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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT00033293
First received: April 9, 2002
Last updated: April 15, 2014
Last verified: April 2014
  Purpose

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. Chemotherapy(cyclophosphamide), prednisone and intravenous gamma globulin all suppress the immune system which may be helpful in treating opsoclonus-myoclonus-ataxia (OMA).


Condition Intervention Phase
Disseminated Neuroblastoma
Localized Resectable Neuroblastoma
Localized Unresectable Neuroblastoma
Regional Neuroblastoma
Stage 4S Neuroblastoma
Biological: therapeutic immune globulin
Other: clinical observation
Drug: cyclophosphamide
Drug: prednisone
Procedure: magnetic resonance imaging
Other: laboratory biomarker analysis
Drug: Corticotropin-Releasing Hormone
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase III Randomized Trial of Intravenous Gammaglobulin Therapy for Patients With Neuroblastoma Associated Opsoclonus-Myoclonus-Ataxia Syndrome Treated With Chemotherapy and Prednisone

Resource links provided by NLM:


Further study details as provided by Children's Oncology Group:

Primary Outcome Measures:
  • Response of opsoclonus-myoclonus-ataxia (OMA) to treatment as rated by stance, gait, arm and hand function, opsoclonus, and mood/behavior [ Time Frame: Changes from baseline to 2 months, 6 months, and 1 year ] [ Designated as safety issue: No ]
    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:
  • Motor coordination as assessed by neurological examination and Vineland Adaptive Behavior Scale (VABS) [ Time Frame: Changes from baseline to 6 months or 1 year ] [ Designated as safety issue: No ]
    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 and compared using a one-sided t-test with a significance level of .05.

  • Functional outcome as assessed by age-appropriate neuropsychological testing [ Time Frame: At diagnosis and yearly for 10 years after diagnosis ] [ Designated as safety issue: No ]
    Descriptive analyses of the scores from additional neurologic assessment tests will be performed.

  • Biology of neuroblastoma associated opsoclonus-myoclonus-ataxia (OMA) syndrome specifically by MRI findings, anti-neuronal antibodies, cerebrospinal fluid (CSF) findings and tumor biology [ Time Frame: At diagnosis, 6 months, 1 year, 5 and 10 years after diagnosis ] [ Designated as safety issue: No ]
    Descriptive analyses on biologic variables will be performed

  • Long-term prognosis for neurologic recovery by neurological examination [ Time Frame: At diagnosis and yearly for 10 years after diagnosis ] [ Designated as safety issue: No ]
    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 [ Time Frame: At 3 years ] [ Designated as safety issue: No ]
    The EFS and S rates will be calculated.

  • Tumor outcome in terms of overall survival rate [ Time Frame: Assessed up to 10 years ] [ Designated as safety issue: No ]

Enrollment: 53
Study Start Date: March 2004
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (chemotherapy, immunoglobulin therapy)

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 day 0. Patients with low-risk neuroblastoma (and not receiving other chemotherapy) receive cyclophosphamide IV over 1 hr on day 0. Treatment repeats every 4 wks for 6 courses in the absence of disease progression or unacceptable toxicity. All patients receive oral prednisone twice daily for 3 mths and then every other day for 7-15 mths.

Patients receive therapeutic immune globulin IV on days -2 and -1, at wks 4, 8, 12, 16, 20, and 24, and then at mths 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. In case of progression of opsoclonus-myoclonus-ataxia (OMA) during evaluation, patient will be switched to another steroid, corticotropin-releasing hormone (ACTH).

Biological: therapeutic immune globulin
Given IV
Other Names:
  • BayGam
  • Gamimune N
  • Gammar-P
  • IG
  • Venoglobulin-I
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: prednisone
Given orally
Other Names:
  • DeCortin
  • Deltra
Procedure: magnetic resonance imaging
Correlative studies
Other Names:
  • MRI
  • NMR imaging
  • NMRI
  • nuclear magnetic resonance imaging
Other: laboratory biomarker analysis
Correlative studies
Drug: Corticotropin-Releasing Hormone
administered subcutaneously
Other Names:
  • ACTH
  • adrenocorticotropic hormone
  • NSC # 25933
Active Comparator: Arm II (chemotherapy, 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 therapeutic 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
Undergo observation
Other Name: observation
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: prednisone
Given orally
Other Names:
  • DeCortin
  • Deltra
Procedure: magnetic resonance imaging
Correlative studies
Other Names:
  • MRI
  • NMR imaging
  • NMRI
  • nuclear magnetic resonance imaging
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine if immunosuppressive therapy with cyclophosphamide and prednisone is an effective therapy for neuroblastoma associated opsoclonus-myoclonus-ataxia (OMA) and can constitute a back-bone therapy upon which to build additional therapy.

II. Determine in a randomized study if the addition of intravenous gammaglobulin therapy to the back-bone therapy of prednisone and cyclophosphamide improves response of neuroblastoma associated OMA.

SECONDARY OBJECTIVES:

I. Determine if intravenous gammaglobulin therapy improves the motor coordination of children diagnosed with neuroblastoma and presenting with OMA syndrome as assessed by neurological examination and the Vineland Adaptive Behavior Scale (VABS).

II. Determine these regimens improve functional outcome in these patients. III. 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.

IV. Define better the long-term prognosis for neurologic recovery in the child with neuroblastoma associated with OMA syndrome.

V. Define the event-free and overall survival of patients with neuroblastoma associated opsoclonus-myoclonus-ataxia syndrome.

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.

  Eligibility

Ages Eligible for Study:   up to 8 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  • 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
  • Patients must be free of any organ dysfunction or disorder that the treating physician feels may preclude the use of corticosteroid therapy (ACTH or prednisone), cyclophosphamide therapy or intravenous gammaglobulin therapy.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00033293

  Hide Study Locations
Locations
United States, Alabama
Children's Hospital of Alabama
Birmingham, Alabama, United States, 35233
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294
United States, Arizona
University of Arizona Health Sciences Center
Tucson, Arizona, United States, 85724
United States, Arkansas
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States, 72205
United States, California
Loma Linda University Medical Center
Loma Linda, California, United States, 92354
Miller Children's Hospital
Long Beach, California, United States, 90806
Cedars-Sinai Medical Center
Los Angeles, California, United States, 90048
Children's Hospital Central California
Madera, California, United States, 93636-8762
Kaiser Permanente-Oakland
Oakland, California, United States, 94611
Lucile Packard Children's Hospital Stanford University
Palo Alto, California, United States, 94304
Rady Children's Hospital - San Diego
San Diego, California, United States, 92123
University of California San Francisco Medical Center-Parnassus
San Francisco, California, United States, 94143
United States, Colorado
Children's Hospital Colorado
Aurora, Colorado, United States, 80045
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
Denver, Colorado, United States, 80218
United States, Connecticut
Connecticut Children's Medical Center
Hartford, Connecticut, United States, 06106
United States, Delaware
Alfred I duPont Hospital for Children
Wilmington, Delaware, United States, 19803
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
Lombardi Comprehensive Cancer Center at Georgetown University
Washington, District of Columbia, United States, 20057
United States, Florida
Broward Health Medical Center
Fort Lauderdale, Florida, United States, 33316
Lee Memorial Health System
Fort Myers, Florida, United States, 33901
Nemours Children's Clinic - Jacksonville
Jacksonville, Florida, United States, 32207-8426
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, United States, 33136
Nemours Childrens Clinic - Orlando
Orlando, Florida, United States, 32806
Nemours Children's Clinic - Pensacola
Pensacola, Florida, United States, 32504
All Children's Hospital
Saint Petersburg, Florida, United States, 33701
Saint Joseph Children's Hospital of Tampa
Tampa, Florida, United States, 33607
Saint Mary's Hospital
West Palm Beach, Florida, United States, 33407
United States, Georgia
Children's Healthcare of Atlanta - Egleston
Atlanta, Georgia, United States, 30322
United States, Idaho
Saint Luke's Mountain States Tumor Institute
Boise, Idaho, United States, 83712
United States, Illinois
Childrens Memorial Hospital
Chicago, Illinois, United States, 60614
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, United States, 60637-1470
Saint Jude Midwest Affiliate
Peoria, Illinois, United States, 61602
United States, Indiana
Riley Hospital for Children
Indianapolis, Indiana, United States, 46202
United States, Kentucky
University of Kentucky
Lexington, Kentucky, United States, 40536
Kosair Children's Hospital
Louisville, Kentucky, United States, 40202
United States, Louisiana
Tulane University Health Sciences Center
New Orleans, Louisiana, United States, 70112
United States, Maryland
Sinai Hospital of Baltimore
Baltimore, Maryland, United States, 21215
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, United States, 02114
United States, Michigan
Saint John Hospital and Medical Center
Detroit, Michigan, United States, 48236
Hurley Medical Center
Flint, Michigan, United States, 48502
Helen DeVos Children's Hospital at Spectrum Health
Grand Rapids, Michigan, United States, 49503
Michigan State University - Breslin Cancer Center
Lansing, Michigan, United States, 48910
United States, Mississippi
University of Mississippi Medical Center
Jackson, Mississippi, United States, 39216
United States, Missouri
The Childrens Mercy Hospital
Kansas City, Missouri, United States, 64108
United States, Nevada
Nevada Cancer Research Foundation CCOP
Las Vegas, Nevada, United States, 89106
United States, New Jersey
Hackensack University Medical Center
Hackensack, New Jersey, United States, 07601
Morristown Memorial Hospital
Morristown, New Jersey, United States, 07962
UMDNJ - Robert Wood Johnson University Hospital
New Brunswick, New Jersey, United States, 08903
Newark Beth Israel Medical Center
Newark, New Jersey, United States, 07112
Saint Joseph's Regional Medical Center
Paterson, New Jersey, United States, 07503
Overlook Hospital
Summit, New Jersey, United States, 07902
United States, New York
Albany Medical Center
Albany, New York, United States, 12208
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Columbia University Medical Center
New York, New York, United States, 10032
State University of New York Upstate Medical University
Syracuse, New York, United States, 13210
United States, North Carolina
University of North Carolina
Chapel Hill, North Carolina, United States, 27599
Carolinas Medical Center
Charlotte, North Carolina, United States, 28203
Duke University Medical Center
Durham, North Carolina, United States, 27710
Wake Forest University Health Sciences
Winston-Salem, North Carolina, United States, 27157
United States, Ohio
Children's Hospital Medical Center of Akron
Akron, Ohio, United States, 44308
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
The Children's Medical Center of Dayton
Dayton, Ohio, United States, 45404
United States, Oklahoma
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, United States, 73104
United States, Oregon
Legacy Emanuel Children's Hospital
Portland, Oregon, United States, 97227
Legacy Emanuel Hospital and Health Center
Portland, Oregon, United States, 97227
United States, Pennsylvania
Penn State Hershey Children's Hospital
Hershey, Pennsylvania, United States, 17033
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Saint Christopher's Hospital for Children
Philadelphia, Pennsylvania, United States, 19134
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States, 15224
United States, South Carolina
Palmetto Health Richland
Columbia, South Carolina, United States, 29203
BI-LO Charities Children's Cancer Center
Greenville, South Carolina, United States, 29605
Greenville Cancer Treatment Center
Greenville, South Carolina, United States, 29605
United States, South Dakota
Sanford USD Medical Center - Sioux Falls
Sioux Falls, South Dakota, United States, 57117-5134
United States, Tennessee
East Tennessee Childrens Hospital
Knoxville, Tennessee, United States, 37916
United States, Texas
Texas Tech University Health Science Center-Amarillo
Amarillo, Texas, United States, 79106
Driscoll Children's Hospital
Corpus Christi, Texas, United States, 78411
Medical City Dallas Hospital
Dallas, Texas, United States, 75230
Cook Children's Medical Center
Fort Worth, Texas, United States, 76104
Methodist Children's Hospital of South Texas
San Antonio, Texas, United States, 78229
University of Texas Health Science Center at San Antonio
San Antonio, Texas, United States, 78229-3900
United States, Vermont
University of Vermont
Burlington, Vermont, United States, 05401
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States, 98105
Providence Sacred Heart Medical Center and Children's Hospital
Spokane, Washington, United States, 99204
United States, West Virginia
West Virginia University Charleston
Charleston, West Virginia, United States, 25304
United States, Wisconsin
Midwest Children's Cancer Center
Milwaukee, Wisconsin, United States, 53226
Australia, New South Wales
The Children's Hospital at Westmead
Sydney, New South Wales, Australia, 2145
Australia, Western Australia
Princess Margaret Hospital for Children
Perth, Western Australia, Australia, 6008
Canada, British Columbia
British Columbia Children's Hospital
Vancouver, British Columbia, Canada, V6H 3V4
Canada, Nova Scotia
IWK Health Centre
Halifax, Nova Scotia, Canada, B3J 3G9
Canada, Quebec
Hospital Sainte-Justine
Montreal, Quebec, Canada, H3T 1C5
Canada, Saskatchewan
Saskatoon Cancer Centre
Saskatoon, Saskatchewan, Canada, S7N 4H4
Sponsors and Collaborators
Children's Oncology Group
Investigators
Principal Investigator: Pedro De Alarcon, MD Children's Oncology Group
  More Information

No publications provided

Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT00033293     History of Changes
Other Study ID Numbers: ANBL00P3, NCI-2009-00399, CDR0000069271, COG-ANBL00P3, U10CA013539, U10CA098543
Study First Received: April 9, 2002
Last Updated: April 15, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Neuroblastoma
Opsoclonus-Myoclonus Syndrome
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Paraneoplastic Syndromes, Nervous System
Nervous System Neoplasms
Neoplasms by Site
Paraneoplastic Syndromes
Ocular Motility Disorders
Central Nervous System Diseases
Nervous System Diseases
Cranial Nerve Diseases
Neurodegenerative Diseases
Myoclonus
Dyskinesias
Neurologic Manifestations
Eye Diseases
Adrenocorticotropic Hormone
Corticotropin-Releasing Hormone
Hormones
Prednisone
Beta-Endorphin
Cyclophosphamide

ClinicalTrials.gov processed this record on August 26, 2014