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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00033293
Recruitment Status : Unknown
Verified June 2015 by Children's Oncology Group.
Recruitment status was:  Active, not recruiting
First Posted : January 27, 2003
Results First Posted : October 3, 2016
Last Update Posted : March 25, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Tracking Information
First Submitted Date  ICMJE April 9, 2002
First Posted Date  ICMJE January 27, 2003
Results First Submitted Date  ICMJE January 28, 2016
Results First Posted Date  ICMJE October 3, 2016
Last Update Posted Date March 25, 2020
Actual Study Start Date  ICMJE March 15, 2004
Actual Primary Completion Date December 10, 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 9, 2016)
Number of Responders [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 18, 2017)
  • Motor Coordination as Assessed by Neurological Examination and Vineland Adaptive Behavior Scale (VABS) [ Time Frame: 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 [ Time Frame: 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.
  • 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 ]
    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 ]
    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: Up to 3 years ]
    EFS rate for neuroblastoma event from time of study enrollment.
  • Tumor Outcome in Terms of Overall Survival (OS) Rate [ Time Frame: Up to 3 years ]
    OS rate from time of study enrollment.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Cyclophosphamide and Prednisone With or Without Immunoglobulin in Treating Abnormal Muscle Movement in Children With Neuroblastoma
Official Title  ICMJE A Pilot Study Randomized Trial of Intravenous Gammaglobulin Therapy for Patients With Neuroblastoma Associated Opsoclonus-Myoclonus-Ataxia Syndrome Treated With Chemotherapy and Prednisone
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 eye and trunk muscle movements (known as opsoclonus myoclonus ataxia) 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).
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 if 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Disseminated Neuroblastoma
  • Localized Resectable Neuroblastoma
  • Localized Unresectable Neuroblastoma
  • Regional Neuroblastoma
  • Stage 4S Neuroblastoma
Intervention  ICMJE
  • Biological: therapeutic immune globulin
    Given IV
    Other Names:
    • BayGam
    • Gamimune N
    • Gammar-P
    • IG
    • Venoglobulin-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
  • Drug: Corticotropin-Releasing Hormone
    administered subcutaneously
    Other Names:
    • ACTH
    • adrenocorticotropic hormone
    • NSC # 25933
Study Arms  ICMJE
  • 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).

    Interventions:
    • Biological: therapeutic immune globulin
    • Drug: cyclophosphamide
    • Drug: prednisone
    • Procedure: magnetic resonance imaging
    • Other: laboratory biomarker analysis
    • Drug: Corticotropin-Releasing Hormone
  • 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.

    Interventions:
    • Other: clinical observation
    • Drug: cyclophosphamide
    • Drug: prednisone
    • Procedure: magnetic resonance imaging
    • Other: laboratory biomarker analysis
Publications * de Alarcon PA, Matthay KK, London WB, Naranjo A, Tenney SC, Panzer JA, Hogarty MD, Park JR, Maris JM, Cohn SL. Intravenous immunoglobulin with prednisone and risk-adapted chemotherapy for children with opsoclonus myoclonus ataxia syndrome associated with neuroblastoma (ANBL00P3): a randomised, open-label, phase 3 trial. Lancet Child Adolesc Health. 2018 Jan;2(1):25-34. doi: 10.1016/S2352-4642(17)30130-X. Epub 2017 Nov 3.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Actual Enrollment  ICMJE
 (submitted: June 11, 2013)
53
Original Enrollment  ICMJE Not Provided
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date December 10, 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 8 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Canada,   United States
Removed Location Countries Netherlands,   New Zealand,   Puerto Rico,   Switzerland
 
Administrative Information
NCT Number  ICMJE NCT00033293
Other Study ID Numbers  ICMJE ANBL00P3
NCI-2009-00399 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000069271 ( Other Identifier: Clinical Trials.gov )
COG-ANBL00P3 ( Other Identifier: Children's Oncology Group )
U10CA013539 ( U.S. NIH Grant/Contract )
U10CA098543 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Children's Oncology Group
Study Sponsor  ICMJE Children's Oncology Group
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Pedro De Alarcon, MD Children's Oncology Group
PRS Account Children's Oncology Group
Verification Date June 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP