Dinutuximab With Chemotherapy, Surgery and Stem Cell Transplantation for the Treatment of Children With Newly Diagnosed High Risk Neuroblastoma

Neuroblastoma Clinical Trial

Official title:

A Phase 3 Study of Dinutuximab Added to Intensive Multimodal Therapy for Children With Newly Diagnosed High-Risk Neuroblastoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06172296
• Other study ID #: NCI-2023-08530
• Secondary ID: NCI-2023-08530AN
• Status: Recruiting
• Phase: Phase 3
• Start date: April 19, 2024
• Est. completion date: December 31, 2029

Study information

• Verified date: May 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase III trial tests how well adding dinutuximab to induction chemotherapy along with standard of care surgery radiation and stem cell transplantation 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 in greater than normal amounts on some types of cancer cells. This helps cells of the immune system kill the cancer cells. Chemotherapy drugs such as cyclophosphamide, topotecan, cisplatin, etoposide, vincristine, dexrazoxane, doxorubicin, temozolomide, irinotecan and isotretinoin, 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. During induction, chemotherapy and surgery are used to kill and remove as much tumor as possible. During consolidation, very high doses of chemotherapy are given to kill any remaining cancer cells. This chemotherapy also destroys healthy bone marrow, where blood cells are made. A stem cell transplant is a procedure that helps the body make new healthy blood cells to replace the blood cells that may have been harmed by the cancer and/or chemotherapy. Radiation therapy is also given to the site where the cancer originated (primary site) and to any other areas that are still active at the end of induction.

Description:

PRIMARY OBJECTIVE: I. To determine if the event-free survival (EFS) of patients with newly diagnosed high-risk neuroblastoma assigned to early chemoimmunotherapy during Induction differs from that of patients who are not assigned to treatment that includes early chemoimmunotherapy. SECONDARY OBJECTIVES: I. To determine if early chemoimmunotherapy during Induction therapy improves end of induction (EOI) response rates and overall survival (OS) for patients with newly diagnosed high-risk neuroblastoma. II. To determine response rates, EFS, and OS following an extended induction regimen with chemoimmunotherapy in patients with progressive disease or a poor response to Induction therapy. III. To compare the toxicities experienced by patients treated with chemoimmunotherapy during induction versus those experienced by patients treated with standard induction and to describe toxicities experienced during extended induction. IV. To determine GD2 expression on tumor tissue and tumor cells in bone marrow and assess for associations with response and outcome. EXPLORATORY OBJECTIVES: I. To describe the association between tumor and host factors and outcomes in patients receiving protocol therapy. II. To evaluate circulating biomarkers and markers of minimal residual disease at baseline and during therapy, and assess for associations with response and outcome. III. To compare patterns of failure between patients treated with and without dinutuximab during induction. IV. To determine the effect of telomere maintenance mechanisms on end of Induction response rates, EFS, and OS. V. To explore the impact of high-risk neuroblastoma (HRNBL) and its therapy, including the addition of dinutuximab to Induction chemotherapy, on functional and quality of life outcomes in patients with HRNBL, as measured by caregiver (parent/legal guardian) and patient questionnaires. VI. To describe the adequacy of diagnostic biopsy specimens, including those obtained by percutaneous core needle biopsy. VII. To explore the associations between family-reported adverse social determinants of health and both clinical outcomes and biology. VIII. To develop and validate deep learning predictors of Induction response based on diagnostic MIBG scans. (Imaging Objective) IX. To compare institutional versus central determination of overall response, individual response components (primary tumor, soft tissue and bone metastatic disease, and bone marrow metastatic disease), and poor end of induction response (PEIR) and good end of induction response (GEIR) determination. (Imaging Objective) X. To describe late toxicities (including impaired organ function, neuropsychiatric toxicity, and incidence of secondary malignancy) in patients treated with dinutuximab during Induction or Extended Induction to late toxicities in patients who have not received dinutuximab during these phases of therapy. XI. To evaluate whether reduced dose radiotherapy to the primary site clinical target volume (CTV) in patients with complete response of the primary site at EOI results in comparable local control relative to historical cohorts. XII. To compare post-transplant complications between treatment arms, and assess for associations with outcome. XIII. To assess for associations between EOI response (including good end of Induction response [GEIR] and poor end of Induction response [PEIR]) and individual response components (primary tumor, soft tissue and bone metastatic disease, and bone marrow metastatic disease) with outcome (EFS and OS). XIV. To describe and compare the changes in image-defined risk factors (IDRFs) between patients treated with and without dinutuximab during Induction and associate with surgical outcomes and local failure rates following primary tumor resection. XV. To bank serial samples of blood, bone marrow, and tumor tissue for future research. OUTLINE: Patients receive induction cycle 1. Patients are then randomized to 1 of 2 arms. INDUCTION CYCLE 1: Patients receive cyclophosphamide intravenously (IV) over 30 minutes and topotecan IV over 30 minutes on days 1-5 in the absence of unacceptable toxicity. ARM A: INDUCTION CYCLES 2-4: Patients receive cyclophosphamide IV over 30 minutes and topotecan IV over 30 minutes on days 1-5 of cycle 2 in the absence of unacceptable toxicity. Patients then undergo stem cell harvest via apheresis. Patients then receive cisplatin IV over 4 hours and etoposide IV over 4 hours on days 1-3 of cycle 3 and vincristine IV on day 1 and dexrazoxane IV over 5-15 minutes, doxorubicin over 15 minutes, and cyclophosphamide over 1 hours on days 1-2 of cycle 4 in the absence of unacceptable toxicity. Patients undergo testing to determine response and proceed to surgery followed by induction cycle 5 or extended induction. INDUCTION CYCLE 5: Patients receive cisplatin IV over 4 hours and etoposide IV over 2 hours on days 1-3 in the absence of unacceptable toxicity. Patients with a response to therapy proceed to consolidation. EXTENDED INDUCTION: Patients whose cancer did not respond receive temozolomide orally (PO), via nasogastric tube (NG), or via gastric tube (G-tube) on days 1-5, irinotecan IV over 90 minutes on days 1-5, and dinutuximan IV over 10 hours. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 1 hour on days -5 to -2. Patients then receive stem cell infusion IV on day 0. Between 6 and 10 weeks after stem cell infusion patients receive melphalan IV over 30 minutes on days -7 to -5, etoposide IV over 24 hours on days -7 to -4, and carboplatin over 24 hours on days -7 to -4. Patients receive stem cell infusion IV on day 0. Between day +42 and day +80 after second transplant, patients receive radiation daily for 12 treatments in the absence of disease progression or unacceptable toxicity. POST CONSOLIDATION: Patients receive dinutuximab IV over 10 hours on days 4-7 and isotretinoin PO twice daily (BID) on days 11-24 of each cycle. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive isotretinoin PO BID on days 15-28 for 1 additional cycle. Patients undergo bone marrow aspiration and/or biopsy, computed tomography (CT) scan, magnetic resonance imaging (MRI), iodine-123 meta-iodobenzylguanidine (I-MIBG) scan and fluorodeoxyglucose position emission tomography (FDG-PET) scan throughout the study. ARM B: INDUCTION CYCLES 2-4: Patients receive cyclophosphamide IV over 30 minutes, topotecan IV over 30 minutes on days 1-5, and dinutuximab IV over 10 hours on days 2-5 of cycle 2 in the absence of unacceptable toxicity. Patients then undergo stem cell harvest via apheresis. Patients receive cisplatin IV over 4 hours and etoposide IV over 4 hours on days 1-3 and dinutuximab IV on days 2-5 on cycle 3 and vincristine IV on day 1 and dexrazoxane IV over 5-15 minutes, doxorubicin over 15 minutes, and cyclophosphamide over 1 hours on days 1-2, and dinutuximab IV over 10 hours on days 2-5 of cycle 4 in the absence of unacceptable toxicity. Patients then undergo testing to determine response and proceed to surgery followed by induction cycle 5 or extended induction. INDUCTION CYCLE 5: Patients receive cisplatin IV over 4 hours and etoposide IV over 2 hours on days 1-3 and dinutuximab IV on days 2-5 in the absence of unacceptable toxicity. Patients with a response to therapy proceed to consolidation. EXTENDED INDUCTION: Patients receive temozolomide PO, via NG, or via G-tube on days 1-5, irinotecan IV over 90 minutes on days 1-5, and dinutuximan IV over 10 hours. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity CONSOLIDATION: Patients receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 1 hour on days -5 to -2. Patients then receive stem cell infusion IV on day 0. Between 6 and 10 weeks after stem cell infusion patients receive melphalan IV over 30 minutes on days -7 to -5, etoposide IV over 24 hours on days -7 to -4, and carboplatin over 24 hours on days -7 to -4. Patients receive stem cell infusion IV on day 0. Between day +42 and day +80 after second transplant, patients receive radiation daily for 12 treatments in the absence of disease progression or unacceptable toxicity. POST CONSOLIDATION: Patients receive dinutuximab IV over 10 hours on days 4-7 and isotretinoin PO BID on days 11-24 of each cycle. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive isotretinoin PO BID on days 15-28 for 1 additional cycle. Patients undergo bone marrow aspiration and/or biopsy, CT scan, MRI, I-MIBG scan and FGD-PET scan throughout the study. After completion of study treatment, patients are followed up at 3, 6, 9,12, 15, 18, 24, 30, 36, 42, 48, 54, and 60 months and then periodically for up to 10 years from enrollment.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 478
• Est. completion date: December 31, 2029
• Est. primary completion date: December 31, 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 30 Years

Eligibility

Inclusion Criteria:

• 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

Newly diagnosed, high risk neuroblastoma (HRNBL) defined as one of the following:

• Any age with International Neuroblastoma Risk Group (INRG) Stage L2, MS, or M and MYCN amplification
• Age = 547 days and INRG stage M regardless of biologic features (clinical MYCN testing not required prior to enrollment)
• Any age initially diagnosed with INRG Stage L1 MYCN amplified NBL who have progressed to stage M without systemic chemotherapy
• Age = 547 days of age initially diagnosed with INRG Stage L1, L2, or MS who have progressed to stage M without systemic chemotherapy (clinical MYCN testing not required prior to enrollment)
• Patients must have a BSA = 0.25 m^2
• No prior anti-cancer therapy except as outlined below:
• Patients initially recognized to have high-risk disease treated with topotecan/cyclophosphamide initiated on an emergent basis and within allowed timing, and with consent
• Patients observed or treated with a single cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (eg, as per ANBL0531, ANBL1232 or similar) for what initially appeared to be non-high-risk disease but subsequently found to meet the criteria
• Patients who received localized emergency radiation to sites of life threatening or function-threatening disease prior to or immediately after establishment of the definitive diagnosis
• Human immunodeficiency virus (HIV) -infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• A serum creatinine based on age/sex derived from the Schwartz formula for estimating glomerular filtration rate (GFR) utilizing child length and stature data published by the CDC or
• a 24-hour urine creatinine clearance = 70 mL/min/1.73 m^2 or
• a GFR = 70 mL/min/1.73 m^2. GFR must be performed using direct measurement with a nuclear blood sampling method or direct small molecule clearance method (iothalamate or other molecule per institutional standard) Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility
• Total bilirubin = 1.5 x upper limit of normal (ULN) for age
• Serum glutamic pyruvic transaminase (SGPT) (Alanine aminotransferase [ALT]) = 10 x ULN*
• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
• Shortening fraction of = 27% by echocardiogram, or ejection fraction of = 50% by echocardiogram or radionuclide angiogram
• Ability to tolerate Peripheral Blood Stem Cell (PBSC) Collection:

No known contraindication to PBSC collection. Examples of contraindications might be a weight or size less than the collecting institution finds feasible, or a physical condition that would limit the ability of the child to undergo apheresis catheter placement (if necessary) and/or the apheresis procedure

Exclusion Criteria:

• 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 (eg, 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
• Patients with a primary immunodeficiency syndrome who require ongoing immune globulin replacement therapy
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required prior to enrollment for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, food and drug administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Related Conditions & MeSH terms

• Ganglioneuroblastoma
• Neuroblastoma

Intervention

Procedure:
• Biospecimen Collection
Undergo blood sample collection
• Bone Marrow Aspiration
Undergo bone marrow aspiration
• Bone Marrow Biopsy
Undergo bone marrow biopsy
• Bone Scan
Undergo MIBG scan

Drug:
• Carboplatin
Given IV
• Cisplatin
Given IV

Procedure:
• Computed Tomography
Undergo CT scan

Drug:
• Cyclophosphamide
Given IV
• Dexrazoxane
Given IV

Biological:
• Dinutuximab
Given IV

Drug:
• Doxorubicin
Given IV
• Etoposide
Given IV

Procedure:
• FDG-Positron Emission Tomography and Computed Tomography Scan
Undergo FDG PET
• Hematopoietic Cell Transplantation
Undergo stem cell infusion

Drug:
• Irinotecan
Given IV
• Isotretinoin
Given PO

Procedure:
• Leukapheresis
Undergo apheresis
• Magnetic Resonance Imaging
Undergo MRI

Drug:
• Melphalan
Given IV

Radiation:
• Radiation Therapy
Undergo radiation therapy

Other:
• Survey Administration
Ancillary studies

Drug:
• Temozolomide
Given PO or via NG or G tube
• Thiotepa
Given IV
• Topotecan
Given IV

Procedure:
• Tumor Resection
Undergo tumor resection surgery

Drug:
• Vincristine
Given IV

Locations

Country	Name	City	State
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Dell Children's Medical Center of Central Texas	Austin	Texas
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	Prisma Health Richland Hospital	Columbia	South Carolina
United States	Driscoll Children's Hospital	Corpus Christi	Texas
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	East Carolina University	Greenville	North Carolina
United States	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	NYU Winthrop Hospital	Mineola	New York
United States	The Children's Hospital at TriStar Centennial	Nashville	Tennessee
United States	Kaiser Permanente-Oakland	Oakland	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Children's Hospital of San Antonio	San Antonio	Texas
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio
United States	New York Medical College	Valhalla	New York

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.	Up to 12 years
Other	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 [ctDNA], circulating free DNA [cfDNA], circulating tumor cells [CTCs], 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 (GEE) as appropriate.	Up to 12 years
Other	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.	During induction therapy
Other	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 (mRNA) expression of TERT and analysis of telomeric DNA C-circles: telomerase (TERT) positive, alternative of lengthening of telomeres (ALT) positive, or no identified TMM.	Up to 12 years
Other	Functional and quality of life outcomes	we will descriptively summarize and compare the total Memorial Symptom Assessment Scale (MSAS) scores, total sub-domain scores, and individual symptom scores between patients randomized to receive dinutuximab during Induction (arm B) to those of patients randomized to standard Induction (arm A).	At serial time points during induction, extended induction, post-consolidation, and at the end of therapy
Other	Adequacy of diagnostic biopsy specimens	Will be evaluated by descriptively comparing the successful delineation of histologic classification, MYCN amplification status, and ALK status via the traditional method of obtaining tissue for diagnosis, open surgical biopsy, versus the less invasive percutaneous core needle biopsy.	At time of tissue collection
Other	Associations between family-reported adverse social determinants of health and both clinical outcomes and biology	Kaplan-Meier curves of EFS and OS will be generated and used to calculate 3-year EFS and OS estimates. Associations between social determinants of health (SDOH) and survival outcomes and time to receipt of dinutuximab will be evaluated with univariate and multivariate Cox proportional hazard models. Log-binomial regression will be used to estimate risk ratios and 95% CI for the occurrence of dinutuximab consent to randomization and therapy receipt by SDOH exposure. Effect modification of outcomes as a function of poverty, stratified by race/ethnicity, will be explored.	Up to 12 years
Other	Develop and validate deep learning predictors of induction response (imaging objective)	Scans will be given as input to a convolutional neural network trained to predict EOI response.	At diagnosis, EOI (pre-consolidation), during extended induction, and end of extended induction (pre-consolidation)
Other	Compare institutional versus central determination of overall response, individual response components, and PEIR and GEIR determination (imaging objective)	Will be assessed by calculating the percentage of patients receiving the same EOI institutional and centrally reviewed determination of overall response, individual response components (primary tumor, soft tissue and bone metastatic disease, and bone marrow metastatic disease), and PEIR and GEIR. In addition, Cohen's kappa will be calculated to evaluate the concordance in each of these response measures.	Up to 12 years
Other	Incidence of late toxicities	Will be addressed by calculating the proportion of treated patients with each late effect, including but not limited to impaired organ function, neuropsychiatric toxicity, and secondary malignancy. A 95% confidence interval will be placed on each proportion.	Up to 12 years
Other	Reduced dose radiotherapy to the primary site clinical target volume (CTV) in patients with complete response of the primary site at EOI results in comparable local control relative to historical cohorts	The cumulative incidence of local progression (CILP) in patients with complete response of the primary site at EOI and GEIR on this study will be compared to the CILP rate of 11.2±1.8% observed on ANBL0532^88 using Gray's test.	Up to 12 years
Other	Post-transplant complications	Will be evaluated by calculating the incidence of endothelial injury complications (EICs) and non-relapse mortality (NRM) within 100 days of transplant, transplant-associated thrombotic microangiopathy (TA-TMA), severe TA-TMA, and sinusoidal obstruction syndrome (SOS) on Arms A and B and comparing between arms with a chi-squared test. The impact of TA-TMA occurrence on the timing or exclusion of subsequent therapy and interventions utilized to treat the TA-TMA, and associations with outcomes (EFS and OS) will be assessed.	Up to 100 days post transplant
Other	Associations between end of induction (EOI) response and individual response components	Log-rank tests will be used to explore the association between EOI response (using both the revised INRC and GEIR/PEIR classification) and individual response components (primary tumor, soft tissue and bone metastatic disease, and bone marrow metastatic disease) with outcome (EFS and OS).	Up to 12 years
Other	Changes in image-defined risk factors (IDRF)	The proportion of patients in the analytic cohort for whom each particular IDRF and also the presence of any IDRF is absent prior to surgical resection will be computed. McNemar's test for paired observations will be applied to determine whether there is a difference in the proportion of each IDRF and any IDRF present before and after initial therapy, and conditional logistic regression will be used to compare between treatment arms A and B. The IDRF status after initial therapy and whether there has been a change from diagnosis will be associated with surgical outcome (complete vs. incomplete resection, presence or absence of surgical complications) using chi-squared tests, and compared between treatment arms A and B with the Cochran-Mantel-Haenszel test. The association of IDRF status with presence or absence of local failure after primary tumor resection will also be evaluated using a chi-squared test, and compared between treatment arms A and B with the Cochran-Mantel-Haenszel.	Up to 12 years
Primary	Event free survival (EFS)	An intent-to-treat log-rank test comparison of EFS starting from the time of randomization between the standard Children's Oncology Group (COG) induction therapy with or without extended Induction (arm A) and induction chemoimmunotherapy (arm B) with or without extended induction arms will be performed. A final analysis two-sided p-value <0.05 will indicate success. In addition, a sensitivity analysis will be performed consisting of a log-rank test comparison of EFS starting from the time of randomization between patients treated without dinutuximab during induction or extended induction (patients on arm A with GEIR) versus patients treated with dinutuximab during Induction (arm B) who do not receive extended induction.	From time of randomization to first episode of disease relapse or progression post-randomization, first occurrence of a second malignancy, or death, whichever occurs first, up to 12 years
Secondary	End of induction (EOI) response rate	Will be evaluated per the 2017 revised International Neuroblastoma Response Criteria (INRC), with patients categorized as good end of induction response (GEIR) or poor end of induction response (PEIR) and also assigned standard INRC overall EOI response. Will be assessed with an intent-to-treat log-rank test comparison of overall survival (OS) starting from the time of randomization between the standard COG induction therapy with or without extended induction (arm A) and induction chemoimmunotherapy (arm B) with or without extended induction. Depending on the sample size, a chi-square or Fisher's exact test will be used to evaluate the difference in EOI response rates in these two arms. Response will be determined using both the revised INRC and GEIR/PEIR classification.	From randomization to end of extended induction
Secondary	Overall survival	Response rates at the end of extended Induction (defined as the last complete disease evaluation prior to consolidation or removal from protocol therapy), 3-year EFS with 95% confidence interval (CI), and 3-year OS with 95% CI will be calculated for arm A and arm B patients that receive an extended induction regimen with chemoimmunotherapy due to PD or a PEIR to Induction therapy. Response will be determined using both the revised INRC and GEIR/PEIR classification.	Time to death, up to 12 years
Secondary	Incidence of adverse events	Common terminology criteria for adverse events (CTCAE) version (v) 5.0 will be used to tabulate grade = 3 non-hematologic and grade = 4 hematologic toxicities. Will be compared with a Fisher's exact/chi-square test. In addition, the rates of grade = 3 non-hematologic and grade = 4 hematologic toxicities experienced during extended induction will be tabulated.	Up to 12 years
Secondary	GD2 expression	Dinutuximab binding to pre-therapy patient tumor samples will be measured and categorized as high or low. Will evaluate for an association between GD2 binding and event-free survival.	At baseline, end of induction, extended induction, post consolidation, relapse/progression and primary tumor resection