrine therapy: Prior corticosteroids allowed Radiotherapy: No prior radiotherapy Surgery: Not specified

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 21 Years

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment 1, Etoposide, 50mg/m2/day<br>Patients begin treatment within 1 month of surgery. Patients receive 6 weeks of radiation therapy to the head and spine, with boosts to the posterior fossa and to sites of metastasis. Patients also receive 2 courses of oral etoposide once daily for 3 weeks concurrent with and immediately following radiotherapy (weeks 1-3 and 5-7). Patients then receive adjuvant chemotherapy consisting of cisplatin IV once every 4 weeks for 3 courses beginning on week 11, oral etoposide daily for 21 days every 4 weeks for 3 courses (weeks 11, 15, and 19), cyclophosphamide IV on days 1 and 2 with filgrastim (G-CSF) SQ daily for at least 10 days every 4 weeks for 8 courses (weeks 23-51), and vincristine IV on days 1, 8, and 15 every 4 weeks for 8 courses (weeks 23-51). | Biological: filgrastim<br> <br> * Other names: NSC #614629;Drug: cisplatin<br> <br> * Other names: NSC #119875;Drug: cyclophosphamide<br> <br> * Other names: IND #7089;Drug: etoposide<br> <br> * Other names: IND #9197;Drug: vincristine sulfate<br> <br> * Other names: IND #7161;Radiation: radiation therapy<br> <br> |
| Experimental: Treatment 2, Etoposide, 35mg/m2/day<br>Patients begin treatment within 1 month of surgery. Patients receive 6 weeks of radiation therapy to the head and spine, with boosts to the posterior fossa and to sites of metastasis. Patients also receive 2 courses of oral etoposide once daily for 3 weeks concurrent with and immediately following radiotherapy (weeks 1-3 and 5-7). Patients then receive adjuvant chemotherapy consisting of cisplatin IV once every 4 weeks for 3 courses beginning on week 11, oral etoposide daily for 21 days every 4 weeks for 3 courses (weeks 11, 15, and 19), cyclophosphamide IV on days 1 and 2 with filgrastim (G-CSF) SQ daily for at least 10 days every 4 weeks for 8 courses (weeks 23-51), and vincristine IV on days 1, 8, and 15 every 4 weeks for 8 courses (weeks 23-51). | Biological: filgrastim<br> <br> * Other names: NSC #614629;Drug: cisplatin<br> <br> * Other names: NSC #119875;Drug: cyclophosphamide<br> <br> * Other names: IND #7089;Drug: etoposide<br> <br> * Other names: IND #9197;Drug: vincristine sulfate<br> <br> * Other names: IND #7161;Radiation: radiation therapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the efficacy of oral etoposide at 50 mg/m2/day given concurrently with radiotherapy followed with dose intensive adjuvant chemotherapy in children with newly diagnosed high stage medulloblastoma | It is possible that unacceptably high levels of toxicity may arise. For this reason, there is a 3-stage stopping rule designed to allow the Study Coordinator to stop this study early if it appears that the true proportion of eligible patients who suffer unacceptable levels of toxicity exceeds 10%. | End of course 1 (week 10) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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untreated childhood medulloblastoma