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

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT00033293
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 53
• Locations: 92
• Arms: 2
• Anticipated Duration (Months): 237.5
• Patients Per Site: 0.6
• Patients Per Site Per Month: 0

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	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

Detailed Description

PRIMARY OBJECTIVES:

1. 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.

2. 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:

1. 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).

2. 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.

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

4. 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 Design

• Study Type: Interventional
• Actual Enrollment: 53 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study Randomized Trial of Intravenous Gammaglobulin Therapy for Patients With Neuroblastoma Associated Opsoclonus-Myoclonus-Ataxia Syndrome Treated With Chemotherapy and Prednisone
• Actual Study Start Date: Mar 15, 2004
• Actual Primary Completion Date: Dec 10, 2013
• Anticipated Study Completion Date: Dec 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
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 Names: 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

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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.

3. 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

4. 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.

5. 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.

6. Tumor Outcome in Terms of Overall Survival (OS) Rate [Up to 3 years]

   OS rate from time of study enrollment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 8 Years
• Sexes Eligible for Study: All
• Accepts 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

• 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

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Alabama	Birmingham	Alabama	United States	35233
2	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
3	University of Arizona Health Sciences Center	Tucson	Arizona	United States	85724
4	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
5	Loma Linda University Medical Center	Loma Linda	California	United States	92354
6	Miller Children's Hospital	Long Beach	California	United States	90806
7	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
8	Children's Hospital Central California	Madera	California	United States	93636-8762
9	Kaiser Permanente-Oakland	Oakland	California	United States	94611
10	Lucile Packard Children's Hospital Stanford University	Palo Alto	California	United States	94304
11	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
12	University of California San Francisco Medical Center-Parnassus	San Francisco	California	United States	94143
13	Children's Hospital Colorado	Aurora	Colorado	United States	80045
14	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado	United States	80218
15	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
16	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
17	Children's National Medical Center	Washington	District of Columbia	United States	20010
18	Lombardi Comprehensive Cancer Center at Georgetown University	Washington	District of Columbia	United States	20057
19	Broward Health Medical Center	Fort Lauderdale	Florida	United States	33316
20	Lee Memorial Health System	Fort Myers	Florida	United States	33901
21	Nemours Children's Clinic - Jacksonville	Jacksonville	Florida	United States	32207-8426
22	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
23	Nemours Childrens Clinic - Orlando	Orlando	Florida	United States	32806
24	Nemours Children's Clinic - Pensacola	Pensacola	Florida	United States	32504
25	All Children's Hospital	Saint Petersburg	Florida	United States	33701
26	Saint Joseph Children's Hospital of Tampa	Tampa	Florida	United States	33607
27	Saint Mary's Hospital	West Palm Beach	Florida	United States	33407
28	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
29	Saint Luke's Mountain States Tumor Institute	Boise	Idaho	United States	83712
30	Childrens Memorial Hospital	Chicago	Illinois	United States	60614
31	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637-1470
32	Saint Jude Midwest Affiliate	Peoria	Illinois	United States	61602
33	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
34	University of Kentucky	Lexington	Kentucky	United States	40536
35	Kosair Children's Hospital	Louisville	Kentucky	United States	40202
36	Tulane University Health Sciences Center	New Orleans	Louisiana	United States	70112
37	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
38	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
39	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
40	Saint John Hospital and Medical Center	Detroit	Michigan	United States	48236
41	Hurley Medical Center	Flint	Michigan	United States	48502
42	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
43	Michigan State University - Breslin Cancer Center	Lansing	Michigan	United States	48910
44	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
45	The Childrens Mercy Hospital	Kansas City	Missouri	United States	64108
46	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada	United States	89106
47	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
48	Morristown Memorial Hospital	Morristown	New Jersey	United States	07962
49	UMDNJ - Robert Wood Johnson University Hospital	New Brunswick	New Jersey	United States	08903
50	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
51	Saint Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
52	Overlook Hospital	Summit	New Jersey	United States	07902
53	Albany Medical Center	Albany	New York	United States	12208
54	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
55	Columbia University Medical Center	New York	New York	United States	10032
56	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
57	University of North Carolina	Chapel Hill	North Carolina	United States	27599
58	Carolinas Medical Center	Charlotte	North Carolina	United States	28203
59	Duke University Medical Center	Durham	North Carolina	United States	27710
60	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
61	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
62	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
63	The Children's Medical Center of Dayton	Dayton	Ohio	United States	45404
64	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
65	Legacy Emanuel Children's Hospital	Portland	Oregon	United States	97227
66	Legacy Emanuel Hospital and Health Center	Portland	Oregon	United States	97227
67	Penn State Hershey Children's Hospital	Hershey	Pennsylvania	United States	17033
68	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
69	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States	19134
70	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
71	Palmetto Health Richland	Columbia	South Carolina	United States	29203
72	BI-LO Charities Children's Cancer Center	Greenville	South Carolina	United States	29605
73	Greenville Cancer Treatment Center	Greenville	South Carolina	United States	29605
74	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
75	East Tennessee Childrens Hospital	Knoxville	Tennessee	United States	37916
76	Texas Tech University Health Science Center-Amarillo	Amarillo	Texas	United States	79106
77	Driscoll Children's Hospital	Corpus Christi	Texas	United States	78411
78	Medical City Dallas Hospital	Dallas	Texas	United States	75230
79	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
80	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229-3900
81	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229
82	University of Vermont	Burlington	Vermont	United States	05401
83	Seattle Children's Hospital	Seattle	Washington	United States	98105
84	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington	United States	99204
85	West Virginia University Charleston	Charleston	West Virginia	United States	25304
86	Midwest Children's Cancer Center	Milwaukee	Wisconsin	United States	53226
87	The Children's Hospital at Westmead	Sydney	New South Wales	Australia	2145
88	Princess Margaret Hospital for Children	Perth	Western Australia	Australia	6008
89	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
90	IWK Health Centre	Halifax	Nova Scotia	Canada	B3J 3G9
91	Hospital Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5
92	Saskatoon Cancer Centre	Saskatoon	Saskatchewan	Canada	S7N 4H4

Sponsors and Collaborators

• Children's Oncology Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Pedro De Alarcon, MD, Children's Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT00033293
• Other Study ID Numbers: ANBL00P3; NCI-2009-00399; CDR0000069271; COG-ANBL00P3; U10CA013539; U10CA098543
• First Posted: Jan 27, 2003
• Last Update Posted: Jan 13, 2022
• Last Verified: Jan 1, 2022

• Additional relevant MeSH terms: Neuroblastoma; Prednisone; Cyclophosphamide; Immunoglobulins; Antibodies; gamma-Globulins; Immunoglobulins, Intravenous; Rho(D) Immune Globulin; Hormones; Adrenocorticotropic Hormone; Melanocyte-Stimulating Hormones; Corticotropin-Releasing Hormone; beta-Endorphin

Study Results

Participant Flow

Arm/Group Title	Arm I (Chemotherapy, Immunoglobulin Therapy)	Arm II (Chemotherapy, Observation)
Arm/Group Description	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).	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.
Period Title: Overall Study
STARTED	26	27
COMPLETED	16	9
NOT COMPLETED	10	18

Baseline Characteristics

Arm/Group Title	Arm I (Chemotherapy, Immunoglobulin Therapy)	Arm II (Chemotherapy, Observation)	Total
Arm/Group Description	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).	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.	Total of all reporting groups
Overall Participants	26	27	53
Age (Count of Participants)
<=18 years	26 100%	27 100%	53 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	1.4 (0.9)	1.2 (0.5)	1.3 (0.7)
Sex: Female, Male (Count of Participants)
Female	18 69.2%	15 55.6%	33 62.3%
Male	8 30.8%	12 44.4%	20 37.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 19.2%	7 25.9%	12 22.6%
Not Hispanic or Latino	20 76.9%	20 74.1%	40 75.5%
Unknown or Not Reported	1 3.8%	0 0%	1 1.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 3.8%	0 0%	1 1.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	5 19.2%	6 22.2%	11 20.8%
White	19 73.1%	17 63%	36 67.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 3.8%	4 14.8%	5 9.4%
Region of Enrollment (participants) [Number]
United States	26 100%	27 100%	53 100%

Outcome Measures

1. Primary Outcome

Title	Number of Responders
Description	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

Outcome Measure Data

Analysis Population Description

Eligible patients

Arm/Group Title	Arm I (Chemotherapy, Immunoglobulin Therapy)	Arm II (Chemotherapy, Observation)
Arm/Group Description	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).	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.
Measure Participants	26	26
Number [participants]	21 80.8%	11 40.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Chemotherapy, Immunoglobulin Therapy), Arm II (Chemotherapy, Observation)
	Comments	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.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0044
	Comments	No adjustments for multiple comparisons.
	Method	Chi-squared
	Comments	A two-way test with a null hypothesis of no association, using SAS 9.4.
Method of Estimation	Estimation Parameter	Chi-squared test statistic
	Estimated Value	8.125
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Motor Coordination as Assessed by Neurological Examination and Vineland Adaptive Behavior Scale (VABS)
Description	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

Outcome Measure Data

Analysis Population Description

All eligible patients who had VABS measures at diagnosis and at least one of 6 months or 1 year.

Arm/Group Title	Arm I (Chemotherapy, Immunoglobulin Therapy)	Arm II (Chemotherapy, Observation)
Arm/Group Description	Randomized to chemotherapy, immunoglobulin therapy.	Randomized to chemotherapy, observation
Measure Participants	17	11
Mean (Standard Deviation) [Change in VABS score]	84.53 (115.91)	144.73 (110.69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Chemotherapy, Immunoglobulin Therapy), Arm II (Chemotherapy, Observation)
	Comments	The two samples from the respective treatment arms were compared using a one-sided t-test with a significance level of .05.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0919
	Comments
	Method	t-test, 1 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	60.1979
	Confidence Interval	(1-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Functional Outcome as Assessed by Age-appropriate Neuropsychological Testing
Description	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

Outcome Measure Data

Analysis Population Description

All eligible patients who had Bayley's measures at diagnosis and at least one of 6 months or 1 year.

Arm/Group Title	Arm I (Chemotherapy, Immunoglobulin Therapy)	Arm II (Chemotherapy, Observation)
Arm/Group Description	Randomized to chemotherapy, immunoglobulin therapy.	Randomized to chemotherapy, observation
Measure Participants	4	4
Mean (Standard Deviation) [Change in Bayley's score]	117.5 (35.35)	100.75 (25.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Chemotherapy, Immunoglobulin Therapy), Arm II (Chemotherapy, Observation)
	Comments
	Type of Statistical Test	Other
	Comments	The two samples from the respective treatment arms were compared using a one-sided t-test with a significance level of .05.
Statistical Test of Hypothesis	p-Value	0.2364
	Comments
	Method	t-test, 1 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	16.75
	Confidence Interval	(1-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Biology of Neuroblastoma Associated Opsoclonus-myoclonus-ataxia (OMA) Syndrome Specifically by MRI Findings, Anti-neuronal Antibodies, Cerebrospinal Fluid (CSF) Findings and Tumor Biology
Description	Descriptive analyses on biologic variables will be performed
Time Frame	At diagnosis, 6 months, 1 year, 5 and 10 years after diagnosis

Outcome Measure Data

Analysis Population Description

The data is not available at this time. Investigators have not finished analyzing the specimens or reviewing the patient study data required to evaluate this study objective.

Arm/Group Title	Arm I (Chemotherapy, Immunoglobulin Therapy)	Arm II (Chemotherapy, Observation)
Arm/Group Description	Randomized to chemotherapy, immunoglobulin therapy.	Randomized to chemotherapy, observation
Measure Participants	0	0

5. Secondary Outcome

Title	Long-term Prognosis for Neurologic Recovery by Neurological Examination
Description	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

Outcome Measure Data

Analysis Population Description

The data is not available at this time. Investigators have not finished analyzing the specimens or reviewing the patient study data required to evaluate this study objective.

Arm/Group Title	Arm I (Chemotherapy, Immunoglobulin Therapy)	Arm II (Chemotherapy, Observation)
Arm/Group Description	Randomized to chemotherapy, immunoglobulin therapy.	Randomized to chemotherapy, observation
Measure Participants	0	0

6. Secondary Outcome

Title	Tumor Outcome in Terms of Event-free Survival (EFS) Rate Defined as a Relapse or Progression of Neuroblastoma, a Second Malignancy, or Death
Description	EFS rate for neuroblastoma event from time of study enrollment.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

All eligible randomized patients.

Arm/Group Title	Arm I (Chemotherapy, Immunoglobulin Therapy)	Arm II (Chemotherapy, Observation)
Arm/Group Description	Randomized to chemotherapy, immunoglobulin therapy.	Randomized to chemotherapy, observation
Measure Participants	26	27
Number (95% Confidence Interval) [3 year EFS]	92.3	96.0

7. Secondary Outcome

Title	Tumor Outcome in Terms of Overall Survival (OS) Rate
Description	OS rate from time of study enrollment.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

All eligible randomized patients.

Arm/Group Title	Arm I (Chemotherapy, Immunoglobulin Therapy)	Arm II (Chemotherapy, Observation)
Arm/Group Description	Randomized to chemotherapy, immunoglobulin therapy.	Randomized to chemotherapy, observation
Measure Participants	26	27
Number (95% Confidence Interval) [3 year OS]	100	96.0

Adverse Events

Adverse Event Reporting Description	The SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs), regardless of grade. The other AE field contains all CTCAEs reported on study excluding those that were reported as SAEs, regardless of grade.
Arm/Group Title	Arm I (Chemotherapy, Immunoglobulin Therapy)		Arm II (Chemotherapy, Observation)
Arm/Group Description	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).		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.
All Cause Mortality
	Arm I (Chemotherapy, Immunoglobulin Therapy)		Arm II (Chemotherapy, Observation)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I (Chemotherapy, Immunoglobulin Therapy)		Arm II (Chemotherapy, Observation)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/26 (3.8%)		1/27 (3.7%)
Infections and infestations
53100-Lung infection	0/26 (0%)	0	1/27 (3.7%)	1
Investigations
15000-Aspartate aminotransferase increased	1/26 (3.8%)	1	0/27 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm I (Chemotherapy, Immunoglobulin Therapy)		Arm II (Chemotherapy, Observation)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/26 (50%)		18/27 (66.7%)
Blood and lymphatic system disorders
13200-Anemia	1/26 (3.8%)	3	4/27 (14.8%)	6
33300-Febrile neutropenia	1/26 (3.8%)	2	1/27 (3.7%)	3
Cardiac disorders
74200-Sinus bradycardia	0/26 (0%)	0	1/27 (3.7%)	1
Endocrine disorders
11200-Adrenal insufficiency	0/26 (0%)	0	1/27 (3.7%)	1
24200-Cushingoid	0/26 (0%)	0	2/27 (7.4%)	3
Gastrointestinal disorders
22100-Colitis	0/26 (0%)	0	1/27 (3.7%)	1
25700-Diarrhea	1/26 (3.8%)	1	0/27 (0%)	0
31200-Esophagitis	0/26 (0%)	0	1/27 (3.7%)	1
36700-Gastrointestinal disorders - Other specify	0/26 (0%)	0	1/27 (3.7%)	1
46300-Intra-abdominal hemorrhage(targeted toxicity)	0/26 (0%)	0	1/27 (3.7%)	1
55600-Mucositis oral	0/26 (0%)	0	1/27 (3.7%)	1
57600-Nausea(targeted toxicity)	1/26 (3.8%)	1	2/27 (7.4%)	5
87900-Vomiting(targeted toxicity)	5/26 (19.2%)	6	5/27 (18.5%)	10
General disorders
33900-Fever	1/26 (3.8%)	1	1/27 (3.7%)	1
48700-Irritability	0/26 (0%)	0	3/27 (11.1%)	4
Infections and infestations
16800-Bladder infection	2/26 (7.7%)	2	1/27 (3.7%)	1
20500-Catheter related infection	1/26 (3.8%)	1	2/27 (7.4%)	2
29500-Enterocolitis infectious	0/26 (0%)	0	1/27 (3.7%)	1
44800-Infections and infestations - Other specify	2/26 (7.7%)	2	7/27 (25.9%)	14
82300-Upper respiratory infection	0/26 (0%)	0	1/27 (3.7%)	1
83100-Urinary tract infection	0/26 (0%)	0	1/27 (3.7%)	1
Injury, poisoning and procedural complications
34900-Fracture	0/26 (0%)	0	2/27 (7.4%)	2
Investigations
11600-Alanine aminotransferase increased	2/26 (7.7%)	4	0/27 (0%)	0
15000-Aspartate aminotransferase increased	1/26 (3.8%)	1	0/27 (0%)	0
53700-Lymphocyte count decreased	0/26 (0%)	0	1/27 (3.7%)	1
58300-Neutrophil count decreased	1/26 (3.8%)	4	3/27 (11.1%)	8
65800-Platelet count decreased	0/26 (0%)	0	1/27 (3.7%)	3
88200-Weight gain	0/26 (0%)	0	1/27 (3.7%)	1
88500-White blood cell decreased	1/26 (3.8%)	4	2/27 (7.4%)	3
Metabolism and nutrition disorders
13500-Anorexia	1/26 (3.8%)	2	0/27 (0%)	0
24700-Dehydration	0/26 (0%)	0	2/27 (7.4%)	2
41300-Hypercalcemia	1/26 (3.8%)	1	0/27 (0%)	0
41400-Hyperglycemia(targeted toxicity)	1/26 (3.8%)	2	4/27 (14.8%)	6
41600-Hyperkalemia	1/26 (3.8%)	1	0/27 (0%)	0
42600-Hypoalbuminemia	1/26 (3.8%)	2	0/27 (0%)	0
42700-Hypocalcemia	1/26 (3.8%)	3	1/27 (3.7%)	3
42900-Hypoglycemia	0/26 (0%)	0	1/27 (3.7%)	1
43100-Hypokalemia	1/26 (3.8%)	1	2/27 (7.4%)	3
43300-Hyponatremia	0/26 (0%)	0	1/27 (3.7%)	1
43500-Hypophosphatemia	0/26 (0%)	0	2/27 (7.4%)	3
Nervous system disorders
15300-Ataxia	1/26 (3.8%)	1	4/27 (14.8%)	6
58700-Nystagmus	2/26 (7.7%)	3	9/27 (33.3%)	14
69300-Pyramidal tract syndrome	0/26 (0%)	0	1/27 (3.7%)	1
Psychiatric disorders
11400-Agitation	4/26 (15.4%)	8	11/27 (40.7%)	25
13700-Anxiety(targeted toxicity)	0/26 (0%)	0	1/27 (3.7%)	1
64400-Personality change	1/26 (3.8%)	1	0/27 (0%)	0
Respiratory, thoracic and mediastinal disorders
43900-Hypoxia	0/26 (0%)	0	1/27 (3.7%)	1
Skin and subcutaneous tissue disorders
41500-Hyperhidrosis	1/26 (3.8%)	1	0/27 (0%)	0
69700-Rash maculo-papular(targeted toxicity)	1/26 (3.8%)	1	0/27 (0%)	0
Vascular disorders
42100-Hypertension	0/26 (0%)	0	3/27 (11.1%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Must obtain prior Sponsor approval