Biological Therapy, Sargramostim, and Isotretinoin in Treating Patients With Relapsed or Refractory Neuroblastoma

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT01334515
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 52
• Locations: 76
• Arms: 2
• Duration (Months): 97
• Patients Per Site: 0.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase II trial is studying how well hu14.18-interleukin-2 (IL2) fusion protein works when given together with sargramostim and isotretinoin in treating patients with relapsed or refractory neuroblastoma. Biological therapy, such as hu14.18-IL2 fusion protein, and sargramostim work in different ways to stimulate the immune system and stop tumor cells from growing. Drugs used in chemotherapy, such as isotretinoin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving hu14.18-IL2 fusion protein together with sargramostim and isotretinoin may kill more tumor cells.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Neuroblastoma	Biological: hu14.18-IL2 fusion protein; Drug: isotretinoin; Biological: sargramostim; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To evaluate the safety and tolerability of sargramostim (GM-CSF) and isotretinoin given in combination with hu14.18-IL-2 (hu14.18-IL2 fusion protein), as a test of feasibility for a future Phase III study.

2. To evaluate the anti-tumor activity of hu14.18-IL2 given in combination with GM-CSF and isotretinoin in patients with recurrent or refractory neuroblastoma with disease measurable by standard radiographic criteria (stratum-1).

3. To evaluate the anti-tumor activity of hu14.18-IL2 given in combination with GM-CSF and isotretinoin in patients with recurrent or refractory neuroblastoma evaluable only by meta iodo benzyl guanidine I 123 (MIBG) scintigraphy and/or bone marrow histology (stratum-2).

SECONDARY OBJECTIVES:

1. To describe the disease burden of stratum-2 patients by semi-quantitative assessment of bone marrow and MIBG scintigraphy and determine whether there is an association between lower disease burden and response to hu14.18-IL2.

2. To assess molecular parameters of response (reverse-transcriptase (RT) polymerase chain reaction (PCR)) for patients meeting complete response (CR) criteria.

3. To evaluate the immunologic activation induced in vivo by hu14.18-IL2. IV. To determine the induction of anti-hu14.18-IL2 antibody by treatment with hu14.18-IL2.

4. To test for associations between tumor response versus immune activation and anti-hu14.18-IL2 activity, and between measurements of toxicity versus immune activation and anti-hu14.18-IL2 activity.

OUTLINE: This is a multicenter study. Patients are stratified according to measurable disease (disease measurable by standard radiographic criteria [stratum-1] vs disease evaluable only by meta iodo benzyl guanidine I 123 (MIBG) and/or bone marrow histology [stratum-2]).

Patients receive sargramostim subcutaneously (SC [preferred]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin orally (PO) twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve stable disease (SD) after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies.

After completion of study therapy, patients are followed up every 3 months for 1 year, every 6 months for 2 years, and then yearly for 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Feasibility/Phase II Study of hu14.18-IL2 Immunocytokine + GM-CSF and Isotretinoin in Patients With Relapsed or Refractory Neuroblastoma
• Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Dec 31, 2013
• Actual Study Completion Date: Sep 30, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Disease measured by standard radiographic criteria Treatment (hu14.18-Interleukin 2(IL2) fusion protein and isotretinoin). Patients receive sargramostim (SC [preferred]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin PO twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve stable disease (SD) after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies.	Biological: hu14.18-IL2 fusion protein; Given IV; Other Names: EMD 273063 hu14.18-IL2 ; Drug: isotretinoin; Given PO; Other Names: 13-CRA Amnesteem Cistane Claravis Sotret ; Biological: sargramostim; Given SC; Other Names: GM-CSF Leukine Prokine ; Other: laboratory biomarker analysis; Correlative studies
Experimental: Disease evaluable only by I-MIBG or BM histology Treatment (hu14.18-Interleukin 2(IL2) fusion protein and isotretinoin). Patients receive sargramostim (SC [preferred]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin PO twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve stable disease (SD) after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies.	Biological: hu14.18-IL2 fusion protein; Given IV; Other Names: EMD 273063 hu14.18-IL2 ; Drug: isotretinoin; Given PO; Other Names: 13-CRA Amnesteem Cistane Claravis Sotret ; Biological: sargramostim; Given SC; Other Names: GM-CSF Leukine Prokine ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Unacceptable Dose Limiting Toxicities (DLTs) [Up to 10 courses]

   Test for tolerability and monitor for the occurrence of too many unacceptable DLTs using a two-stage stopping rule: (Stage 1) Accrue 10 patients. If more than 1 experience at least one unacceptable DLT during the first treatment cycle, the regimen will be considered to have unacceptable toxicity, and accrual will be temporarily closed, to review all relevant data and consider modifying the regimen to improve safety. If 1 or no patients have an unacceptable DLT in the first treatment cycle, then continue. (Stage 2) Accrue 20 more patients. If 7 or more experience at least one unacceptable DLT in the first treatment cycle, temporarily close the study for possible dosing-safety modifications. If 6 or fewer have an unacceptable DLT in the first treatment cycle, it is reasonable to assume that the combination therapy is safe.

Secondary Outcome Measures

1. Overall Response Evaluated in This Study Using the New International Criteria Proposed by the Revised Response Evaluation Criteria in Solid Tumors (RECIST) [Every two cycles (each cycle lasts 28 days)]

   Number of patients where best overall response is a complete response (CR)-[disappearance of all target lesions and disappearance of any other measureable disease], a very Good Partial Response (VGPR)- [>90% decrease of the disease measurement for CT/MRI lesions, taking as reference the disease measurement done to confirm measurable disease at study entry. Non-target CT/MRI lesions stable to smaller in size], or partial Response (PR)- [>= 30% decrease in the disease measurement, taking as reference the disease measurement done to confirm measurable disease at study entry. Non-target CT/MRI lesions stable to smaller in size], and maintains the response. It is possible that a subject's response to therapy may not occur until after several months of treatment. In order to prevent bias, the maximum duration of time/treatment over which a subject's response is to be assessed for determination of the best overall response is after the completion of up to 10 courses.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 30 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• The target tumor is limited to neuroblastoma; patients must have had histologic verification of neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased urinary catecholamines at the time of initial diagnosis

• Patients must have resistant/refractory or recurrent neuroblastoma

• Tumor imaging and bone marrow evaluation for histologic analysis of marrow tumor cell quantity must be obtained within 3 weeks (21 days) prior to enrollment onto study and patients must have one of the following:

• Measurable tumor on magnetic resonance imaging (MRI), computed tomography (CT) scan, or x-ray defined as minimum of 20 mm in at least one dimension; measurable is defined as minimum of 20 mm in at least one dimension; for patients who are in first response (i.e., those patients with persistent sites of tumor after frontline therapy, but who have never relapsed), a biopsy of a lesion or bone marrow must demonstrate viable neuroblastoma following completion of therapy; if the lesion was irradiated, the biopsy must be done at least 4 weeks after radiation is completed

• Meta iodo benzyl guanidine I 123 (MIBG) scan with positive uptake at minimum of one site; for patients in first response, a biopsy of site must demonstrate viable tumor; if lesion was radiated, biopsy must be done at least 4 weeks after radiation completed

• Bone marrow with tumor cells seen on routine morphology (not by neuron specific enolase (NSE) staining only) of bilateral aspirate and/or biopsy on one bone marrow sample

• Patients must have a performance status of 0, 1 or 2; use Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age

• Patients must have a life expectancy of ≥ 8 weeks

• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study

• Myelosuppressive chemotherapy: Must not have received within 3 weeks of entry onto this study (4 weeks if prior nitrosourea).

• Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a non-myelosuppressive biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; for information on half-lives of these agents, refer to the table provided in the following link: https://members.childrensoncologygroup.org/_files/disc/dvl/Half-lifetableforeligibilit y.pdf

• External beam radiation therapy (XRT): >= 2 wks for local palliative XRT (small port);

= 6 months must have elapsed if prior craniospinal XRT or if >= 50% radiation of pelvis; >= 6 weeks must have elapsed if other substantial bone marrow (BM) radiation

• Autologous stem cell transplant (ASCT): Patients are eligible > 56 days after autologous stem cell infusion following myeloablative therapy; patients receiving an autologous stem cell infusion to support non-myeloablative therapy (including 131I-MIBG given as a single agent) are eligible at any time as long as they meet the hematologic and other organ function criteria for eligibility; patients who have received an allogenic stem cell transplant are excluded

• radioactive iodine (131 I) MIBG therapy: Patients are eligible > 6 weeks after therapeutic 131I-MIBG

• Study specific limitations on prior therapy: Subjects who have previously received in vivo anti-GD2 monoclonal antibodies for biologic therapy or for tumor imaging, are eligible unless they have had progressive disease or a severe allergic reaction while receiving prior anti-disialoganglioside (GD2) therapy; subjects who have received autologous marrow infusions or autologous stem cell infusions using monoclonal antibody linked to beads to purge specimens, but no other form of anti-GD2 monoclonal antibody, are eligible

• Growth factor(s): Must not have received within 1 week of entry onto this study

• Steroids: Patients who require or are likely to require corticosteroid or other immunosuppressive drugs for intercurrent disease (any other significant medical problem related to or independent from the neuroblastoma or its treatment) while tentatively scheduled to be receiving treatment on this study are ineligible; the only exception is for patients known to require 2 mg/kg or less of hydrocortisone (or an equivalent dose of an alternative corticosteroid) as premedication for blood product transfusion in order to avoid allergic transfusion reactions

• Peripheral absolute phagocyte count (APC=neutrophils + monocytes) >= 1000/uL

• Platelet count ≥ 20,000/μL*

• Hemoglobin ≥ 8 g/dL*

• Transfusions are permitted to meet these platelet and hemoglobin criteria, if the patient is known to have a history of bone marrow involvement with tumor; patients with platelet counts < 20,000/uL who are refractory to platelet transfusions are not eligible for this study; patients requiring transfusions of platelets or red blood cells (RBC) to meet eligibility criteria will not be evaluable for hematologic toxicity

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min OR serum creatinine based on age/gender as follows:

• 0.4 mg/dL (1 month to < 6 months of age)

• 0.5 mg/dL (6 months to < 1 years of age)

• 0.6 mg/dL (1 to < 2 years of age)

• 0.8 mg/dL (2 to < 6 years of age)

• 1.0 mg/dL (6 to < 10 years of age)

• 1.2 mg/dL (10 to < 13 years of age)

• 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)

• 1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age)

• Total bilirubin =< 1.5 times upper limit of normal (ULN)

• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5 x upper limit of normal (ULN) for age

• Shortening fraction of >= 27% by echocardiogram

• Ejection fraction of >= 55% by gated radionuclide study (interleukin 2 [IL2] is associated with capillary leak and, at high doses, pulmonary edema)

• Corrected QT (QTC) interval < 450 msec

• Due to risk of IL2 associated vascular leak and pulmonary edema, patients must have normal respiratory function; this is defined as no evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% on room air; if pulmonary function tests (PFTs) are performed, the forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) must be greater than 60%

• Patients with a history of central nervous system (CNS) disease must have no clinical or radiological evidence of CNS disease at the time of protocol enrollment; (it is currently unknown whether hu14.18-IL2 penetrates the blood brain barrier to provide effective CNS treatment)

• Patients with seizure disorders may be enrolled if on anti-convulsants and well-controlled

• CNS toxicity =< grade 2

Exclusion Criteria:

• Females of childbearing potential must have a negative pregnancy test

• Patients of childbearing potential must agree to use an effective birth control method (as isotretinoin is known to be teratogenic)

• Female patients who are lactating must agree to stop breast-feeding

• Patients with symptoms of congestive heart failure or uncontrolled cardiac rhythm disturbance are not eligible

• Patients with symptomatic pleural effusions or ascites (requiring constant or intermittent drainage) because IL2 is associated with capillary leak are not eligible

• Patients who have had major surgery (i.e., laparotomy or thoracotomy) within the past 2 weeks are not eligible, due to the capillary leak associated with IL2

• Patients with organ allografts (including bone marrow or stem cell) due to the immune activating effects of IL2 are not eligible; patients receiving prior autologous bone marrow or stem cell re-infusions are eligible

• Patients with prior history of ventilator support related to lung injury (lung injury such as pneumonia, hemorrhagic pneumonitis, capillary leakage) are excluded

• Patients with significant serious intercurrent illnesses (any other ongoing serious medical problem unrelated to cancer or its treatment) that is not covered by the detailed exclusion criteria and which is expected to interfere with the action of hu14.18-IL2 or to significantly increase the severity of the toxicities experienced from hu14.18-IL2 treatment are not eligible

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
3	Children's Oncology Group	Arcadia	California	United States	91006-3776
4	Loma Linda University Medical Center	Loma Linda	California	United States	92354
5	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
6	Children's Hospital Central California	Madera	California	United States	93636-8762
7	Childrens Hospital of Orange County	Orange	California	United States	92868-3874
8	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
9	University of California San Francisco Medical Center-Parnassus	San Francisco	California	United States	94143
10	Children's Hospital Colorado	Aurora	Colorado	United States	80045
11	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado	United States	80218
12	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
13	Children's National Medical Center	Washington	District of Columbia	United States	20010
14	Lee Memorial Health System	Fort Myers	Florida	United States	33901
15	Nemours Children's Clinic - Jacksonville	Jacksonville	Florida	United States	32207-8426
16	Miami Children's Hospital	Miami	Florida	United States	33155
17	Florida Hospital	Orlando	Florida	United States	32803
18	All Children's Hospital	Saint Petersburg	Florida	United States	33701
19	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
20	University of Hawaii	Honolulu	Hawaii	United States	96813
21	University of Illinois	Chicago	Illinois	United States	60612
22	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637-1470
23	Southern Illinois University	Springfield	Illinois	United States	62702
24	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
25	Raymond Blank Children's Hospital	Des Moines	Iowa	United States	50309
26	University of Kentucky	Lexington	Kentucky	United States	40536
27	Kosair Children's Hospital	Louisville	Kentucky	United States	40202
28	Tulane University Health Sciences Center	New Orleans	Louisiana	United States	70112
29	Children's Hospital-Main Campus	New Orleans	Louisiana	United States	70118
30	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
31	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
32	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
33	Kalamazoo Center for Medical Studies	Kalamazoo	Michigan	United States	49008
34	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
35	Mayo Clinic	Rochester	Minnesota	United States	55905
36	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri	United States	63104
37	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
38	Morristown Memorial Hospital	Morristown	New Jersey	United States	07962
39	Overlook Hospital	Summit	New Jersey	United States	07902
40	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87106
41	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
42	Columbia University Medical Center	New York	New York	United States	10032
43	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
44	New York Medical College	Valhalla	New York	United States	10595
45	University of North Carolina	Chapel Hill	North Carolina	United States	27599
46	Carolinas Medical Center	Charlotte	North Carolina	United States	28203
47	Presbyterian Hospital	Charlotte	North Carolina	United States	28204
48	Duke University Medical Center	Durham	North Carolina	United States	27710
49	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
50	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
51	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
52	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
53	The Children's Medical Center of Dayton	Dayton	Ohio	United States	45404
54	The Toledo Hospital/Toledo Children's Hospital	Toledo	Ohio	United States	43606
55	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
56	Natalie W Bryant Cancer Center	Tulsa	Oklahoma	United States	74136
57	Oregon Health and Science University	Portland	Oregon	United States	97239
58	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania	United States	18017
59	Penn State Hershey Children's Hospital	Hershey	Pennsylvania	United States	17033
60	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
61	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
62	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
63	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
64	Medical City Dallas Hospital	Dallas	Texas	United States	75230
65	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
66	Primary Children's Medical Center	Salt Lake City	Utah	United States	84113
67	Childrens Hospital-King's Daughters	Norfolk	Virginia	United States	23507
68	Virginia Commonwealth University	Richmond	Virginia	United States	23298
69	Seattle Children's Hospital	Seattle	Washington	United States	98105
70	Saint Vincent Hospital	Green Bay	Wisconsin	United States	54301
71	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
72	Alberta Children's Hospital	Calgary	Alberta	Canada	T3B 6A8
73	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
74	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
75	The Montreal Children's Hospital of the MUHC	Montreal	Quebec	Canada	H3H 1P3
76	Hospital Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Suzanne Shusterman, MD, Children's Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT01334515
• Other Study ID Numbers: ANBL1021; NCI-2011-02672; CDR0000698589; U10CA098543; COG-ANBL1021
• First Posted: Apr 13, 2011
• Last Update Posted: Oct 21, 2019
• Last Verified: Oct 1, 2019

• Additional relevant MeSH terms: Neuroblastoma; Isotretinoin; Sargramostim

Study Results

Participant Flow

Arm/Group Title	Disease Measured by Standard Radiographic Criteria	Disease Evaluable Only by I-MIBG or BM Histology
Arm/Group Description	Treatment (hu14.18-IL2 fusion protein and isotretinoin). Patients receive sargramostim (SC [preferred]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin PO twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve SD after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies. hu14.18-IL2 fusion protein: Given IV isotretinoin: Given PO sargramostim: Given SC laboratory biomarker analysis: Correlative studies	Treatment (hu14.18-IL2 fusion protein and isotretinoin). Patients receive sargramostim (SC [preferred]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin PO twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve SD after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies. hu14.18-IL2 fusion protein: Given IV isotretinoin: Given PO sargramostim: Given SC laboratory biomarker analysis: Correlative studies
Period Title: Overall Study
STARTED	16	36
COMPLETED	4	7
NOT COMPLETED	12	29

Baseline Characteristics

Arm/Group Title	Disease Measured by Standard Radiographic Criteria	Disease Evaluable Only by I-MIBG or BM Histology	Total
Arm/Group Description	Treatment (hu14.18-IL2 fusion protein and isotretinoin). Patients receive sargramostim (SC [preferred]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin PO twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve SD after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies. hu14.18-IL2 fusion protein: Given IV isotretinoin: Given PO sargramostim: Given SC laboratory biomarker analysis: Correlative studies	Treatment (hu14.18-IL2 fusion protein and isotretinoin). Patients receive sargramostim (SC [preferred]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin PO twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve SD after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies. hu14.18-IL2 fusion protein: Given IV isotretinoin: Given PO sargramostim: Given SC laboratory biomarker analysis: Correlative studies	Total of all reporting groups
Overall Participants	16	36	52
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	6.94	8.75	8.31
Age (Count of Participants)
<=18 years	15 93.8%	32 88.9%	47 90.4%
Between 18 and 65 years	1 6.3%	4 11.1%	5 9.6%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	6 37.5%	12 33.3%	18 34.6%
Male	10 62.5%	24 66.7%	34 65.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 2.8%	1 1.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 18.8%	3 8.3%	6 11.5%
White	11 68.8%	25 69.4%	36 69.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 12.5%	7 19.4%	9 17.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 31.3%	3 8.3%	8 15.4%
Not Hispanic or Latino	11 68.8%	30 83.3%	41 78.8%
Unknown or Not Reported	0 0%	3 8.3%	3 5.8%
Region of Enrollment (participants) [Number]
United States	14 87.5%	33 91.7%	47 90.4%
Canada	2 12.5%	3 8.3%	5 9.6%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Unacceptable Dose Limiting Toxicities (DLTs)
Description	Test for tolerability and monitor for the occurrence of too many unacceptable DLTs using a two-stage stopping rule: (Stage 1) Accrue 10 patients. If more than 1 experience at least one unacceptable DLT during the first treatment cycle, the regimen will be considered to have unacceptable toxicity, and accrual will be temporarily closed, to review all relevant data and consider modifying the regimen to improve safety. If 1 or no patients have an unacceptable DLT in the first treatment cycle, then continue. (Stage 2) Accrue 20 more patients. If 7 or more experience at least one unacceptable DLT in the first treatment cycle, temporarily close the study for possible dosing-safety modifications. If 6 or fewer have an unacceptable DLT in the first treatment cycle, it is reasonable to assume that the combination therapy is safe.
Time Frame	Up to 10 courses

Outcome Measure Data

Analysis Population Description

This outcome measure evaluates the first 30 patients to enroll and who receive at least one dose of hu14.18-IL2.

Arm/Group Title	Disease Measured by Standard Radiographic Criteria	Disease Evaluable Only by I-MIBG or BM Histology
Arm/Group Description	Treatment (hu14.18-IL2 fusion protein and isotretinoin). Patients receive sargramostim (SC [preferred]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin PO twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve SD after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies. hu14.18-IL2 fusion protein: Given IV isotretinoin: Given PO sargramostim: Given SC laboratory biomarker analysis: Correlative studies	Treatment (hu14.18-IL2 fusion protein and isotretinoin). Patients receive sargramostim (SC [preferred]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin PO twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve SD after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies. hu14.18-IL2 fusion protein: Given IV isotretinoin: Given PO sargramostim: Given SC laboratory biomarker analysis: Correlative studies
Measure Participants	10	20
Patients with Unacceptable DLTs	1 6.3%	2 5.6%
Patients without Unacceptable DLTs	9 56.3%	18 50%

2. Secondary Outcome

Title	Overall Response Evaluated in This Study Using the New International Criteria Proposed by the Revised Response Evaluation Criteria in Solid Tumors (RECIST)
Description	Number of patients where best overall response is a complete response (CR)-[disappearance of all target lesions and disappearance of any other measureable disease], a very Good Partial Response (VGPR)- [>90% decrease of the disease measurement for CT/MRI lesions, taking as reference the disease measurement done to confirm measurable disease at study entry. Non-target CT/MRI lesions stable to smaller in size], or partial Response (PR)- [>= 30% decrease in the disease measurement, taking as reference the disease measurement done to confirm measurable disease at study entry. Non-target CT/MRI lesions stable to smaller in size], and maintains the response. It is possible that a subject's response to therapy may not occur until after several months of treatment. In order to prevent bias, the maximum duration of time/treatment over which a subject's response is to be assessed for determination of the best overall response is after the completion of up to 10 courses.
Time Frame	Every two cycles (each cycle lasts 28 days)

Outcome Measure Data

Analysis Population Description

Patients will be evaluable for inclusion in the analysis of response if they have an event at any time on the study or if they complete at least 2 cycles of hu14.18-IL2 therapy. Patients who go off-protocol therapy prior to the completion of 2 cycles due to parent/family choice and/or due to toxicity will not be considered evaluable for response.

Arm/Group Title	Disease Measured by Standard Radiographic Criteria	Disease Evaluable Only by I-MIBG or BM Histology
Arm/Group Description	Treatment (hu14.18-IL2 fusion protein and isotretinoin). Patients receive sargramostim (SC [preferred]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin PO twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve SD after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies. hu14.18-IL2 fusion protein: Given IV isotretinoin: Given PO sargramostim: Given SC laboratory biomarker analysis: Correlative studies	Treatment (hu14.18-IL2 fusion protein and isotretinoin). Patients receive sargramostim (SC [preferred]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin PO twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve SD after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies. hu14.18-IL2 fusion protein: Given IV isotretinoin: Given PO sargramostim: Given SC laboratory biomarker analysis: Correlative studies
Measure Participants	15	30
Responders	1 6.3%	6 16.7%
Non-Responders	14 87.5%	24 66.7%

Adverse Events

Adverse Event Reporting Description	SAE field contains NCI Common Toxicity Criteria for Adverse Effects (CTCAE) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. Only Grade 3 and higher Adverse Events were collected/assessed in this study.
Arm/Group Title	Disease Measured by Standard Radiographic Criteria		Disease Evaluable Only by I-MIBG or BM Histology
Arm/Group Description	Treatment (hu14.18-IL2 fusion protein and isotretinoin). Patients receive sargramostim (SC [preferred]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin PO twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve SD after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies. hu14.18-IL2 fusion protein: Given IV isotretinoin: Given PO sargramostim: Given SC laboratory biomarker analysis: Correlative studies		Treatment (hu14.18-IL2 fusion protein and isotretinoin). Patients receive sargramostim (SC [preferred]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin PO twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve SD after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies. hu14.18-IL2 fusion protein: Given IV isotretinoin: Given PO sargramostim: Given SC laboratory biomarker analysis: Correlative studies
All Cause Mortality
	Disease Measured by Standard Radiographic Criteria		Disease Evaluable Only by I-MIBG or BM Histology
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Disease Measured by Standard Radiographic Criteria		Disease Evaluable Only by I-MIBG or BM Histology
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/16 (43.8%)		18/36 (50%)
Blood and lymphatic system disorders
Anemia	1/16 (6.3%)	1	0/36 (0%)	0
Gastrointestinal disorders
Vomiting	0/16 (0%)	0	1/36 (2.8%)	1
General disorders
Death NOS	1/16 (6.3%)	1	0/36 (0%)	0
Fever	0/16 (0%)	0	2/36 (5.6%)	2
Malaise	0/16 (0%)	0	1/36 (2.8%)	1
Pain	1/16 (6.3%)	1	2/36 (5.6%)	2
Investigations
Alanine aminotransferase increased	0/16 (0%)	0	3/36 (8.3%)	3
Aspartate aminotransferase increased	0/16 (0%)	0	3/36 (8.3%)	3
Blood bilirubin increased	4/16 (25%)	5	6/36 (16.7%)	7
GGT increased	0/16 (0%)	0	1/36 (2.8%)	1
Platelet count decreased	0/16 (0%)	0	1/36 (2.8%)	1
Metabolism and nutrition disorders
Anorexia	0/16 (0%)	0	1/36 (2.8%)	1
Dehydration	0/16 (0%)	0	1/36 (2.8%)	1
Hypercalcemia	1/16 (6.3%)	1	0/36 (0%)	0
Hypoalbuminemia	1/16 (6.3%)	1	0/36 (0%)	0
Hypocalcemia	1/16 (6.3%)	1	1/36 (2.8%)	1
Hypokalemia	1/16 (6.3%)	2	1/36 (2.8%)	1
Hypophosphatemia	1/16 (6.3%)	1	0/36 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	1/16 (6.3%)	1	0/36 (0%)	0
Nervous system disorders
Depressed level of consciousness	0/16 (0%)	0	1/36 (2.8%)	1
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/16 (6.3%)	1	1/36 (2.8%)	1
Pleural effusion	1/16 (6.3%)	1	0/36 (0%)	0
Respiratory failure	0/16 (0%)	0	1/36 (2.8%)	1
Sore throat	0/16 (0%)	0	1/36 (2.8%)	1
Skin and subcutaneous tissue disorders
Erythroderma	0/16 (0%)	0	1/36 (2.8%)	1
Rash maculo-papular	1/16 (6.3%)	1	0/36 (0%)	0
Vascular disorders
Capillary leak syndrome	3/16 (18.8%)	4	2/36 (5.6%)	2
Hypotension	1/16 (6.3%)	1	1/36 (2.8%)	1
Other (Not Including Serious) Adverse Events
	Disease Measured by Standard Radiographic Criteria		Disease Evaluable Only by I-MIBG or BM Histology
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/16 (81.3%)		31/36 (86.1%)
Blood and lymphatic system disorders
Anemia	9/16 (56.3%)	11	11/36 (30.6%)	11
Febrile neutropenia	0/16 (0%)	0	1/36 (2.8%)	1
Cardiac disorders
Cardiac disorders - Other	0/16 (0%)	0	1/36 (2.8%)	1
Mitral valve disease	0/16 (0%)	0	1/36 (2.8%)	1
Ear and labyrinth disorders
Hearing impaired	0/16 (0%)	0	3/36 (8.3%)	3
Eye disorders
Eye disorders - Other	0/16 (0%)	0	1/36 (2.8%)	1
Photophobia	0/16 (0%)	0	1/36 (2.8%)	1
Gastrointestinal disorders
Abdominal pain	1/16 (6.3%)	2	5/36 (13.9%)	5
Gastroesophageal reflux disease	0/16 (0%)	0	1/36 (2.8%)	1
Nausea	0/16 (0%)	0	2/36 (5.6%)	3
Small intestinal obstruction	1/16 (6.3%)	1	0/36 (0%)	0
Vomiting	0/16 (0%)	0	1/36 (2.8%)	1
General disorders
Fatigue	2/16 (12.5%)	2	0/36 (0%)	0
Fever	1/16 (6.3%)	1	10/36 (27.8%)	22
Pain	2/16 (12.5%)	2	6/36 (16.7%)	10
Immune system disorders
Allergic reaction	0/16 (0%)	0	2/36 (5.6%)	2
Infections and infestations
Catheter related infection	0/16 (0%)	0	2/36 (5.6%)	3
Enterocolitis infectious	1/16 (6.3%)	1	0/36 (0%)	0
Infections and infestations - Other	2/16 (12.5%)	4	1/36 (2.8%)	1
Lung infection	0/16 (0%)	0	1/36 (2.8%)	1
Otitis media	1/16 (6.3%)	1	0/36 (0%)	0
Upper respiratory infection	1/16 (6.3%)	1	1/36 (2.8%)	1
Investigations
Alanine aminotransferase increased	3/16 (18.8%)	4	14/36 (38.9%)	20
Alkaline phosphatase increased	2/16 (12.5%)	2	0/36 (0%)	0
Aspartate aminotransferase increased	2/16 (12.5%)	2	11/36 (30.6%)	13
Blood bilirubin increased	2/16 (12.5%)	4	4/36 (11.1%)	10
GGT increased	0/16 (0%)	0	2/36 (5.6%)	4
Lymphocyte count decreased	2/16 (12.5%)	3	10/36 (27.8%)	16
Neutrophil count decreased	2/16 (12.5%)	2	5/36 (13.9%)	6
Platelet count decreased	5/16 (31.3%)	7	11/36 (30.6%)	20
Weight gain	0/16 (0%)	0	1/36 (2.8%)	1
Weight loss	1/16 (6.3%)	1	0/36 (0%)	0
White blood cell decreased	1/16 (6.3%)	2	8/36 (22.2%)	9
Metabolism and nutrition disorders
Anorexia	0/16 (0%)	0	3/36 (8.3%)	3
Hyperglycemia	5/16 (31.3%)	5	2/36 (5.6%)	4
Hypernatremia	1/16 (6.3%)	1	0/36 (0%)	0
Hypertriglyceridemia	1/16 (6.3%)	1	2/36 (5.6%)	2
Hypoalbuminemia	2/16 (12.5%)	2	2/36 (5.6%)	2
Hypocalcemia	2/16 (12.5%)	2	2/36 (5.6%)	3
Hypokalemia	2/16 (12.5%)	2	6/36 (16.7%)	9
Hypomagnesemia	0/16 (0%)	0	1/36 (2.8%)	1
Hyponatremia	1/16 (6.3%)	2	0/36 (0%)	0
Hypophosphatemia	2/16 (12.5%)	4	3/36 (8.3%)	6
Metabolism and nutrition disorders - Other	0/16 (0%)	0	1/36 (2.8%)	1
Obesity	0/16 (0%)	0	1/36 (2.8%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/16 (6.3%)	1	2/36 (5.6%)	3
Bone pain	0/16 (0%)	0	3/36 (8.3%)	3
Buttock pain	0/16 (0%)	0	1/36 (2.8%)	1
Musculoskeletal and connective tissue disorder - Other	0/16 (0%)	0	1/36 (2.8%)	1
Neck pain	0/16 (0%)	0	1/36 (2.8%)	1
Pain in extremity	0/16 (0%)	0	2/36 (5.6%)	2
Nervous system disorders
Headache	0/16 (0%)	0	1/36 (2.8%)	1
Psychiatric disorders
Anxiety	1/16 (6.3%)	1	0/36 (0%)	0
Insomnia	0/16 (0%)	0	1/36 (2.8%)	1
Renal and urinary disorders
Renal and urinary disorders - Other	0/16 (0%)	0	1/36 (2.8%)	1
Respiratory, thoracic and mediastinal disorders
Cough	0/16 (0%)	0	1/36 (2.8%)	1
Hypoxia	1/16 (6.3%)	1	4/36 (11.1%)	10
Nasal congestion	0/16 (0%)	0	1/36 (2.8%)	1
Pleural effusion	1/16 (6.3%)	1	0/36 (0%)	0
Pneumonitis	0/16 (0%)	0	1/36 (2.8%)	1
Skin and subcutaneous tissue disorders
Dry skin	0/16 (0%)	0	1/36 (2.8%)	1
Pruritus	0/16 (0%)	0	1/36 (2.8%)	1
Rash maculo-papular	0/16 (0%)	0	2/36 (5.6%)	2
Vascular disorders
Capillary leak syndrome	1/16 (6.3%)	1	3/36 (8.3%)	3
Hypotension	0/16 (0%)	0	7/36 (19.4%)	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.