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

Phase 3

Completed

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

Interventions: Other: Clinical Observation
Drug: Cyclophosphamide
Other: Laboratory Biomarker Analysis
Procedure: Magnetic Resonance Imaging
Drug: Prednisone
Biological: Therapeutic Immune Globulin

Registration Number: NCT00033293

Lead Sponsor: Children's Oncology Group

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 53

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (chemotherapy, immunoglobulin therapy)	Laboratory Biomarker Analysis	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.
Arm II (chemotherapy, observation)	Clinical Observation	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.
Arm I (chemotherapy, immunoglobulin therapy)	Magnetic Resonance Imaging	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.
Arm I (chemotherapy, immunoglobulin therapy)	Therapeutic Immune Globulin	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.
Arm II (chemotherapy, observation)	Laboratory Biomarker Analysis	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.
Arm II (chemotherapy, observation)	Magnetic Resonance Imaging	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.
Arm I (chemotherapy, immunoglobulin therapy)	Cyclophosphamide	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.
Arm I (chemotherapy, immunoglobulin therapy)	Prednisone	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.
Arm II (chemotherapy, observation)	Cyclophosphamide	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.
Arm II (chemotherapy, observation)	Prednisone	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.

Primary Outcome Measures

Name	Time	Method
Number of Responders	Changes from baseline to 2 months, 6 months, and 1 year	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.

Secondary Outcome Measures

Name	Time	Method
Biology of Neuroblastoma Associated Opsoclonus-myoclonus-ataxia (OMA) Syndrome Specifically by MRI Findings, Anti-neuronal Antibodies, Cerebrospinal Fluid (CSF) Findings and Tumor Biology	At diagnosis, 6 months, 1 year, 5 and 10 years after diagnosis	Descriptive analyses on biologic variables will be performed
Long-term Prognosis for Neurologic Recovery by Neurological Examination	At diagnosis and yearly for 10 years after diagnosis	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.
Tumor Outcome in Terms of Event-free Survival (EFS) Rate Defined as a Relapse or Progression of Neuroblastoma, a Second Malignancy, or Death	Up to 3 years	EFS rate for neuroblastoma event from time of study enrollment.
Tumor Outcome in Terms of Overall Survival (OS) Rate	Up to 3 years	OS rate from time of study enrollment.
Motor Coordination as Assessed by Neurological Examination and Vineland Adaptive Behavior Scale (VABS)	Changes from baseline to the better of 6 months or 1 year	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.
Functional Outcome as Assessed by Age-appropriate Neuropsychological Testing	Changes from baseline to the better of 6 months or 1 year	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.

Trial Locations

Locations (104): Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Indiana University/Melvin and Bren Simon Cancer Center
🇺🇸
Indianapolis, Indiana, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
Wayne State University/Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
Ascension Saint John Hospital
🇺🇸
Detroit, Michigan, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
🇺🇸
Denver, Colorado, United States
Legacy Emanuel Children's Hospital
🇺🇸
Portland, Oregon, United States
Loma Linda University Medical Center
🇺🇸
Loma Linda, California, United States
Cedars Sinai Medical Center
🇺🇸
Los Angeles, California, United States
Nemours Children's Clinic-Jacksonville
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Jacksonville, Florida, United States
UCSF Medical Center-Mount Zion
🇺🇸
San Francisco, California, United States
Lee Memorial Health System
🇺🇸
Fort Myers, Florida, United States
Valley Children's Hospital
🇺🇸
Madera, California, United States
Miller Children's and Women's Hospital Long Beach
🇺🇸
Long Beach, California, United States
Children's Hospital of Alabama
🇺🇸
Birmingham, Alabama, United States
Kaiser Permanente-Oakland
🇺🇸
Oakland, California, United States
Children's Healthcare of Atlanta - Egleston
🇺🇸
Atlanta, Georgia, United States
Emory University Hospital/Winship Cancer Institute
🇺🇸
Atlanta, Georgia, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
🇺🇸
New York, New York, United States
Saint Jude Midwest Affiliate
🇺🇸
Peoria, Illinois, United States
Nemours Children's Clinic - Pensacola
🇺🇸
Pensacola, Florida, United States
Sacred Heart Hospital
🇺🇸
Pensacola, Florida, United States
Broward Health Medical Center
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Fort Lauderdale, Florida, United States
Albany Medical Center
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Albany, New York, United States
University of Kentucky/Markey Cancer Center
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Lexington, Kentucky, United States
Spectrum Health at Butterworth Campus
🇺🇸
Grand Rapids, Michigan, United States
Michigan State University Clinical Center
🇺🇸
East Lansing, Michigan, United States
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
🇺🇸
New Brunswick, New Jersey, United States
Sinai Hospital of Baltimore
🇺🇸
Baltimore, Maryland, United States
Tufts Children's Hospital
🇺🇸
Boston, Massachusetts, United States
Massachusetts General Hospital Cancer Center
🇺🇸
Boston, Massachusetts, United States
New York Medical College
🇺🇸
Valhalla, New York, United States
Overlook Hospital
🇺🇸
Summit, New Jersey, United States
Carolinas Medical Center/Levine Cancer Institute
🇺🇸
Charlotte, North Carolina, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
Penn State Children's Hospital
🇺🇸
Hershey, Pennsylvania, United States
Children's Hospital Medical Center of Akron
🇺🇸
Akron, Ohio, United States
Medical University of South Carolina
🇺🇸
Charleston, South Carolina, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸
Chapel Hill, North Carolina, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸
Pittsburgh, Pennsylvania, United States
West Virginia University Charleston Division
🇺🇸
Charleston, West Virginia, United States
East Tennessee Childrens Hospital
🇺🇸
Knoxville, Tennessee, United States
The Children's Hospital at Westmead
🇦🇺
Westmead, New South Wales, Australia
Greenville Cancer Treatment Center
🇺🇸
Greenville, South Carolina, United States
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸
Spokane, Washington, United States
Cook Children's Medical Center
🇺🇸
Fort Worth, Texas, United States
Westmead Hospital
🇦🇺
Westmead, New South Wales, Australia
University of Texas Health Science Center at San Antonio
🇺🇸
San Antonio, Texas, United States
British Columbia Children's Hospital
🇨🇦
Vancouver, British Columbia, Canada
Driscoll Children's Hospital
🇺🇸
Corpus Christi, Texas, United States
IWK Health Centre
🇨🇦
Halifax, Nova Scotia, Canada
Princess Margaret Hospital for Children
🇦🇺
Perth, Western Australia, Australia
Children's Hospital Colorado
🇺🇸
Aurora, Colorado, United States
Children's Hospital of Wisconsin
🇺🇸
Milwaukee, Wisconsin, United States
University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
Saint Christopher's Hospital for Children
🇺🇸
Philadelphia, Pennsylvania, United States
Penn State Milton S Hershey Medical Center
🇺🇸
Hershey, Pennsylvania, United States
Texas Tech University Health Sciences Center-Amarillo
🇺🇸
Amarillo, Texas, United States
Medical City Dallas Hospital
🇺🇸
Dallas, Texas, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸
Palo Alto, California, United States
Rady Children's Hospital - San Diego
🇺🇸
San Diego, California, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
🇺🇸
Miami, Florida, United States
Nemours Children's Clinic - Orlando
🇺🇸
Orlando, Florida, United States
Johns Hopkins All Children's Hospital
🇺🇸
Saint Petersburg, Florida, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
🇺🇸
Tampa, Florida, United States
Saint Mary's Hospital
🇺🇸
West Palm Beach, Florida, United States
Lurie Children's Hospital-Chicago
🇺🇸
Chicago, Illinois, United States
University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Helen DeVos Children's Hospital at Spectrum Health
🇺🇸
Grand Rapids, Michigan, United States
Hurley Medical Center
🇺🇸
Flint, Michigan, United States
State University of New York Upstate Medical University
🇺🇸
Syracuse, New York, United States
Legacy Emanuel Hospital and Health Center
🇺🇸
Portland, Oregon, United States
Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
Harbor-University of California at Los Angeles Medical Center
🇺🇸
Torrance, California, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
University of Alabama at Birmingham Cancer Center
🇺🇸
Birmingham, Alabama, United States
Banner University Medical Center - Tucson
🇺🇸
Tucson, Arizona, United States
UCSF Medical Center-Parnassus
🇺🇸
San Francisco, California, United States
Riley Hospital for Children
🇺🇸
Indianapolis, Indiana, United States
Norton Children's Hospital
🇺🇸
Louisville, Kentucky, United States
Tulane University Health Sciences Center
🇺🇸
New Orleans, Louisiana, United States
Morristown Medical Center
🇺🇸
Morristown, New Jersey, United States
Saint Joseph's Regional Medical Center
🇺🇸
Paterson, New Jersey, United States
Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
Prisma Health Richland Hospital
🇺🇸
Columbia, South Carolina, United States
Methodist Children's Hospital of South Texas
🇺🇸
San Antonio, Texas, United States
University of Vermont and State Agricultural College
🇺🇸
Burlington, Vermont, United States
Centre Hospitalier Universitaire Sainte-Justine
🇨🇦
Montreal, Quebec, Canada
Saskatoon Cancer Centre
🇨🇦
Saskatoon, Saskatchewan, Canada
Saint Luke's Cancer Institute - Boise
🇺🇸
Boise, Idaho, United States
University of Arkansas for Medical Sciences
🇺🇸
Little Rock, Arkansas, United States
Connecticut Children's Medical Center
🇺🇸
Hartford, Connecticut, United States
University of Mississippi Medical Center
🇺🇸
Jackson, Mississippi, United States
Alfred I duPont Hospital for Children
🇺🇸
Wilmington, Delaware, United States
MedStar Georgetown University Hospital
🇺🇸
Washington, District of Columbia, United States
Nevada Cancer Research Foundation NCORP
🇺🇸
Las Vegas, Nevada, United States
Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
Newark Beth Israel Medical Center
🇺🇸
Newark, New Jersey, United States
BI-LO Charities Children's Cancer Center
🇺🇸
Greenville, South Carolina, United States
Children's Mercy Hospitals and Clinics
🇺🇸
Kansas City, Missouri, United States
Dayton Children's Hospital
🇺🇸
Dayton, Ohio, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸
Sioux Falls, South Dakota, United States
Children's National Medical Center
🇺🇸
Washington, District of Columbia, United States