Monoclonal Antibody 3F8 and Sargramostim in Treating Patients With Neuroblastoma

• Sponsor: Memorial Sloan Kettering Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00072358
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 291
• Location: 1
• Arms: 2
• Duration (Months): 210.5
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

RATIONALE: Monoclonal antibodies, such as monoclonal antibody 3F8, can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Colony-stimulating factors, such as sargramostim, may increase the number of immune cells found in bone marrow or peripheral blood. Combining monoclonal antibody 3F8 with sargramostim may cause a stronger immune response and kill more tumor cells.

PURPOSE: Phase II trial to study the effectiveness of combining monoclonal antibody 3F8 with sargramostim in treating patients who have neuroblastoma.

Condition or Disease	Intervention/Treatment	Phase
Neuroblastoma	Biological: anti-GD2 murine IgG3 monoclonal antibody 3F8; Biological: anti-GD2 murine IgG3 monoclonal antibody 3F8	Phase 2

Detailed Description

OBJECTIVES:

• Determine the efficacy of sargramostim (GM-CSF) in enhancing monoclonal antibody 3F8-mediated ablation in patients with high-risk neuroblastoma.

• Determine the prognostic impact of minimal residual bone marrow disease on relapse-free survival of patients treated with this regimen.

• Compare the effects of short-term (2-hour intravenous) vs prolonged (subcutaneous release) daily GM-CSF on granulocyte activation, in order to establish the optimal route for tumor-cell kill in these patients.

OUTLINE: This is an open-label study. Patients are stratified according to evaluable disease (yes [primary refractory bone marrow disease] vs no [no evidence of disease]).

Patients receive sargramostim (GM-CSF) subcutaneously on days -5 to 4 and monoclonal antibody 3F8 IV over 0.5-1.5 hours on days 0-4. Treatment repeats every 3 weeks for 4 courses and then every 8 weeks for up to a total of 24 months in the absence of disease progression or unacceptable toxicity.

Beginning after 2 courses of GM-CSF and monoclonal antibody 3F8, patients also receive oral isotretinoin twice daily on days 1-14 (when no monoclonal antibody 3F8 is administered). Treatment with isotretinoin repeats approximately every 28 days for 6 courses.

PROJECTED ACCRUAL: A total of 340 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 291 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Anti-GD2 3F8 Antibody and GM-CSF for High-Risk Neuroblastoma
• Study Start Date: Jul 1, 2003
• Actual Primary Completion Date: Jan 15, 2021
• Actual Study Completion Date: Jan 15, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: patients have refractory bone marrow disease This phase II trial of the anti-GD2 murine IgG3 monoclonal antibody 3F8 combined with granulocyte-macrophage colony stimulating factor (GM-CSF) will assess response of minimal residual disease (MRD) in patients with high-risk neuroblastoma (NB) and help establish the optimal way to use GM-CSF.	Biological: anti-GD2 murine IgG3 monoclonal antibody 3F8; The total dosage of 3F8 per cycle is the same as in prior trials (100 mg/m2), administered at 20 mg/m2/day and infused over ~1.5 hr or less (0.5 hr is customary), with analgesics and antihistamines used as needed for expected side-effects. 3F8 is started ~1 hr after completion of GM-CSF administration. GM-CSF is dosed at 250 mcg/m2/day from day -5 to day +1 (Wednesday to Tuesday is customary) , and is 500 mcg/m2/day thereafter (i.e., on days +2 to +4; Wednesday to Friday), as in the predecessor protocol.18,74 Patients come off study if progressive disease occurs or if there is life-threatening grade 4 toxicity from 3F8; otherwise, patients will receive a minimum of 4 cycles of treatment and will continue treatment through 24 months. It is expected that patients will receive ~10 cycles.; Other Names: patients (enrolled on study for treatment of primary refractory disease), the break between end of a cycle of 3F8/GM-CSF and start of next cycle is 2-to-4-weeks through 4 cycles after achievement of CR in BM; subsequent breaks are ~8 weeks. In this group, isotretinoin is started after documentation of response to, and after >2 cycles of, 3F8/GM-CSF.
Experimental: patients have no evidence of disease This phase II trial of the anti-GD2 murine IgG3 monoclonal antibody 3F8 combined with granulocyte-macrophage colony stimulating factor (GM-CSF) will assess response of minimal residual disease (MRD) in patients with high-risk neuroblastoma (NB) and help establish the optimal way to use GM-CSF.	Biological: anti-GD2 murine IgG3 monoclonal antibody 3F8; The total dosage of 3F8 per cycle is the same as in prior trials (100 mg/m2), administered at 20 mg/m2/day and infused over ~1.5 hr or less (0.5 hr is customary), with analgesics and antihistamines used as needed for expected side-effects. 3F8 is started ~1 hr after completion of GM-CSF administration. GM-CSF is dosed at 250 mcg/m2/day from day -5 to day +1 (Wednesday to Tuesday is customary) , and is 500 mcg/m2/day thereafter (i.e., on days +2 to +4; Wednesday to Friday), as in the predecessor protocol.18,74 Patients come off study if progressive disease occurs or if there is life-threatening grade 4 toxicity from 3F8; otherwise, patients will receive a minimum of 4 cycles of treatment and will continue treatment through 24 months. It is expected that patients will receive ~10 cycles.; Other Names: For Group 2 patients (enrolled on study in CR/VGPR, i.e., with no evidence of disease), the break between end of a cycle and start of next cycle is 2-to-4 weeks through 4 cycles; subsequent breaks are ~8 weeks. Isotretinoin is started after cycle 2 of 3F8/GM-CSF. Road map/schema is in section 4.2. Regarding patients in second or greater CR from relapse in the central nervous system, if they develop early HAMA which precludes timely completion of the minimum of 4 cycles of 3F8/GM-CSF, they are eligible to go off protocol, to be treated with low-dose maintenance regimens of irinotecan,94 temozolomide,95 or the two agents combined;96 they can resume treatment with 3F8/GM-CSF if HAMA becomes negative.

Outcome Measures

Primary Outcome Measures

1. Efficacy at Completion of Treatment [3 years]

2. Relapse-free Survival Every 3 Months [3 years]

Secondary Outcome Measures

1. Compare Granulocyte Activation in Patients Treated With Short-term vs Prolonged Daily Exposure to Sargramostim (GM-CSF) After 4 Courses [3 years]

2. Simplify Treatment With Consequent Reduction in Cost [3 years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis of neuroblastoma by histopathology OR bone marrow metastases and high urine catecholamine levels

• Disease must meet risk-related treatment guidelines and any of the following

International Neuroblastoma Staging System stages:

• Stage 4 with (any age) OR without (> 18 months of age of age) MYCN amplification

• MYCN-amplified other than stage 1

• No evidence of disease (i.e., in complete response/remission or very good partial response/remission) OR disease resistant to standard therapy (i.e., incomplete response in bone marrow)

• No progressive disease or MIBG-avid soft tissue tumor

PATIENT CHARACTERISTICS:

• No existing renal, cardiac, hepatic, neurologic, pulmonary, or gastrointestinal toxicity ≥ grade 3

• No human anti-mouse antibody (HAMA) titer greater than 1,000 Elisa units/mL

• No history of allergy to mouse proteins

• No active life-threatening infection

• Not pregnant

• Negative pregnancy test

PRIOR CONCURRENT THERAPY:

• Not specified

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065

Sponsors and Collaborators

• Memorial Sloan Kettering Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Brian H. Kushner, MD, Memorial Sloan Kettering Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 11, 2020

More Information

Publications

None provided.

• Responsible Party: Memorial Sloan Kettering Cancer Center
• ClinicalTrials.gov Identifier: NCT00072358
• Other Study ID Numbers: 03-077; MSKCC-03077
• First Posted: Nov 6, 2003
• Last Update Posted: May 16, 2022
• Last Verified: Apr 1, 2022

• Keywords provided by Memorial Sloan Kettering Cancer Center: disseminated neuroblastoma; localized unresectable neuroblastoma; recurrent neuroblastoma; regional neuroblastoma; stage 4S neuroblastoma
• Additional relevant MeSH terms: Neuroblastoma; Carbamide Peroxide; Antineoplastic Agents, Immunological; Irinotecan; Temozolomide; Molgramostim; Isotretinoin; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Sargramostim; Immunoglobulin G

Study Results

Participant Flow

Arm/Group Title	Participants With Refractory Bone Marrow Disease and High Risk of Recurrence
Arm/Group Description	Participants included have refractory bone marrow disease and high risk of recurrence of refractory bone marrow disease. All participants will receive anti-GD2 murine IgG3 monoclonal antibody 3F8. As per the study team, the data were not collected in the manner requested. As a result they cannot separate the patients into the respective protocol groups
Period Title: Overall Study
STARTED	291
COMPLETED	291
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Participants With Refractory Bone Marrow Disease and High Risk of Recurrence
Arm/Group Description	Participants included have refractory bone marrow disease and high risk of recurrence of refractory bone marrow disease. All participants will receive anti-GD2 murine IgG3 monoclonal antibody 3F8. As per the study team, the data were not collected in the manner requested. As a result they cannot separate the patients into the respective protocol groups
Overall Participants	291
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	4
Sex: Female, Male (Count of Participants)
Female	112 38.5%
Male	179 61.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	21 7.2%
Not Hispanic or Latino	270 92.8%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	10 3.4%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	28 9.6%
White	238 81.8%
More than one race	0 0%
Unknown or Not Reported	15 5.2%
Region of Enrollment (Count of Participants)
United States	291 100%

Outcome Measures

1. Primary Outcome

Title	Efficacy at Completion of Treatment
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

Data were not collected

Arm/Group Title	Participants With Refractory Bone Marrow Disease and High Risk of Recurrence
Arm/Group Description	Participants included have refractory bone marrow disease and high risk of recurrence of refractory bone marrow disease. All participants will receive anti-GD2 murine IgG3 monoclonal antibody 3F8
Measure Participants	0

2. Primary Outcome

Title	Relapse-free Survival Every 3 Months
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

Data were not collected

Arm/Group Title	Participants With Refractory Bone Marrow Disease and High Risk of Recurrence
Arm/Group Description	Participants included have refractory bone marrow disease and high risk of recurrence of refractory bone marrow disease. All participants will receive anti-GD2 murine IgG3 monoclonal antibody 3F8
Measure Participants	0

3. Secondary Outcome

Title	Compare Granulocyte Activation in Patients Treated With Short-term vs Prolonged Daily Exposure to Sargramostim (GM-CSF) After 4 Courses
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

Data were not collected

Arm/Group Title	Participants With Refractory Bone Marrow Disease and High Risk of Recurrence
Arm/Group Description	Participants included have refractory bone marrow disease and high risk of recurrence of refractory bone marrow disease. All participants will receive anti-GD2 murine IgG3 monoclonal antibody 3F8
Measure Participants	0

4. Secondary Outcome

Title	Simplify Treatment With Consequent Reduction in Cost
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

Data were not collected

Arm/Group Title	Participants With Refractory Bone Marrow Disease and High Risk of Recurrence
Arm/Group Description	Participants included have refractory bone marrow disease and high risk of recurrence of refractory bone marrow disease. All participants will receive anti-GD2 murine IgG3 monoclonal antibody 3F8
Measure Participants	0

Adverse Events

Time Frame	2 years
Arm/Group Title	Participants With Refractory Bone Marrow Disease and High Risk of Recurrence
Arm/Group Description	Participants included have refractory bone marrow disease and high risk of recurrence of refractory bone marrow disease. All participants will receive anti-GD2 murine IgG3 monoclonal antibody 3F8. As per the study team, the data were not collected in the manner requested. As a result they cannot separate the patients into the respective protocol groups.
All Cause Mortality
	Participants With Refractory Bone Marrow Disease and High Risk of Recurrence
	Affected / at Risk (%)	# Events
Total	135/291 (46.4%)
Serious Adverse Events
	Participants With Refractory Bone Marrow Disease and High Risk of Recurrence
	Affected / at Risk (%)	# Events
Total	153/291 (52.6%)
Blood and lymphatic system disorders
Blood,Bone marrow,other	1/291 (0.3%)
Febrile neutropenia	11/291 (3.8%)
Leukocytes	2/291 (0.7%)
Cardiac disorders
Cardiac left vent	1/291 (0.3%)
Cardiovascular, Arrhythmia other	1/291 (0.3%)
Cardiovascular, other	2/291 (0.7%)
Sinus bradycardia	1/291 (0.3%)
Sinus tachycardia	9/291 (3.1%)
Ear and labyrinth disorders
Middle ear/hearing	2/291 (0.7%)
Gastrointestinal disorders
Diarrhea	8/291 (2.7%)
Dysphagia, esophagitis	1/291 (0.3%)
GI, other	2/291 (0.7%)
Hematemesis	1/291 (0.3%)
Nausea	6/291 (2.1%)
Vomiting	16/291 (5.5%)
General disorders
Fatigue	2/291 (0.7%)
Fever	121/291 (41.6%)
Pain, other	5/291 (1.7%)
Rigors, chills	18/291 (6.2%)
Immune system disorders
Allergic Reaction/Hyper	11/291 (3.8%)
Infections and infestations
Catheter-rel inf	5/291 (1.7%)
Infection unk ANC	6/291 (2.1%)
Infection w.out neutropenia	57/291 (19.6%)
Infection with grade 3/4 neut	3/291 (1%)
Infection/Feb Neut-Other	1/291 (0.3%)
Investigations
Neutrophils/gran	5/291 (1.7%)
Platelets	1/291 (0.3%)
SGPT (ALT)	3/291 (1%)
Weight loss	2/291 (0.7%)
Metabolism and nutrition disorders
Dehydration	1/291 (0.3%)
Hypercalcemia	1/291 (0.3%)
Hyperglycemia	5/291 (1.7%)
Hyperkalemia	1/291 (0.3%)
Hypocalcemia	4/291 (1.4%)
Hypoglycemia	3/291 (1%)
Hypokalemia	9/291 (3.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary malignancy, other	4/291 (1.4%)
Nervous system disorders
Ataxia	1/291 (0.3%)
CNS hemorrhage	2/291 (0.7%)
Depressed level of cons	1/291 (0.3%)
Headache	4/291 (1.4%)
Neurology, other	6/291 (2.1%)
Seizure	4/291 (1.4%)
Psychiatric disorders
Irritability < 3 years	1/291 (0.3%)
Mood alteration-anxiety	1/291 (0.3%)
Respiratory, thoracic and mediastinal disorders
ARDS	1/291 (0.3%)
Apnea	1/291 (0.3%)
Cough	6/291 (2.1%)
Dyspnea	3/291 (1%)
Hypoxia	9/291 (3.1%)
Pneumonitis	1/291 (0.3%)
Pulmonary, other	1/291 (0.3%)
Skin and subcutaneous tissue disorders
Pruritus	1/291 (0.3%)
Rash, desquamation	2/291 (0.7%)
Urticaria	3/291 (1%)
Vascular disorders
Hypertension	12/291 (4.1%)
Hypotension	10/291 (3.4%)
Thrombosis	1/291 (0.3%)
Other (Not Including Serious) Adverse Events
	Participants With Refractory Bone Marrow Disease and High Risk of Recurrence
	Affected / at Risk (%)	# Events
Total	287/291 (98.6%)
Gastrointestinal disorders
Vomiting	90/291 (30.9%)
Nausea	78/291 (26.8%)
Diarrhea (Pts w/out col)	38/291 (13.1%)
Abdominal pain/cramping	20/291 (6.9%)
Constipation	19/291 (6.5%)
General disorders
Pain, other	157/291 (54%)
Fever	63/291 (21.6%)
Edema	58/291 (19.9%)
Injection site reaction	33/291 (11.3%)
Fatigue	18/291 (6.2%)
Immune system disorders
Allergy, other	16/291 (5.5%)
Metabolism and nutrition disorders
Anorexia	35/291 (12%)
Musculoskeletal and connective tissue disorders
Bone pain	29/291 (10%)
Nervous system disorders
Headache	40/291 (13.7%)
Psychiatric disorders
Mood alteration-anxiety	22/291 (7.6%)
Irritability < 3 years	16/291 (5.5%)
Reproductive system and breast disorders
Pulmonary, other	32/291 (11%)
Respiratory, thoracic and mediastinal disorders
Cough	80/291 (27.5%)
Hypoxia	24/291 (8.2%)
Skin and subcutaneous tissue disorders
Urticaria	142/291 (48.8%)
Pruritus	100/291 (34.4%)
Dry skin	53/291 (18.2%)
Rash, desquamation	42/291 (14.4%)
Vascular disorders
Flushing	103/291 (35.4%)
Hypertension	18/291 (6.2%)
Hypotension	16/291 (5.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.