This phase III trial tests how well the addition of dinutuximab to Induction chemotherapy along with standard of care surgical resection of the primary tumor, radiation, stem cell transplantation, and immunotherapy works for treating children with newly diagnosed high-risk neuroblastoma. Dinutuximab is a monoclonal antibody that binds to a molecule called GD2, which is found on the surface of neuroblastoma cells, but is not present on many healthy or normal cells in the body. When dinutuximab binds to the neuroblastoma cells, it helps signal the immune system to kill the tumor cells. This helps the cells of the immune system kill the cancer cells, this is a type of immunotherapy. When chemotherapy and immunotherapy are given together, during the same treatment cycle, it is called chemoimmunotherapy. This clinical trial randomly assigns patients to receive either standard chemotherapy and surgery or chemoimmunotherapy (chemotherapy plus dinutuximab) and surgery during Induction therapy. Chemotherapy drugs administered during Induction include, cyclophosphamide, topotecan, cisplatin, etoposide, vincristine, and doxorubicin. These drugs work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing or by stopping them from spreading. Upon completion of 5 cycles of Induction therapy, a disease evaluation is completed to determine how well the treatment worked. If the tumor responds to therapy, patients receive a tandem transplantation with stem cell rescue. If the tumor has little improvement or worsens, patients receive chemoimmunotherapy on Extended Induction. During Extended Induction, dinutuximab is given with irinotecan, temozolomide. Patients with a good response to therapy move on to Consolidation therapy, when very high doses of chemotherapy are given at two separate points to kill any remaining cancer cells. Following, transplant, radiation therapy is given to the site where the cancer originated (primary site) and to any other areas that are still active at the end of Induction. The final stage of therapy is Post-Consolidation. During Post-Consolidation, dinutuximab is given with isotretinoin, with the goal of maintaining the response achieved with the previous therapy. Adding dinutuximab to Induction chemotherapy along with standard of care surgical resection of the primary tumor, radiation, stem cell transplantation, and immunotherapy may be better at treating children with newly diagnosed high-risk neuroblastoma.
Patients must be enrolled on APEC14B1 and have consented to testing through the Molecular Characterization Initiative (MCI), prior to enrollment on ANBL2131
≤ 30 years at the time of initial diagnosis with high-risk disease
* Must have a diagnosis of neuroblastoma (NBL) or ganglioneuroblastoma (nodular) verified by tumor pathology analysis or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamines
Any age with International Neuroblastoma Risk Group (INRG) Stage L2, MS, or M and MYCN amplification
Patients who are 365-546 days of age with INRG Stage M and MYCN non-amplified NBL, irrespective of additional biologic features
Patients ≥ 547 days of age with INRG Stage L2, MYCN non-amplified NBL, regardless of additional biologic features
Patients with known bone marrow failure syndromes
Patients on chronic immunosuppressive medications (e.g., tacrolimus, cyclosporine, corticosteroids) for reasons other than prevention/treatment of allergic reactions and adrenal replacement therapy are not eligible. Topical and inhaled corticosteroids are acceptable
Parallel
Biospecimen Collection
Procedure/SurgeryUndergo blood and urine sample collection
Bone Marrow Aspiration
Procedure/SurgeryUndergo bone marrow aspiration
Bone Marrow Biopsy
Procedure/SurgeryUndergo bone marrow biopsy
Carboplatin
DrugGiven IV
Cisplatin
DrugGiven IV
Computed Tomography
Procedure/SurgeryUndergo CT scan
Cyclophosphamide
DrugGiven IV
Dinutuximab
Biological/VaccineGiven IV
Doxorubicin
DrugGiven IV
Echocardiography Test
Procedure/SurgeryUndergo ECHO
Etoposide
DrugGiven IV
FDG-Positron Emission Tomography and Computed Tomography Scan
Procedure/SurgeryUndergo FDG PET
Hematopoietic Cell Transplantation
Procedure/SurgeryUndergo stem cell infusion
Irinotecan
DrugGiven IV
Isotretinoin
DrugGiven PO
Leukapheresis
Procedure/SurgeryUndergo apheresis
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Melphalan
DrugGiven IV
Multigated Acquisition Scan
Procedure/SurgeryUndergo MUGA
Radiation Therapy
RadiationUndergo radiation therapy
Radionuclide Imaging
Procedure/SurgeryUndergo I-MIBG scan
Survey Administration
Other interventionAncillary studies
Temozolomide
DrugGiven PO or via NG or G tube
Thiotepa
DrugGiven IV
Topotecan
DrugGiven IV
Tumor Resection
Procedure/SurgeryUndergo tumor resection surgery
Vincristine
DrugGiven IV
Event free survival (EFS)
EFS time is calculated from time of randomization to Arms A or B to first episode of disease relapse or progression, second malignancy, or death, or until last contact if no event has occurred.
End of Induction (EOI) response rate
The response rate will be calculated among all evaluable patients at end of Induction. Responders are defined as patients who achieve a \>= partial response per the revised 2017 International Neuroblastoma Response Criteria (INRC)
Overall survival (OS)
OS time is calculated from time of randomization to Arms A or B until death, or until last contact if patient is alive.
Incidence of adverse events
The proportion of patients with at least one grade 3 or higher non-hematologic toxicity or grade 4 or higher hematologic toxicity during protocol therapy, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, will be reported.
GD2 expression
Dinutuximab binding to pre-therapy patient tumor samples will be measured and categorized as high or low.
Association between tumor and host factors and outcomes
A series of univariate and multivariate Cox proportional hazards (for EFS and OS) and logistic regression (for responders vs. non-responders) models will be fit for patients in Arms A and B to evaluate the relationship between tumor and host factors (including tumor ALK and other somatic mutations, copy-number aberrations, gene fusions, gene expression, and pathogenic germline variants) and chemo-immunotherapy during Induction with outcome.
Circulating biomarkers and markers of minimal residual disease
Will be assessed by comparing the proportion of patients with detectable vs. non-detectable tumor markers (including circulating tumor deoxyribonucleic acid, circulating free DNA, circulating tumor cells, and immune function profiling) between Arms A and B during and after induction and post-consolidation therapy using chi-squared tests at each individual time point, and Cochran's Q across time points to determine if there is a consistent difference in proportions between arms across time. In addition, the tumor markers will be analyzed as continuous variables using longitudinal data analysis methodology such as mixed effects models or generalized estimating equations as appropriate.
Patterns of failure
The impact of early or late chemoimmunotherapy during Induction on the probability of the involvement of a specific disease site at first relapse will be evaluated using Fisher's exact test.
Effect of telomere maintenance mechanisms
A series of univariate and multivariate Cox proportional hazards (for EFS and OS) and logistic regression (for responders vs. non-responders) models will be fit for patients in arms A and B to evaluate the relationship between telomere maintenance mechanism and chemoimmunotherapy during Induction with outcome. Patients will be classified into 3 groups by telomere maintenance mechanism (TMM) based on messenger ribonucleic acid expression of TERT and analysis of telomeric DNA C-circles: telomerase (TERT) positive, alternative of lengthening of telomeres (ALT) positive, or no identified TMM.
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