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.
Minimum age: 1 Year.
Maximum age: 30 Years.
Gender(s): Both.
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-lifetableforeligibility. 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
University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
Alberta Children's Hospital, Calgary, Alberta T3B 6A8, Canada
University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States
British Columbia Children's Hospital, Vancouver, British Columbia V6H 3V4, Canada
Children's Oncology Group, Arcadia, California 91006-3776, United States
Loma Linda University Medical Center, Loma Linda, California 92354, United States
Children's Hospital Los Angeles, Los Angeles, California 90027, United States
Children's Hospital Central California, Madera, California 93636-8762, United States
Childrens Hospital of Orange County, Orange, California 92868-3874, United States
Rady Children's Hospital - San Diego, San Diego, California 92123, United States
University of California San Francisco Medical Center-Parnassus, San Francisco, California 94143, United States
Children's Hospital Colorado, Aurora, Colorado 80045, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center, Denver, Colorado 80218, United States
Connecticut Children's Medical Center, Hartford, Connecticut 06106, United States
Children's National Medical Center, Washington, District of Columbia 20010, United States
Lee Memorial Health System, Fort Myers, Florida 33901, United States
Nemours Children's Clinic - Jacksonville, Jacksonville, Florida 32207-8426, United States
Miami Children's Hospital, Miami, Florida 33155, United States
Florida Hospital, Orlando, Florida 32803, United States
All Children's Hospital, Saint Petersburg, Florida 33701, United States
Children's Healthcare of Atlanta - Egleston, Atlanta, Georgia 30322, United States
University of Hawaii, Honolulu, Hawaii 96813, United States
University of Chicago Comprehensive Cancer Center, Chicago, Illinois 60637-1470, United States
University of Illinois, Chicago, Illinois 60612, United States
Southern Illinois University, Springfield, Illinois 62702, United States
Riley Hospital for Children, Indianapolis, Indiana 46202, United States
Raymond Blank Children's Hospital, Des Moines, Iowa 50309, United States
University of Kentucky, Lexington, Kentucky 40536, United States
Kosair Children's Hospital, Louisville, Kentucky 40202, United States
Children's Hospital-Main Campus, New Orleans, Louisiana 70118, United States
Tulane University Health Sciences Center, New Orleans, Louisiana 70112, United States
Sinai Hospital of Baltimore, Baltimore, Maryland 21215, United States
Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States
Bronson Methodist Hospital, Kalamazoo, Michigan 49007, United States
Kalamazoo Center for Medical Studies, Kalamazoo, Michigan 49008, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis, Minneapolis, Minnesota 55404, United States
Mayo Clinic, Rochester, Minnesota 55905, United States
Cardinal Glennon Children's Medical Center, Saint Louis, Missouri 63104, United States
Washington University School of Medicine, Saint Louis, Missouri 63110, United States
Morristown Memorial Hospital, Morristown, New Jersey 07962, United States
Overlook Hospital, Summit, New Jersey 07902, United States
University of New Mexico Cancer Center, Albuquerque, New Mexico 87106, United States
Roswell Park Cancer Institute, Buffalo, New York 14263, United States
Columbia University Medical Center, New York, New York 10032, United States
State University of New York Upstate Medical University, Syracuse, New York 13210, United States
New York Medical College, Valhalla, New York 10595, United States
University of North Carolina, Chapel Hill, North Carolina 27599, United States
Carolinas Medical Center, Charlotte, North Carolina 28203, United States
Presbyterian Hospital, Charlotte, North Carolina 28204, United States
Duke University Medical Center, Durham, North Carolina 27710, United States
Children's Hospital Medical Center of Akron, Akron, Ohio 44308, United States
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, United States
Cleveland Clinic Foundation, Cleveland, Ohio 44195, United States
Rainbow Babies and Childrens Hospital, Cleveland, Ohio 44106, United States
The Children's Medical Center of Dayton, Dayton, Ohio 45404, United States
The Toledo Hospital/Toledo Children's Hospital, Toledo, Ohio 43606, United States
University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States
Natalie W Bryant Cancer Center, Tulsa, Oklahoma 74136, United States
Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
Oregon Health and Science University, Portland, Oregon 97239, United States
Lehigh Valley Hospital - Muhlenberg, Bethlehem, Pennsylvania 18017, United States
Penn State Hershey Children's Hospital, Hershey, Pennsylvania 17033, United States
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States
Hospital Sainte-Justine, Montreal, Quebec H3T 1C5, Canada
The Montreal Children's Hospital of the MUHC, Montreal, Quebec H3H 1P3, Canada
Sanford USD Medical Center - Sioux Falls, Sioux Falls, South Dakota 57117-5134, United States
St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States
Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232, United States
Medical City Dallas Hospital, Dallas, Texas 75230, United States
Cook Children's Medical Center, Fort Worth, Texas 76104, United States
Primary Children's Medical Center, Salt Lake City, Utah 84113, United States
Childrens Hospital-King's Daughters, Norfolk, Virginia 23507, United States
Virginia Commonwealth University, Richmond, Virginia 23298, United States
Seattle Children's Hospital, Seattle, Washington 98105, United States
Saint Vincent Hospital, Green Bay, Wisconsin 54301, United States
University of Wisconsin Hospital and Clinics, Madison, Wisconsin 53792, United States