Combination Chemotherapy With or Without Filgrastim Before Surgery, High-Dose Chemotherapy, and Radiation Therapy Followed by Isotretinoin With or Without Monoclonal Antibody in Treating Patients With Neuroblastoma

Study Overview
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Brief Summary
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RATIONALE: Colony-stimulating factors such as filgrastim may increase the number of immune cells found in bone marrow or peripheral blood and may help a person's immune system recover from the side effects of chemotherapy. Combining chemotherapy with peripheral stem cell transplant may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. Monoclonal antibodies can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Combining isotretinoin and monoclonal antibodies may kill any remaining tumor cells following surgery. It is not yet known which treatment regimen is more effective in treating neuroblastoma. PURPOSE: This randomized phase III trial is studying how well combination chemotherapy with or without filgrastim before surgery, high-dose chemotherapy, and radiation therapy followed by isotretinoin with or without monoclonal antibody work in treating patients with neuroblastoma.

Detailed Description
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OBJECTIVES: Compare the efficacy of myeloablative therapy with busulfan and melphalan vs carboplatin, etoposide, and melphalan, in terms of 3- and 5-year event-free survival (EFS), progression-free survival (PFS), and overall survival (OS), in patients with high-risk neuroblastoma. Compare the 3-year EFS in these patients treated with isotretinoin with or without monoclonal antibody Ch14.18 after myeloablative therapy. Determine the response at metastatic sites after induction chemotherapy in these patients. Determine the effect of metastatic disease response after induction chemotherapy on EFS, PFS, and OS in these patients. Compare the toxicity and episodes of febrile neutropenia in patients treated with induction chemotherapy with or without filgrastim (G-CSF). Determine the effect of elective hematopoietic support with G-CSF during induction chemotherapy on peripheral blood stem cell collection in these patients. Compare the acute and long-term toxic effects of the 2 myeloablative therapy regimens in these patients. Determine the effect of radiotherapy on pre-surgical tumor volume at the primary site on local control, EFS, PFS, and OS in these patients. Determine the tolerability of isotretinoin with or without monoclonal antibody Ch14.18 after myeloablative therapy in these patients. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to disease stage (2 or 3 with MycN amplification vs 4). Patients are randomized to 1 of 8 treatment arms: Arm I: Patients receive induction chemotherapy comprising vincristine IV, carboplatin IV over 1 hour, and etoposide IV over 4 hours on days 1 and 41; vincristine IV and cisplatin IV over 24 hours on days 11, 31, 51, and 71; and vincristine IV on days 21 and 61 and cyclophosphamide IV and etoposide over 4 hours on days 21, 22, 61, and 62. Patients receive filgrastim (G-CSF) subcutaneously on days 3-8, 12-18, 23-28, 32-38, 43-48, 52-58, 63-68, and 72 until peripheral blood stem cell (PBSC) collection. Patients undergo PBSC collection beginning on day 80. Patients then undergo surgery on day 95. Patients receive myeloablative therapy comprising oral busulfan 4 times daily on days -6 to -3 and melphalan IV over 15 minutes on day -2. Patients undergo PBSC infusion on day 0. Patients undergo radiotherapy in 14 fractions over 21 days. Beginning within 30 days after radiotherapy, patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for 6 courses. Arm II: Patients receive induction chemotherapy as in arm I, but with no G-CSF. Patients then undergo PBSC collection and surgery as in arm I. Patients receive myeloablative therapy and undergo PBSC infusion as in arm I. Patients undergo radiotherapy as in arm I. Patients receive oral isotretinoin twice daily on days 1-14 and monoclonal antibody Ch14.18 IV over 8 hours on days 1-5. Treatment repeats every 28 days for 6 courses for isotretinoin and every 28 days for 5 courses for monoclonal antibody Ch14.18. Arm III: Patients receive induction chemotherapy and G-CSF as in arm I. Patients then undergo PBSC collection and surgery as in arm I. Patients receive myeloablative therapy and undergo PBSC infusion as in arm I. Patients undergo radiotherapy as in arm I. Patients receive isotretinoin as in arm I. Arm IV: Patients receive induction chemotherapy as in arm II. Patients then undergo PBSC collection and surgery as in arm I. Patients receive myeloablative therapy and undergo PBSC infusion as in arm I. Patients undergo radiotherapy as in arm I. Patients receive isotretinoin and monoclonal antibody Ch14.18 as in arm II. Arm V: Patients receive induction chemotherapy and G-CSF as in arm I. Patients receive myeloablative therapy comprising carboplatin IV continuously and etoposide IV continuously on days -7 to -4 and melphalan IV over 15 minutes on days -7 to -5. Patients undergo PBSC infusion on day 0. Patients undergo radiotherapy as in arm I. Patients receive isotretinoin as in arm I. Arm VI: Patients receive induction chemotherapy as in arm II. Patients receive myeloablative therapy and undergo PBSC infusion as in arm V. Patients undergo radiotherapy as in arm I. Patients receive isotretinoin and monoclonal antibody Ch14.18 as in arm II. Arm VII: Patients receive induction chemotherapy and G-CSF as in arm I. Patients receive myeloablative therapy and undergo PBSC infusion as in arm V. Patients undergo radiotherapy as in arm I. Patients receive isotretinoin as in arm I. Arm VIII: Patients receive induction chemotherapy as in arm II. Patients receive myeloablative therapy and undergo PBSC infusion as in arm V. Patients undergo radiotherapy as in arm I. Patients receive isotretinoin and monoclonal antibody Ch14.18 as in arm II. Patients on all treatment arms are followed every 6 months for 3 years and then annually for 2 years. Peer Reviewed and Funded or Endorsed by Cancer Research UK PROJECTED ACCRUAL: Approximately 175 patients per year will be accrued for this study.

Official Title
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High Risk Neuroblastoma Study 1 Of Siop-Europe

Conditions
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Neuroblastoma

Intervention / Treatment
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* Biological: filgrastim
* Biological: monoclonal antibody Ch14.18
* Drug: busulfan
* Drug: carboplatin
* Drug: cyclophosphamide
* Drug: etoposide
* Drug: isotretinoin
* Drug: melphalan
* Drug: vincristine sulfate
* Procedure: bone marrow ablation with stem cell support
* Procedure: conventional surgery
* Procedure: peripheral blood stem cell transplantation
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of neuroblastoma according to International Neuroblastoma Staging System Stage 2 or 3 with MycN amplification Stage 4 Tumor material available for determination of biological prognostic factors PATIENT CHARACTERISTICS: Age: 1 to 20 at diagnosis Performance status: Not specified Life expectancy: Not specified Hematopoietic: Not specified Hepatic: Bilirubin less than 3 times normal ALT less than 3 times normal Renal: Creatinine less than 1.5 mg/mL Creatinine clearance and/or glomerular filtration rate at least 60 mL/min Cardiovascular: Shortening fraction at least 28% OR Ejection fraction at least 55% No clinical congestive heart failure Pulmonary: Chest x-ray normal Oxygen saturation normal Other: HIV negative No Brock grade 2 or greater No uncontrolled infections requiring IV antivirals, antibiotics, or antifungals Not pregnant or nursing Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: No more than 1 prior chemotherapy regimen for localized unresectable disease No concurrent anthracyclines No other concurrent chemotherapy Endocrine: Not specified Radiotherapy: Not specified Surgery: Not specified Other: No other concurrent investigational therapy

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 20 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: Randomized


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: filgrastim|nan|
|Biological: monoclonal antibody Ch14.18|nan|
|Drug: busulfan|nan|
|Drug: carboplatin|nan|
|Drug: cyclophosphamide|nan|
|Drug: etoposide|nan|
|Drug: isotretinoin|nan|
|Drug: melphalan|nan|
|Drug: vincristine sulfate|nan|
|Procedure: bone marrow ablation with stem cell support|nan|
|Procedure: conventional surgery|nan|
|Procedure: peripheral blood stem cell transplantation|nan|
|Radiation: radiation therapy|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival at 3 years |  |  | 
| Mean number of febrile events during induction |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate assessed by the International Neuroblastoma Response Criteria after 4 and 8 induction chemotherapy courses |  |  | 
| Event-free survival at 5 years |  |  | 
| Overall survival |  |  | 
| Toxicity |  |  | 
| Biological factors (i.e., MycNM amplification, 1p deletion, ploidy, 17 q+, CD44, and Trk-A) |  |  | 
| Serum concentrations of lactic dehydrogenase, ferritin, neurone specific enolase |  |  | 
| Urinary catecholamines at diagnosis |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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regional neuroblastoma, disseminated neuroblastoma, stage 4S neuroblastoma, localized unresectable neuroblastoma