Cyclophosphamide and Prednisone With or Without Immunoglobulin in Treating Abnormal Muscle Movement in Children With Neuroblastoma

Study Overview
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Brief Summary
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This randomized phase III trial is studying cyclophosphamide, prednisone, and immunoglobulin to see how well they work compared to cyclophosphamide and prednisone alone in treating patients with abnormal trunk muscle movements associated with neuroblastoma. Drugs used in chemotherapy, work in different ways to stop tumor cells from dividing so they stop growing or die. Steroid therapy decreases inflammation. Combining chemotherapy and steroid therapy with immunoglobulin may be effective in treating abnormal muscle movement associated with neuroblastoma.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine whether cyclophosphamide and prednisone with or without immune globulin is a reasonable baseline standard therapy for pediatric patients with neuroblastoma-associated opsoclonus-myoclonus-ataxia (OMA) syndrome. II. Determine whether immunosuppressive therapy with cyclophosphamide and prednisone is an effective backbone therapy for OMA upon which to build additional treatment for these patients SECONDARY OBJECTIVES: I. Determine whether these regimens improve OMA syndrome in these patients. II. Determine whether these regimens improve motor coordination in these patients. III. Determine these regimens improve functional outcome in these patients. IV. Investigate the biology of neuroblastoma associated OMA, with specific regard to magnetic resonance imaging (MRI) findings, anti-neuronal antibodies, cerebrospinal fluid (CSF) findings and tumor biology. VI. Define better the long-term prognosis for neurologic recovery in the child with neuroblastoma associated with OMA syndrome. VII. Compare the event-free and overall survival of patients treated with these regimens. OUTLINE: CHEMOTHERAPY: Patients with intermediate-risk or high-risk neuroblastoma receive chemotherapy (including cyclophosphamide) according to the standard of care for the stage of primary neuroblastoma, beginning on day 0. Patients with low-risk neuroblastoma (and not receiving other chemotherapy) receive cyclophosphamide IV over 1 hour on day 0. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. All patients receive oral prednisone twice daily for 3 months and then every other day for 7-15 months. IMMUNE GLOBULIN THERAPY: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive immune globulin IV on days -2 and -1, at weeks 4, 8, 12, 16, 20, and 24, and then at months 8, 10, and 12 after therapy. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients with no response after 6 months go off treatment. ARM II: Patients do not receive immune globulin. Patients with unresponsive opsoclonus-myoclonus-ataxia syndrome after 2 months or progression after 6 months may cross over to arm I. Patients are followed during therapy every month for 6 months, at 1 year, and then annually for up to 10 years.

Official Title
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A Phase III Randomized Trial of Intravenous Gammaglobulin Therapy for Patients With Neuroblastoma Associated Opsoclonus-Myoclonus-Ataxia Syndrome Treated With Chemotherapy and Prednisone

Conditions
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Localized Resectable Neuroblastoma, Localized Unresectable Neuroblastoma, Regional Neuroblastoma, Stage 4 Neuroblastoma, Stage 4S Neuroblastoma

Intervention / Treatment
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* Other: Clinical Observation
* Drug: Cyclophosphamide
* Other: Laboratory Biomarker Analysis
* Procedure: Magnetic Resonance Imaging
* Drug: Prednisone
* Biological: Therapeutic Immune Globulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed neuroblastoma (NBL) or ganglioneuroblastoma with tumor-associated opsoclonus-myoclonus-ataxia syndrome (OMA) Patients with NBL diagnosed within 6 months of OMA diagnosis AND patients with OMA diagnosed within 6 months of NBL diagnosis are eligible Must enroll on study within 4 weeks of diagnosis Presence of opsoclonus, myoclonus, and/or ataxia associated with neuroblastoma considered eligible Currently enrolled on COG neuroblastoma protocols: COG-ANBL00B1 or its successor Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine based on age/gender as follows: ≤ 0.4 mg/dL (for patients 1 to 5 months of age) ≤ 0.5 mg/dL (for patients 6 to 11 months of age) ≤ 0.6 mg/dL (for patients 1 year of age) ≤ 0.8 mg/dL (for patients 2 to 5 years of age) ≤ 1.0 mg/dL (for patients 6 to 9 years of age) ≤ 1.2 mg/dL (for patients 10 to 12 years of age) ≤ 1.4 mg/dL (for female patients ≥ 13 years of age) ≤ 1.5 mg/dL (for male patients 13 to 15 years of age) ≤ 1.6 mg/dL (for male patients ≥ 16 years of age) No prior IV gamma globulin therapy No prior chemotherapy Concurrent chemotherapy allowed No prior prednisone or corticotropin Patients who have received ≤ 14 days of steroids are eligible Concurrent surgery allowed

Ages Eligible for Study
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Maximum Age: 8 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
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (chemotherapy, immunoglobulin therapy)<br>Patients with intermediate-risk or high-risk neuroblastoma receive chemotherapy (including cyclophosphamide) according to the standard of care for the stage of primary neuroblastoma, beginning on day 0. Patients with low-risk neuroblastoma (and not receiving other chemotherapy) receive cyclophosphamide IV over 1 hour on day 0. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. All patients receive oral prednisone twice daily for 3 months and then every other day for 7-15 months. Patients receive immune globulin IV on days -2 and -1, at weeks 4, 8, 12, 16, 20, and 24, and then at months 8, 10, and 12 after therapy. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients with no response after 6 months go off treatment. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Magnetic Resonance Imaging<br>* Correlative studies<br>* Other names: Nuclear Magnetic Resonance Imaging;Drug: Prednisone<br>* Given orally<br>* Other names: SK-Prednisone;Biological: Therapeutic Immune Globulin<br>* Given IV<br>* Other names: WinRho SDF;|
| Active Comparator: Arm II (chemotherapy, observation)<br>Patients with intermediate-risk or high-risk neuroblastoma receive chemotherapy (including cyclophosphamide) according to the standard of care for the stage of primary neuroblastoma, beginning on day 0. Patients with low-risk neuroblastoma (and not receiving other chemotherapy) receive cyclophosphamide IV over 1 hour on day 0. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. All patients receive oral prednisone twice daily for 3 months and then every other day for 7-15 months. Patients do not receive immune globulin. Patients with unresponsive opsoclonus-myoclonus-ataxia syndrome after 2 months or progression after 6 months may cross over to arm I. | Other: Clinical Observation<br>* Undergo observation<br>* Other names: observation;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Magnetic Resonance Imaging<br>* Correlative studies<br>* Other names: Nuclear Magnetic Resonance Imaging;Drug: Prednisone<br>* Given orally<br>* Other names: SK-Prednisone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Responders | A multi-stage design followed by a test of proportions between the treatment arms (chemo vs. chemo + therapeutic immune globulin (IVIG)) will be performed. The first stage of the multi-stage design will also function as an early stopping rule for insufficient activity of chemotherapy in OMA. | Changes from baseline to 2 months, 6 months, and 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Motor Coordination as Assessed by Neurological Examination and Vineland Adaptive Behavior Scale (VABS) | The best score at the two time points will be used in this analysis. For a given patient, this best score will be used to calculate the change from baseline. The mean change from baseline for each treatment group will be calculated. | Changes from baseline to the better of 6 months or 1 year | 
| Functional Outcome as Assessed by Age-appropriate Neuropsychological Testing | The Bayley Scales of infant development mental scale best score of two time points will be used in the analysis. For a given patient, this score will be used to calculate the change from baseline. | Changes from baseline to the better of 6 months or 1 year | 
| Biology of Neuroblastoma Associated Opsoclonus-myoclonus-ataxia (OMA) Syndrome Specifically by MRI Findings, Anti-neuronal Antibodies, Cerebrospinal Fluid (CSF) Findings and Tumor Biology | Descriptive analyses on biologic variables will be performed | At diagnosis, 6 months, 1 year, 5 and 10 years after diagnosis | 
| Long-term Prognosis for Neurologic Recovery by Neurological Examination | A t-test will be performed on the results of each neurologic test, comparing patients who have had disappearance of anti-neural antibodies to patients whose anti-neural antibodies have not disappeared. | At diagnosis and yearly for 10 years after diagnosis | 
| Tumor Outcome in Terms of Event-free Survival (EFS) Rate Defined as a Relapse or Progression of Neuroblastoma, a Second Malignancy, or Death | EFS rate for neuroblastoma event from time of study enrollment. | Up to 3 years | 
| Tumor Outcome in Terms of Overall Survival (OS) Rate | OS rate from time of study enrollment. | Up to 3 years |