Feasibility/Phase II Study of hu14.18-IL2 Immunocytokine + GM-CSF and Isotretinoin in Patients With Relapsed or Refractory Neuroblastoma

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-iodobenzyl 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

- 131I-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-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