Monoclonal Antibody Ch14.18, Sargramostim, Aldesleukin, and Isotretinoin After Autologous Stem Cell Transplant in Treating Patients With Neuroblastoma

PRIMARY OBJECTIVES:

I. To comprehensively define the safety profile of ch14.18 when administered with cytokines
and isotretinoin in high-risk neuroblastoma patients after autologous stem cell transplant
(ASCT).

SECONDARY OBJECTIVES:

I. To further describe and refine the event-free survival (EFS) and overall survival (OS)
estimates and baseline characteristics for subjects receiving chl4.18 + cytokines +
isotretinoin.

II. To further describe the safety and toxicity of chl4.18 + cytokines + isotretinoin with
focus on: a) number of courses delivered per patient; b) number of dose reductions or
stoppage (ch14.18 and/or interleukin [IL]-2 [aldesleukin]); and c) number of toxic deaths.

III. To further describe the immune reconstitution of patients following ASCT, based on
laboratory data obtained just prior to, during, and after treatment with this regimen.

IV. To obtain correlative laboratory data to evaluate and describe mechanisms related to
response, toxicity of immune activation, and allergic phenomena.

OUTLINE:

Patients receive sargramostim subcutaneously (SC) or intravenously (IV) over 2 hours on days
0-13 of courses 1, 3, and 5; monoclonal antibody Ch14.18 IV over 10 hours on days 3-6 of
courses 1, 3, and 5 and on days 7-10 of courses 2 and 4; and isotretinoin orally (PO) twice
daily (BID) on days 11-24 of course 1, on days 14-27 of courses 2, 4, and 6, and on days
10-23 of courses 3 and 5. Patients also receive aldesleukin IV continuously on days 0-3 and
on days 7-10 of courses 2 and 4. Treatment repeats every 24-32 days for 6 courses in the
absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up every 3 months for 1 year, every
6 months for 4 years, and then annually thereafter.

Inclusion Criteria:

- All patients must be diagnosed with neuroblastoma, and categorized as high-risk at the
time of diagnosis

- At pre-ASCT evaluation, patients must meet the International Neuroblastoma Response
Criteria (INRC) for complete response (CR), very good partial response (VGPR), or
partial response (PR) for primary site, soft tissue metastases and bone metastases;
patients who meet those criteria must also meet the protocol specified criteria for
bone marrow response as outlined below: =< 10% tumor (of total nucleated cellular
content) seen on any specimen from a bilateral bone marrow aspirate/biopsy; patients
who have no tumor seen on the prior bone marrow, and then have =< 10% tumor on any of
the bilateral marrow aspirate/biopsy specimens done at pre-ASCT and/or pre-enrollment
evaluation will also be eligible; (Note that, per INRC, this would have been defined
as an "overall" response of progressive disease [PD])

- Prior to enrollment on ANBL0931, a determination of residual disease must be performed
(tumor imaging studies including metaiodobenzylguanidine [MIBG] scan, computed
tomography [CT] or magnetic resonance imaging [MRI], bone marrow aspiration and
biopsy); this disease assessment is required for eligibility, and should be done
preferably within 2 weeks but must be done within a maximum of 4 weeks before
enrollment

- Patients with residual disease are eligible; biopsy is not required

- Patients must not have progressive disease except for protocol specified bone
marrow response

- All patients must have completed therapy including intensive induction chemotherapy
followed by ASCT and radiotherapy to be eligible; radiotherapy may be waived for
patients who either had a small adrenal mass which was completely resected upfront, or
who never had an identifiable primary tumor

- No more than 9 months from the date of starting the first induction chemotherapy after
diagnosis to the date of ASCT except for the rare occasions as noted below; for tandem
ASCT patients, this will be the date of the FIRST stem cell infusion; Exception: for
those who are initially diagnosed as non-high risk neuroblastoma, but later converted
(and/ or relapsed) to high risk neuroblastoma, the 9 months restriction should start
from the date of induction therapy for high risk neuroblastoma (not from the initial
induction therapy for non-high risk disease), to the date of ASCT

- Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of
age; required patients must have a Lansky or Karnofsky performance scale score of >=
50%

- Patients must have a life expectancy of >= 2 months (8 weeks)

- Total absolute phagocyte count (APC = neutrophils + monocytes) is at least 1000/uL

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

- 1 month to < 6 months: 0.4 mg/dL

- 6 months to < 1 year: 0.5 mg/dL

- 1 to < 2 years: 0.6 mg/dL

- 2 to < 6 years: 0.8 mg/dL

- 6 to < 10 years: 1 mg/dL

- 10 to < 13 years: 1.2 mg/dL

- 13 to < 16 years: 1.5 mg/dL (male), 1.4 mg/dL (female)

- >= 16 years: 1.7 mg/dL (male), 1.4 mg/dL (female)

- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age

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

- SOS (sinusoidal obstruction syndrome, formerly known as veno-occlusive disease [VOD]),
if present, should be stable or improving

- Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 55% by
radionuclide angiography

- No evidence of dyspnea at rest

- If pulmonary function tests (PFTs) are performed, forced expiratory volume in one
second (FEV1)/forced vital capacity (FVC) > 60% by pulmonary function test

- Patients with seizure disorder may be enrolled if on anticonvulsants and well
controlled

- Central nervous system (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

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

- Patients must not have received prior anti-GD2 antibody therapy

- Patients must not have received prior vaccine therapy administered as treatment of
neuroblastoma not routine infectious disease vaccinations