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

OBJECTIVES:

Primary

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

- 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).

- 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-iodobenzyl guanidine ^123I (MIBG) scintigraphy and/or bone marrow histology
(stratum-2).

Secondary

- 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.

- To assess molecular parameters of response (RT-PCR) for patients meeting CR criteria.

- To evaluate the immunologic activation induced in vivo by hu14.18-IL2.

- To determine the induction of anti-hu14.18-IL2 antibody by treatment with hu14.18-IL2.

- 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 ^123I-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
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 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.

DISEASE CHARACTERISTICS:

- 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 MRI, CT scan, or x-ray 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 ^123I (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

- No patients with symptomatic pleural effusions or ascites (requiring constant or
intermittent drainage)

- Patients with a history of CNS disease must have no clinical or radiological evidence
of CNS disease at the time of protocol enrollment

PATIENT CHARACTERISTICS:

- Performance status (PS) 0-2

- Karnofsky PS 50-100% for patients > 16 years of age and Lansky PS 50-100% for
patients ≤ 16 years of age

- Patients must have a life expectancy of ≥ 8 weeks

- Absolute phagocyte count (APC) ≥ 1,000/μL

- Platelet count ≥ 20,000/μL*

- Hemoglobin ≥ 8 g/dL*

- Creatinine clearance or radioisotope 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)

- Not pregnant or nursing

- Negative pregnancy test

- Patients of childbearing potential must agree to use an effective birth control
method

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- ALT ≤ 1.5 times ULN

- Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 55% by gated
radionuclide study

- QTC interval < 450 msec

- Patients must have normal respiratory function 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 FEV1/FVC must be greater
than 60%

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

- CNS toxicity ≤ grade 2

- Patients with symptoms of congestive heart failure or uncontrolled cardiac rhythm
disturbance are not 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.

NOTE: *Transfusions are permitted if known history of bone marrow involvement with tumor.

PRIOR CONCURRENT THERAPY:

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

- Must not have received myelosuppressive chemotherapy within 3 weeks of entry onto
this study (4 weeks if prior nitrosourea)

- At least 7 days since the completion of therapy with a non-myelosuppressive biologic
agent

- At least 2 weeks since prior local palliative radiotherapy (RT) (small port)

- Concurrent radiotherapy to localized painful lesions acceptable, provided ≥ 1
measurable/MIBG-evaluable lesion is not irradiated

- At least 6 months since prior craniospinal RT or ≥ 50% of RT of the pelvis

- At least 6 weeks since other prior substantial bone marrow RT

- 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 are eligible > 6 weeks after therapeutic ^131I-MIBG

- Patients who have received an allogenic stem cell transplant are excluded

- Patients 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

- Patients 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

- Must not have received growth factor(s) within 1 week of entry onto this study

- 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

- Patients who have had major surgery (i.e., laparotomy or thoracotomy) within the past
2 weeks are not eligible

- Patients with organ allografts (including bone marrow or stem cell) are not eligible

- No other concurrent anticancer therapy

- No other concurrent cytokines or growth factors