This partially randomized phase III trial studies isotretinoin with dinutuximab, aldesleukin, and sargramostim to see how well it works compared to isotretinoin alone following stem cell transplant in treating patients with neuroblastoma. Drugs used in chemotherapy, such as isotretinoin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as dinutuximab, may block tumor growth in different ways by targeting certain cells. Aldesleukin and sargramostim may stimulate a person's white blood cells to kill cancer cells. It is not yet known if chemotherapy is more effective with or without dinutuximab, aldesleukin, and sargramostim following stem cell transplant in treating neuroblastoma.
PRIMARY OBJECTIVES: 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). SECONDARY OBJECTIVES: 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 PR. III. Determine the toxicities of the combination of monoclonal antibody Ch14.18 with cytokines. 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 (CCG)-3981. 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. TERTIARY OBJECTIVES: 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 survival. 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 EFS. V. To determine a descriptive profile of human anti-chimeric antibody (HACA) during immunotherapy. 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 OS. 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 immunotherapy. After completion of study treatment, patients are followed up periodically for 10 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1,449
Given IV
Given IV
Given PO
Correlative studies
Correlative studies
Ancillary studies
Given IV or SC
Children's Hospital of Alabama
Birmingham, Alabama, United States
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
Providence Alaska Medical Center
Anchorage, Alaska, United States
Phoenix Childrens Hospital
Phoenix, Arizona, United States
Banner University Medical Center - Tucson
Tucson, Arizona, United States
Event-Free Survival (EFS)
Comparison to determine if RA + Immunotherapy improves EFS as compared to RA Only
Time frame: Three years
Event-Free Survival (EFS)
Comparison to determine if RA + Immunotherapy improves EFS as compared to RA Only for the subgroup of randomized patients with INSS Stage 4 disease. Descriptive comparison of outcome data for patients with persistent disease documented by biopsy to historical data for the analogous patients from CCG-3981.
Time frame: Three years
Event-Free Survival (EFS) of Patients From the Non-randomized Portion of the Trial
EFS for patients receiving RA + Immunotherapy following the cessation of the randomized portion of the study.
Time frame: Three years
Incidence of Toxicities Assessed Using Common Terminology Criteria for Adverse Events Version 4.0
Proportion of patients experiencing at least one Grade 3 or higher toxicity.
Time frame: From enrollment to follow-up
Number of Courses of Therapy Delivered
Number of courses of therapy delivered for patients randomized to RA + Immunotherapy vs. patients non-randomly assigned to RA + Immunotherapy, excluding patients with persistent disease.
Time frame: Courses 1-6
Overall Survival (OS)
Comparison to determine if RA + Immunotherapy improves OS as compared to RA Only. Comparison to determine if RA + Immunotherapy improves OS as compared to RA only and for the subgroup of randomized patients with INSS Stage 4 disease.
Time frame: Three years
Overall Survival (OS) of Patients From the Non-randomized Portion of the Trial
OS for patients receiving RA + Immunotherapy following the cessation of the randomized portion of the study.
Time frame: Three years
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