Carboplatin and Vincristine Plus Radiation Therapy Followed By Adjuvant Chemotherapy in Treating Young Patients With Newly Diagnosed CNS Embryonal Tumors

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as carboplatin and vincristine, work in 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 carboplatin and vincristine with radiation therapy followed by adjuvant chemotherapy may kill more tumor cells. PURPOSE: Randomized phase II trial to study the effectiveness of combination chemotherapy plus radiation therapy followed adjuvant chemotherapy in treating young patients who have newly diagnosed high-risk CNS embryonal tumors.

Detailed Description
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OBJECTIVES: Determine the feasible dose and duration of carboplatin combined with craniospinal and local radiotherapy and adjuvant chemotherapy in children with newly diagnosed, high-risk CNS embryonal tumors (Phase I completed as of 11-25-03). Determine the feasibility of administering cyclophosphamide and vincristine with or without cisplatin after concurrent carboplatin, vincristine, and radiotherapy in these patients. Determine the overall and individual toxicity rates of this regimen in these patients. Determine the complete response rate in patients treated with this regimen. Obtain preliminary estimates of event-free survival of patients treated with this regimen. Determine the prognostic significance of enhancing tumor after completion of radiotherapy on event-free survival of these patients. OUTLINE: This is a pilot, dose-escalation study of carboplatin. (Phase I completed as of 11-25-03.) Within 31 days of definitive surgery, all patients receive vincristine IV weekly for 6 weeks and carboplatin IV over 15-20 minutes (after completion of vincristine infusion) 5 days a week for 6 weeks. Patients undergo radiotherapy (1-4 hours after carboplatin infusion) 5 days a week for 6 weeks. Cohorts of 6-12 patients receive escalating doses of carboplatin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which no more than 3 of 12 patients experience dose-limiting toxicity. (Phase I completed as of 11-25-03.) At 6 weeks after completion of radiotherapy, patients are assigned to arm II for adjuvant/maintenance chemotherapy. (Arm I closed to accrual as of 11-25-03.) Arm I (closed to accrual as of 11-25-03): Patients receive cyclophosphamide IV over 1 hour on days 0 and 1, vincristine IV on days 0 and 7, and filgrastim (G-CSF) IV or subcutaneously (SC) beginning on day 2 and continuing for at least 10 days until blood counts recover. Arm II: Patients receive cyclophosphamide IV over 1 hour on days 1 and 2, vincristine IV on days 0 and 7, cisplatin IV over 6 hours on day 0, and G-CSF IV or SC beginning on day 3 and continuing for at least 10 days until blood counts recover. In both arms, adjuvant/maintenance chemotherapy repeats every 4 weeks for 6 courses. Patients are followed every 3 months for 8 months, every 4 months for 1 year, every 6 months for 2 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 162 patients will be accrued for this study.

Official Title
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An Intergroup Pilot Study of Concurrent Carboplatin, Vincristine and Radiotherapy Followed by Adjuvant Chemotherapy in Patients With Newly Diagnosed High-Risk Central Nervous System Embryonal Tumors

Conditions
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Brain Tumors, Central Nervous System Tumors, Neuroblastoma

Intervention / Treatment
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* Biological: filgrastim
* Drug: carboplatin
* Drug: cisplatin
* Drug: cyclophosphamide
* Drug: vincristine sulfate
* Procedure: adjuvant therapy
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically proven high-risk CNS embryonal tumors, including: Primitive neuroectodermal tumors Atypical teratoid/rhabdoid tumor Medulloblastoma Desmoplastic medulloblastoma Ependymoblastoma Medullomyoblastoma Spongioblastoma Spongioblastoma polare Primitive polar spongioblastoma Neuroepitheliomatous neoplasms Medulloepithelioma Neuroblastoma Pineoblastoma No bone marrow involvement or bone metastases No M4 disease M3 disease must have evidence of tumor on spinal MRI PATIENT CHARACTERISTICS: Age: 3 to 21 at diagnosis Performance status: Not specified Life expectancy: At least 8 weeks Hematopoietic: Absolute neutrophil count greater than 1,500/mm^3 Platelet count at least 100,000/mm^3 (transfusion independent) Hemoglobin at least 10.0 g/dL (packed red blood cell transfusions allowed) Hepatic: Bilirubin less than 1.5 mg/dL SGOT/SGPT less than 2.5 times normal Renal: Creatinine less than 1.5 times upper limit of normal OR Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: No prior chemotherapy Endocrine therapy: Not specified Radiotherapy: No prior radiotherapy Surgery: Prior definitive surgery allowed

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Newly diagnosed cerebral PNET with histologic verification<br>Begin therapy within 31 days of surgery. Radiation therapy will be given in standard fractions along with filgrastim. The craniospinal axis will be treated first. Patients will receive carboplatin at 35 mg/m2/day IV over 15-20 minutes Monday through Friday, 1-4 hours prior to radiation for 6 weeks (total of 30 doses). Vincristine sulfate 1.5 mg/m2 IV will be given weekly x 6. Following radiation, patients will receive Maintenance chemotherapy. Patients enrolled prior to Amendment #5 will receive six cycles of cyclophosphamide and vincristine (Regimen A). Patients enrolled after Amendment #5 will receive six cycles of cyclophosphamide, vincristine sulfate and cisplatin (Regimen B). | Biological: filgrastim<br>* Given IV<br>* Other names: NSC-614629;Drug: carboplatin<br>* Given IV<br>* Other names: NSC-241240;Drug: cisplatin<br>* Given IV<br>* Other names: NSC-119875;Drug: cyclophosphamide<br>* Given IV<br>* Other names: NSC-26271;Drug: vincristine sulfate<br>* Given IV<br>* Other names: NSC-67574;Procedure: adjuvant therapy<br> <br> Radiation: radiation therapy<br>* 1.8 Gy/fx x 20fx=36Gy Craniospinal XRT*<br>* Other names: radiotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival | Minimum time to disease progression or recurrence, time to death for any reason, or time to occurrence of a second malignant neoplasm (SMN). | Length of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | Time to death from any cause | Length of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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untreated childhood supratentorial primitive neuroectodermal tumor, untreated childhood medulloblastoma, localized unresectable neuroblastoma, regional neuroblastoma, stage 4S neuroblastoma