Monoclonal Antibody 3F8 and Sargramostim in Treating Patients With Neuroblastoma

Study Overview
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Brief Summary
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RATIONALE: Monoclonal antibodies, such as monoclonal antibody 3F8, can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Colony-stimulating factors, such as sargramostim, may increase the number of immune cells found in bone marrow or peripheral blood. Combining monoclonal antibody 3F8 with sargramostim may cause a stronger immune response and kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of combining monoclonal antibody 3F8 with sargramostim in treating patients who have neuroblastoma.

Detailed Description
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OBJECTIVES: Determine the efficacy of sargramostim (GM-CSF) in enhancing monoclonal antibody 3F8-mediated ablation in patients with high-risk neuroblastoma. Determine the prognostic impact of minimal residual bone marrow disease on relapse-free survival of patients treated with this regimen. Compare the effects of short-term (2-hour intravenous) vs prolonged (subcutaneous release) daily GM-CSF on granulocyte activation, in order to establish the optimal route for tumor-cell kill in these patients. OUTLINE: This is an open-label study. Patients are stratified according to evaluable disease (yes [primary refractory bone marrow disease] vs no [no evidence of disease]). Patients receive sargramostim (GM-CSF) subcutaneously on days -5 to 4 and monoclonal antibody 3F8 IV over 0.5-1.5 hours on days 0-4. Treatment repeats every 3 weeks for 4 courses and then every 8 weeks for up to a total of 24 months in the absence of disease progression or unacceptable toxicity. Beginning after 2 courses of GM-CSF and monoclonal antibody 3F8, patients also receive oral isotretinoin twice daily on days 1-14 (when no monoclonal antibody 3F8 is administered). Treatment with isotretinoin repeats approximately every 28 days for 6 courses. PROJECTED ACCRUAL: A total of 340 patients will be accrued for this study.

Official Title
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Phase II Study of Anti-GD2 3F8 Antibody and GM-CSF for High-Risk Neuroblastoma

Conditions
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Neuroblastoma

Intervention / Treatment
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* Biological: anti-GD2 murine IgG3 monoclonal antibody 3F8
* Biological: anti-GD2 murine IgG3 monoclonal antibody 3F8


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of neuroblastoma by histopathology OR bone marrow metastases and high urine catecholamine levels Disease must meet risk-related treatment guidelines and any of the following International Neuroblastoma Staging System stages: Stage 4 with (any age) OR without (> 18 months of age of age) MYCN amplification MYCN-amplified other than stage 1 No evidence of disease (i.e., in complete response/remission or very good partial response/remission) OR disease resistant to standard therapy (i.e., incomplete response in bone marrow) No progressive disease or MIBG-avid soft tissue tumor PATIENT CHARACTERISTICS: No existing renal, cardiac, hepatic, neurologic, pulmonary, or gastrointestinal toxicity ≥ grade 3 No human anti-mouse antibody (HAMA) titer greater than 1,000 Elisa units/mL No history of allergy to mouse proteins No active life-threatening infection Not pregnant Negative pregnancy test PRIOR CONCURRENT THERAPY: Not specified
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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: patients have refractory bone marrow disease<br>This phase II trial of the anti-GD2 murine IgG3 monoclonal antibody 3F8 combined with granulocyte-macrophage colony stimulating factor (GM-CSF) will assess response of minimal residual disease (MRD) in patients with high-risk neuroblastoma (NB) and help establish the optimal way to use GM-CSF. | Biological: anti-GD2 murine IgG3 monoclonal antibody 3F8<br>* The total dosage of 3F8 per cycle is the same as in prior trials (100 mg/m2), administered at 20 mg/m2/day and infused over  1.5 hr or less (0.5 hr is customary), with analgesics and antihistamines used as needed for expected side-effects. 3F8 is started  1 hr after completion of GM-CSF administration. GM-CSF is dosed at 250 mcg/m2/day from day -5 to day +1 (Wednesday to Tuesday is customary) , and is 500 mcg/m2/day thereafter (i.e., on days +2 to +4; Wednesday to Friday), as in the predecessor protocol.18,74 Patients come off study if progressive disease occurs or if there is life-threatening grade 4 toxicity from 3F8; otherwise, patients will receive a minimum of 4 cycles of treatment and will continue treatment through 24 months. It is expected that patients will receive  10 cycles.<br>* Other names: >2 cycles of, 3F8/GM-CSF.;|
| Experimental: patients have no evidence of disease<br>This phase II trial of the anti-GD2 murine IgG3 monoclonal antibody 3F8 combined with granulocyte-macrophage colony stimulating factor (GM-CSF) will assess response of minimal residual disease (MRD) in patients with high-risk neuroblastoma (NB) and help establish the optimal way to use GM-CSF. | Biological: anti-GD2 murine IgG3 monoclonal antibody 3F8<br>* The total dosage of 3F8 per cycle is the same as in prior trials (100 mg/m2), administered at 20 mg/m2/day and infused over  1.5 hr or less (0.5 hr is customary), with analgesics and antihistamines used as needed for expected side-effects. 3F8 is started  1 hr after completion of GM-CSF administration. GM-CSF is dosed at 250 mcg/m2/day from day -5 to day +1 (Wednesday to Tuesday is customary) , and is 500 mcg/m2/day thereafter (i.e., on days +2 to +4; Wednesday to Friday), as in the predecessor protocol.18,74 Patients come off study if progressive disease occurs or if there is life-threatening grade 4 toxicity from 3F8; otherwise, patients will receive a minimum of 4 cycles of treatment and will continue treatment through 24 months. It is expected that patients will receive  10 cycles.<br>* Other names: they can resume treatment with 3F8/GM-CSF if HAMA becomes negative.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy at Completion of Treatment |  | 3 years | 
| Relapse-free Survival Every 3 Months |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare Granulocyte Activation in Patients Treated With Short-term vs Prolonged Daily Exposure to Sargramostim (GM-CSF) After 4 Courses |  | 3 years | 
| Simplify Treatment With Consequent Reduction in Cost |  | 3 years | 

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