I. Determine if monoclonal antibody Ch14.18 (dinutuximab) + cytokines + isotretinoin
(13-cis-retinoic acid, or RA) improves event free survival after myeloablative therapy and
stem cell rescue as compared to RA alone, in high risk neuroblastoma patients who have
achieved a pre-autologous stem cell transplant (ASCT) response of complete response (CR),
very good partial response (VGPR), or partial response (PR).
I. Determine if monoclonal antibody Ch14.18 + cytokines + isotretinoin (13-cis-retinoic acid,
or RA) improves overall survival after myeloablative therapy and stem cell rescue as compared
to RA alone, in high risk neuroblastoma patients who have achieved a pre-ASCT response of CR,
VGPR, or PR.
II. Determine if immunotherapy + RA improves event free survival and overall survival as
compared to RA alone, in the subgroup of high risk International Neuroblastoma Staging System
(INSS) stage 4 neuroblastoma patients who have achieved a pre-ASCT response of CR, VGPR, or
III. Determine the toxicities of the combination of monoclonal antibody Ch14.18 with
IV. To compare the outcome data of the patients with persistent disease documented by biopsy
(Stratum 07) to the historical data for the analogous patients from Children's Cancer Group
V. To further describe and refine the event free survival (EFS) and overall survival (OS)
estimates and baseline characteristics for subjects receiving Ch14.18 + cytokines + RA,
following cessation of the randomized portion of the study.
VI. To further describe the safety and toxicity of Ch14.18 + cytokines + RA under the new
administration guidelines implemented following cessation of the randomized portion of the
study with focus on: a) number of courses delivered per subject; b) number of dose reductions
or stoppage (ch14.18 and/or interleukin [IL]-2); and c) number of toxic deaths.
I. In the subgroup of neuroblastoma patients who have achieved a pre-ASCT response of CR,
VGPR, or PR, determine if there is a difference between the two randomized regimens in
reducing the minimal residual disease (MRD) burden as detected by the following parameters:
meta-iodobenylguanidine (MIBG) scan, immunocytology (IC) of blood and bone marrow samples,
reverse transcriptase-polymerase chain reaction (RT-PCR) for tyrosine hydroxylase,
phosphoglycolate phosphatase (PGP) 9.5, and melanoma antigen family A, 1 (MAGE-1) in blood
and bone marrow.
II. Determine if change from baseline of MRD is associated with event free and overall
III. Determine whether tumor biology at diagnosis correlates with event-free and overall
survival, for either of the randomized regimens.
IV. To explore the relationship between antibody-dependent cellular cytoxicity (ADCC) and
V. To determine a descriptive profile of human anti-chimeric antibody (HACA) during
VI. To determine the variability of 13-cis-retinoic-acid pharmacokinetics and relationship to
pharmacogenomic parameters and determine if these levels and/or genetic variations correlate
with EFS or systemic toxicity.
VII. To determine the potential effect of ch14.18 on cardiac repolarization and to evaluate
ch14.18 plasma levels.
VIII. To determine if the presence of naturally occurring anti-glycan antibodies correlates
with allergic reactions and blood levels of ch14.18.
IX. To determine if the genotype of Fc receptor (FcR) and killer cell immunoglobulin-like
receptor (Kir)/Kir-ligand correlate with EFS.
X. To determine if natural killer cell p30-related protein (NKp30) isoform expression and
single nucleotide polymorphism (SNP), and circulating ligand B7-H6 are prognostic of EFS or
OUTLINE: Patients stratified with biopsy-confirmed post-ASCT persistent disease who are also
enrolled on Children's Oncology Group (COG)-A3973 or COG-ANBL0532 are assigned to treatment
Arm II. Patients in the first set of strata are randomized to 1 of 2 treatment arms.
ARM I: Beginning on day 56-85 post-ASCT, patients receive isotretinoin orally (PO) twice
daily (BID) for 14 days. Treatment repeats every 28 days for 6 courses in the absence of
disease progression or unacceptable toxicity. Patients may cross over to Arm II provided they
have not experienced disease progression and have not received any further anti-neuroblastoma
therapy following completion of isotretinoin therapy. (closed to accrual as of 4/16/2009)
ARM II: Beginning on day 56-85 post-ASCT, patients receive immunotherapy comprising
sargramostim (GM-CSF) subcutaneously (SC) or intravenously (IV) over 2 hours on days 0-13
during courses 1, 3, and 5 and dinutuximab IV over 10-20 hours on days 3-6 of courses 1-5.
Patients also receive aldesleukin IV continuously on days 0-3 and 7-10 during courses 2 and
4. Immunotherapy repeats every 28 days for 5 courses in the absence of disease progression or
unacceptable toxicity. Patients also receive isotretinoin as in Arm I beginning on day 11 of
After completion of study treatment, patients are followed up periodically for 10 years.