Localized Resectable Neuroblastoma, Localized Unresectable Neuroblastoma, Regional Neuroblastoma, Stage 4 Neuroblastoma, Stage 4S Neuroblastoma
Conditions
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.
Interventions
OTHERClinical Observation
Undergo observation
DRUGCyclophosphamide
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
PROCEDUREMagnetic Resonance Imaging
Correlative studies
DRUGPrednisone
Given orally
BIOLOGICALTherapeutic Immune Globulin
Given IV
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 8 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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. |
| 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. |
| 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. |
Countries
Australia, Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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). | 26 |
| 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. | 27 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Could not be weaned from steroid therapy | 1 | 1 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Lack of Efficacy | 5 | 8 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 3 | 1 |
| Overall Study | Treatment refused | 0 | 6 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Arm I (Chemotherapy, Immunoglobulin Therapy) | Arm II (Chemotherapy, Observation) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 26 Participants | 27 Participants | 53 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 1.4 years STANDARD_DEVIATION 0.9 | 1.2 years STANDARD_DEVIATION 0.5 | 1.3 years STANDARD_DEVIATION 0.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 7 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 20 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 6 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 5 Participants |
| Race (NIH/OMB) White | 19 Participants | 17 Participants | 36 Participants |
| Region of Enrollment United States | 26 participants | 27 participants | 53 participants |
| Sex: Female, Male Female | 18 Participants | 15 Participants | 33 Participants |
| Sex: Female, Male Male | 8 Participants | 12 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 26 | 18 / 27 |
| serious Total, serious adverse events | 1 / 26 | 1 / 27 |
Outcome results
Primary
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.
Time frame: Changes from baseline to 2 months, 6 months, and 1 year
Population: Eligible patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Chemotherapy, Immunoglobulin Therapy) | Number of Responders | 21 participants |
| Arm II (Chemotherapy, Observation) | Number of Responders | 11 participants |
Comparison: The 5 categories of OMA ratings are: stance, gait, arm \& hand function, opsoclonus, \& mood/behavior. For each category, a patient's response will be based on a comparison of the baseline evaluation to the best of 3 time points: 2 months, 6 months \& 1 year. If a patient crosses over to the IVIG arm or switches to ACTH at any time, the patient will be considered a non-responder. The proportion of responders from the 2 treatment arms were compared using a chi-squared test.p-value: 0.0044Chi-squared
Secondary
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
Time frame: At diagnosis, 6 months, 1 year, 5 and 10 years after diagnosis
Population: The necessary data will never be collected, therefore results can't be provided.
Secondary
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.
Time frame: Changes from baseline to the better of 6 months or 1 year
Population: All eligible patients who had Bayley's measures at diagnosis and at least one of 6 months or 1 year.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Chemotherapy, Immunoglobulin Therapy) | Functional Outcome as Assessed by Age-appropriate Neuropsychological Testing | 117.5 Change in Bayley's score | Standard Deviation 35.35 |
| Arm II (Chemotherapy, Observation) | Functional Outcome as Assessed by Age-appropriate Neuropsychological Testing | 100.75 Change in Bayley's score | Standard Deviation 25.76 |
p-value: 0.2364t-test, 1 sided
Secondary
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.
Time frame: At diagnosis and yearly for 10 years after diagnosis
Population: The necessary data will never be collected, therefore results can't be provided.
Secondary
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.
Time frame: Changes from baseline to the better of 6 months or 1 year
Population: All eligible patients who had VABS measures at diagnosis and at least one of 6 months or 1 year.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Chemotherapy, Immunoglobulin Therapy) | Motor Coordination as Assessed by Neurological Examination and Vineland Adaptive Behavior Scale (VABS) | 84.53 Change in VABS score | Standard Deviation 115.91 |
| Arm II (Chemotherapy, Observation) | Motor Coordination as Assessed by Neurological Examination and Vineland Adaptive Behavior Scale (VABS) | 144.73 Change in VABS score | Standard Deviation 110.69 |
Comparison: The two samples from the respective treatment arms were compared using a one-sided t-test with a significance level of .05.p-value: 0.0919t-test, 1 sided
Secondary
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.
Time frame: Up to 3 years
Population: All eligible randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Chemotherapy, Immunoglobulin Therapy) | Tumor Outcome in Terms of Event-free Survival (EFS) Rate Defined as a Relapse or Progression of Neuroblastoma, a Second Malignancy, or Death | 92.3 3 year EFS |
| Arm II (Chemotherapy, Observation) | Tumor Outcome in Terms of Event-free Survival (EFS) Rate Defined as a Relapse or Progression of Neuroblastoma, a Second Malignancy, or Death | 96.0 3 year EFS |
Secondary
Tumor Outcome in Terms of Overall Survival (OS) Rate
OS rate from time of study enrollment.
Time frame: Up to 3 years
Population: All eligible randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Chemotherapy, Immunoglobulin Therapy) | Tumor Outcome in Terms of Overall Survival (OS) Rate | 100 3 year OS |
| Arm II (Chemotherapy, Observation) | Tumor Outcome in Terms of Overall Survival (OS) Rate | 96.0 3 year OS |