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

  Show 92 Study Locations
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:
Opsoclonus-Myoclonus Syndrome
Myoclonus
Neuroblastoma
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
Dyskinesias
Neurologic Manifestations
Eye Diseases
Adrenocorticotropic Hormone
Corticotropin-Releasing Hormone
Hormones
Prednisone
Beta-Endorphin
Cyclophosphamide

ClinicalTrials.gov processed this record on August 25, 2014