Testing the Addition of 131I-MIBG or Lorlatinib to Intensive Therapy in People With High-Risk Neuroblastoma (NBL)

Phase 3

Active, not recruiting

• Conditions: Ganglioneuroblastoma; Neuroblastoma
• Interventions: Procedure: Autologous Hematopoietic Stem Cell Transplantation; Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration and Biopsy; Drug: Carboplatin; Drug: Busulfan; Drug: Cisplatin; Procedure: Computed Tomography; Drug: Cyclophosphamide; Drug: Dexrazoxane Hydrochloride; Biological: Dinutuximab; Drug: Doxorubicin Hydrochloride; Procedure: Echocardiography; Drug: Etoposide Phosphate; Radiation: External Beam Radiation Therapy; Radiation: Iobenguane I-123; Drug: Isotretinoin; Radiation: Iobenguane I-131; Procedure: Multigated Acquisition Scan; Drug: Lorlatinib; Drug: Melphalan Hydrochloride; Procedure: Positron Emission Tomography; Procedure: Magnetic Resonance Imaging; Biological: Sargramostim; Procedure: Therapeutic Conventional Surgery; Drug: Thiotepa; Drug: Topotecan Hydrochloride; Drug: Vincristine Sulfate

• Registration Number: NCT03126916
• Lead Sponsor: Children's Oncology Group

Brief Summary

This phase III trial studies iobenguane I-131 or lorlatinib and standard therapy in treating younger patients with newly-diagnosed high-risk neuroblastoma or ganglioneuroblastoma. Radioactive drugs, such as iobenguane I-131, may carry radiation directly to tumor cells and not harm normal cells. Lorlatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving iobenguane I-131 or lorlatinib and standard therapy may work better compared to lorlatinib and standard therapy alone in treating younger patients with neuroblastoma or ganglioneuroblastoma.

Detailed Description

PRIMARY OBJECTIVES:

I. To determine in the context of a randomized trial whether the event-free survival (EFS) of patients with newly diagnosed high-risk neuroblastoma (NBL) is improved with the addition of iobenguane I-131 (131I-MIBG) during induction, prior to tandem autologous stem cell transplantation (ASCT).

II. To determine whether the addition of lorlatinib to intensive multimodality therapy for patients with high-risk NBL whose tumors harbor activating point mutations in the ALK gene with a variant allele frequency (VAF) \>= 5% results in superior EFS compared to a contemporaneously treated cohort of patients with tumors without documented ALK activating mutations.

SECONDARY OBJECTIVES:

I. To describe the toxicities associated with treatment for high-risk NBL with and without the addition of 131I-MIBG or ALK inhibitor therapy.

II. To estimate EFS and describe toxicity in patients with newly diagnosed high-risk NBL randomized to treatment with an 131I-MIBG-containing induction prior to busulfan/melphalan (BuMel) ASCT.

III. To describe the overall survival (OS) and response rates (evaluated per International Neuroblastoma Response Criteria \[INRC\] criteria prior to ASCT and prior to post-consolidation therapy) for patients with high-risk neuroblastoma treated with or without 131I-MIBG or ALK inhibitor therapy.

IV. To prospectively evaluate the relationship of response rate per revised International Neuroblastoma Response Criteria (INRC) to EFS and OS in patients with high-risk NBL treated with and without the addition of 131I-MIBG or ALK inhibitor therapy.

EXPLORATORY OBJECTIVES:

I. To evaluate whole body radiation dose, tumor factors, and host factors as potential predictors of efficacy and/or toxicity associated with 131I-MIBG therapy and transplant conditioning.

II. To describe end-Induction response, EFS, and OS according to specific ALK mutations, VAF, ALK amplification, the presence of additional genomic findings, or the ALK inhibitor administered.

III. To characterize changes in tumor markers (circulating tumor deoxyribonucleic acid \[DNA\], including ALK and other tumor specific genetic aberrations, and circulating GD2) over time in response to protocol therapy.

IV. To correlate results of tumor and host profiling with end-induction response and EFS.

V. To prospectively evaluate EFS for patients with MIBG non-avid high-risk NBL compared to patients with MIBG-avid high-risk NBL who are randomized to treatment without 131I-MIBG.

VI. To correlate Curie scores calculated from 131I-MIBG post-treatment scans with end-induction response, EFS and OS.

VII. To describe changes in image defined risk factors (IDRFs) over the course of induction therapy, with correlation to surgical outcomes and local failure rates following primary tumor resection.

VIII. To define patterns of failure at time of first relapse or progression in patients with high-risk NBL.

IX. To determine the feasibility of prospectively monitoring adverse events using electronic health records.

X. To compare local, central, and computer assisted Curie score assignment at baseline and during therapy in patients with MIBG-avid high-risk NBL.

XI. To compare late toxicities (including impaired organ function and secondary tumor occurrence) in patients treated with 131I-MIBG or ALK inhibitor therapy to late toxicities in patients who have not received these therapies.

XII. To determine the association between household material hardship (HMH) and clinical outcomes, including event free and overall survival, and 131I-MIBG receipt.

XIII. To compare the outcomes (EFS, OS, and toxicity) of patients treated with post-consolidation therapy that does not contain aldesleukin to historical outcome data for patients treated with similar induction and consolidation regimens followed by post-consolidation therapy that contained aldesleukin.

XIV. To characterize and describe longitudinal neuropsychological and behavioral effects of high-risk neuroblastoma therapy.

XV. To evaluate change in neurobehavioral outcomes over time in patients with neuroblastoma treated with high-risk neuroblastoma therapy plus lorlatinib compared to high-risk therapy alone using parent- or self-report measures of adaptive, executive, and psychosocial functioning.

XVI. To characterize the pharmacokinetics and pharmaceutical properties of lorlatinib in children with high-risk neuroblastoma.

OUTLINE: Patients are randomized or assigned to 1 of 5 arms.

All patients receive cyclophosphamide intravenously (IV) over 15-30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5 during cycle 1 of induction therapy in the absence of disease progression or unacceptable toxicity. Patients not assigned to an Arm by the end of cycle 1 may receive an addition cycle of cyclophosphamide and topotecan.

ARM A:

INDUCTION THERAPY: Patients receive cyclophosphamide IV over 15-30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5 of cycle 2 and cisplatin IV over 4 hours and etoposide phosphate IV over 2 hours on days 1-3 of cycles 3 and 5. Patients also receive vincristine sulfate IV over 1 minute on day 1 and dexrazoxane hydrochloride IV over 5-15 minutes, doxorubicin hydrochloride IV over 1-15 minutes, and cyclophosphamide IV over 1-6 hours on days 1-2 of cycle 4 in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION THERAPY:

HSCT#1: Patients receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 1 hour on days -5 to -2 in the absence of disease progression or unacceptable toxicity.

HSCT#2: Patients receive melphalan hydrochloride IV over 30 minutes on days -7 to -5, and etoposide phosphate IV over 24 hours and carboplatin IV over 24 hours on days -7 to -4 in the absence of disease progression or unacceptable toxicity.

POST-CONSOLIDATION THERAPY: Patients receive sargramostim subcutaneously (SC) on days 1-14, dinutuximab IV over 10 hours on days 4-7 of cycles 1-5, and isotretinoin orally (PO) twice daily (BID) on days 11-24 of cycles 1-5, and days 15-28 during cycle 6 in the absence of disease progression or unacceptable toxicity.

Patients undergo echocardiography or multigated acquisition (MUGA) scan, magnetic resonance imaging (MRI) or computed tomography (CT) scan, receive 123I-MIBG and undergo MIBG imaging, bone marrow aspiration and biopsy and blood sample collection throughout the study.

ARM B:

INDUCTION THERAPY: Patients receive cyclophosphamide, topotecan hydrochloride, cisplatin, and etoposide phosphate as in Arm A, iobenguane I-131 IV over 1.5-2 hours on day 1 beginning 3 weeks after the start of cycle 3, and vincristine sulfate, dexrazoxane hydrochloride, doxorubicin hydrochloride, and cyclophosphamide as in Arm A beginning no sooner than 35 days after the infusion of iobenguane I-131.

CONSOLIDATION THERAPY:

HSCT#1: Patients receive thiotepa and cyclophosphamide as in Arm A.

HSCT#2: Patients receive melphalan, etoposide phosphate, and carboplatin as in Arm A.

POST-CONSOLIDATION THERAPY: Patients receive sargramostim, dinutuximab, and isotretinoin as in Arm A-D.

Patients undergo echocardiography or MUGA scan, MRI or CT scan, receive 123I-MIGB and undergo MIBG imaging, bone marrow aspiration and biopsy and blood sample collection throughout the study.

ARM C (CLOSED TO ACCRUAL AS OF DECEMBER 17, 2020):

INDUCTION THERAPY: Patients receive cyclophosphamide, topotecan hydrochloride, cisplatin, etoposide phosphate, iobenguane I-131, vincristine sulfate, dexrazoxane hydrochloride, doxorubicin hydrochloride, and cyclophosphamide as in Arm B.

CONSOLIDATION THERAPY: Patients receive busulfan IV over 3 hours on days -6 to -3 and melphalan hydrochloride IV over 30 minutes on day -1 in the absence of disease progression or unacceptable toxicity.

POST-CONSOLIDATION THERAPY: Patients receive sargramostim, dinutuximab, and isotretinoin as in Arm A.

Patients undergo echocardiography or MUGA scan, MRI or CT scan, receive 123I-MIGB and undergo MIBG imaging, bone marrow aspiration and biopsy and blood sample collection throughout the study.

ARM D: Patients receive treatment identical to Arm A.

Patients undergo echocardiography or MUGA scan, MRI or CT scan, receive 123I-MIGB and undergo MIBG imaging, bone marrow aspiration and biopsy and blood sample collection throughout the study and may undergo fludeoxyglucose- positron emission tomography (PET) scan on study.

ARM E:

INDUCTION THERAPY: Patients receive cyclophosphamide, topotecan hydrochloride, cisplatin, etoposide phosphate, vincristine sulfate, dexrazoxane hydrochloride, doxorubicin hydrochloride, and cyclophosphamide as in Arm A. Patients also receive lorlatinib PO once daily (QD) starting cycle 2 prior to HSCT #1 in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION THERAPY:

HSCT#1: Patients receive thiotepa and cyclophosphamide as in Arm A. Patients also receive lorlatinib PO QD until day -8 of HSCT#2 in the absence of disease progression or unacceptable toxicity.

HSCT#2: Patients receive melphalan hydrochloride, etoposide phosphate, carboplatin as in Arm A. Lorlatinib is restarted when patient has reached at least day +14 post-HSCT#2 and is able to tolerate enteral medications, provided there is no evidence of disease progression or unacceptable toxicity.

RADIATION THERAPY: Patients receive lorlatinib PO QD concurrently with radiation therapy in the absence of disease progression or unacceptable toxicity.

POST-CONSOLIDATION THERAPY: Patients receive sargramostim and dinutuximab as in Arm A-D. Patients also receive isotretinoin PO BID on days 11-24 of cycles 1-5 and days 15-28 of cycle 6, and lorlatinib PO QD on days 15-28 of cycles 2-5 and days 1-28 of cycle 6 in the absence of disease progression or unacceptable toxicity.

CONTINUATION THERAPY: Patients receive lorlatinib PO QD on days 1-28. Cycles repeat every 28 days for 18 months in the absence of disease progression or unacceptable toxicity.

Patients undergo echocardiography or MUGA scan, MRI or CT scan, receive 123I-MIGB and undergo MIBG imaging, bone marrow aspiration and biopsy and blood sample collection throughout the study and may undergo MRI and PET scan on study.

After completion of study therapy, patients in Arms A-D are followed up every 3 months for 18 months, and then every 6 months for 42 months; patients in Arm E are followed up every 3 months for 6 months, and then every 6 months for 42 months.

Study Timeline

• Study First Submitted: 2017-04-17
• Study First Submitted QC: 2017-04-24
• Study First Posted: 2017-04-25
• Study Start: 2018-05-14
• Status Verified: 2025-02
• Last Update Submitted: 2025-03-18
• Last Update Posted: 2025-03-19
• Primary Completion: 2026-09-30
• Study Completion: 2026-09-30

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 724

Inclusion Criteria

• Patients must be enrolled on ANBL00B1 (NCT00904241) or APEC14B1 (NCT02402244) prior to enrollment on ANBL1531 (NCT03126916)

• Patient must be >= 365 days and =< 30 years of age at diagnosis

• Patients must have a diagnosis of neuroblastoma or ganglioneuroblastoma (nodular) verified by tumor pathology analysis or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites; the following disease groups are eligible:

  • Patients with International Neuroblastoma Risk Group (INRG) stage M disease are eligible if found to have either of the following features:

    • MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of additional biologic features; OR
    • Age > 547 days regardless of biologic features

  • Patients with INRG stage MS disease with MYCN amplification

  • Patients with INRG stage L2 disease with MYCN amplification

  • Patients > 547 days of age initially diagnosed with INRG stage L1, L2 or MS disease who progressed to stage M without prior chemotherapy may enroll within 4 weeks of progression to stage M

  • Patients >= 365 days of age initially diagnosed with MYCN amplified INRG stage L1 disease who progress to stage M without systemic therapy may enroll within 4 weeks of progression to stage M

• Patients initially recognized to have high-risk disease must have had no prior systemic therapy (other than topotecan/cyclophosphamide initiated on an emergent basis and within allowed timing); patients observed or treated with a single cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (e.g., as per ANBL0531, ANBL1232 or similar) for what initially appeared to be non-high risk disease but subsequently found to meet the criteria will also be eligible; patients who receive localized emergency radiation to sites of life-threatening or function-threatening disease prior to or immediately after establishment of the definitive diagnosis will be eligible

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

  • 1 to < 2 years: male = 0.6; female = 0.6
  • 2 to < 6 years: male = 0.8; female = 0.8
  • 6 to < 10 years: male = 1; female = 1
  • 10 to < 13 years: male = 1.2; female = 1.2
  • 13 to < 16 years: male = 1.5; female = 1.4
  • >= 16 years: male = 1.7; female = 1.4

• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age, and

• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 10 x ULN; for the purposes of this study, ULN for SGPT (ALT) is 45

• Shortening fraction of >= 27% by echocardiogram, or ejection fraction of > 50% by echocardiogram or radionuclide angiogram

• No known contraindication to peripheral blood stem cell (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 with INRG stage L2 tumors without amplification of MYCN regardless of tumor histology (may meet criteria for high risk classification but are not eligible for this trial)
• Patients with bone marrow failure syndromes
• Patients for whom targeted radiopharmaceutical therapy would be contraindicated due to underlying medical disorders
• 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 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Etoposide Phosphate	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Melphalan Hydrochloride	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Autologous Hematopoietic Stem Cell Transplantation	See Arm B in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	Doxorubicin Hydrochloride	See Arm A in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	Iobenguane I-123	See Arm A in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	Biospecimen Collection	See Arm A in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	Carboplatin	See Arm A in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	Dexrazoxane Hydrochloride	See Arm A in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	Multigated Acquisition Scan	See Arm A in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	Positron Emission Tomography	See Arm A in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	Computed Tomography	See Arm A in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	Isotretinoin	See Arm A in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	Therapeutic Conventional Surgery	See Arm A in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	Autologous Hematopoietic Stem Cell Transplantation	See Arm A in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	Cisplatin	See Arm A in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	Cyclophosphamide	See Arm A in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	Dinutuximab	See Arm A in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	Bone Marrow Aspiration and Biopsy	See Arm A in detailed description.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Vincristine Sulfate	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm A (chemotherapy, HSCT, EBRT)	Echocardiography	See Arm A in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	Etoposide Phosphate	See Arm A in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	External Beam Radiation Therapy	See Arm A in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	Sargramostim	See Arm A in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	Vincristine Sulfate	See Arm A in detailed description.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Biospecimen Collection	See Arm B in detailed description.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Cisplatin	See Arm B in detailed description.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Computed Tomography	See Arm B in detailed description.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Dexrazoxane Hydrochloride	See Arm B in detailed description.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Echocardiography	See Arm B in detailed description.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	External Beam Radiation Therapy	See Arm B in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	Topotecan Hydrochloride	See Arm A in detailed description.
Arm A (chemotherapy, HSCT, EBRT)	Thiotepa	See Arm A in detailed description.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Iobenguane I-123	See Arm B in detailed description.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Bone Marrow Aspiration and Biopsy	See Arm B in detailed description.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Magnetic Resonance Imaging	See Arm B in detailed description.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Topotecan Hydrochloride	See Arm B in detailed description.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Doxorubicin Hydrochloride	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Isotretinoin	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Positron Emission Tomography	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Carboplatin	See Arm B in detailed description.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Cyclophosphamide	See Arm B in detailed description.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Dinutuximab	See Arm B in detailed description.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Doxorubicin Hydrochloride	See Arm B in detailed description.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Etoposide Phosphate	See Arm B in detailed description.
Arm D (chemotherapy, HSCT, EBRT)	Biospecimen Collection	See Arm D in detailed description.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Bone Marrow Aspiration and Biopsy	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Cyclophosphamide	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Dexrazoxane Hydrochloride	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	External Beam Radiation Therapy	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Therapeutic Conventional Surgery	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Iobenguane I-131	See Arm B in detailed description.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Multigated Acquisition Scan	See Arm B in detailed description.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Vincristine Sulfate	See Arm B in detailed description.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Autologous Hematopoietic Stem Cell Transplantation	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Cisplatin	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Computed Tomography	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Dinutuximab	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Echocardiography	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Sargramostim	See Arm B in detailed description.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Therapeutic Conventional Surgery	See Arm B in detailed description.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Thiotepa	See Arm B in detailed description.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Magnetic Resonance Imaging	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Sargramostim	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Isotretinoin	See Arm B in detailed description.
Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)	Positron Emission Tomography	See Arm B in detailed description.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Biospecimen Collection	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Busulfan	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Iobenguane I-131	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm D (chemotherapy, HSCT, EBRT)	Therapeutic Conventional Surgery	See Arm D in detailed description.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Topotecan Hydrochloride	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Multigated Acquisition Scan	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm D (chemotherapy, HSCT, EBRT)	Dinutuximab	See Arm D in detailed description.
Arm D (chemotherapy, HSCT, EBRT)	Bone Marrow Aspiration and Biopsy	See Arm D in detailed description.
Arm D (chemotherapy, HSCT, EBRT)	Computed Tomography	See Arm D in detailed description.
Arm D (chemotherapy, HSCT, EBRT)	Iobenguane I-123	See Arm D in detailed description.
Arm D (chemotherapy, HSCT, EBRT)	Positron Emission Tomography	See Arm D in detailed description.
Arm D (chemotherapy, HSCT, EBRT)	Autologous Hematopoietic Stem Cell Transplantation	See Arm D in detailed description.
Arm D (chemotherapy, HSCT, EBRT)	External Beam Radiation Therapy	See Arm D in detailed description.
Arm D (chemotherapy, HSCT, EBRT)	Isotretinoin	See Arm D in detailed description.
Arm D (chemotherapy, HSCT, EBRT)	Sargramostim	See Arm D in detailed description.
Arm D (chemotherapy, HSCT, EBRT)	Vincristine Sulfate	See Arm D in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Autologous Hematopoietic Stem Cell Transplantation	See Arm E in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Bone Marrow Aspiration and Biopsy	See Arm E in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Iobenguane I-123	See Arm E in detailed description.
Arm D (chemotherapy, HSCT, EBRT)	Multigated Acquisition Scan	See Arm D in detailed description.
Arm D (chemotherapy, HSCT, EBRT)	Topotecan Hydrochloride	See Arm D in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Echocardiography	See Arm E in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Etoposide Phosphate	See Arm E in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Therapeutic Conventional Surgery	See Arm E in detailed description.
Arm D (chemotherapy, HSCT, EBRT)	Carboplatin	See Arm D in detailed description.
Arm D (chemotherapy, HSCT, EBRT)	Dexrazoxane Hydrochloride	See Arm D in detailed description.
Arm D (chemotherapy, HSCT, EBRT)	Doxorubicin Hydrochloride	See Arm D in detailed description.
Arm D (chemotherapy, HSCT, EBRT)	Etoposide Phosphate	See Arm D in detailed description.
Arm D (chemotherapy, HSCT, EBRT)	Magnetic Resonance Imaging	See Arm D in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Computed Tomography	See Arm E in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Biospecimen Collection	See Arm E in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Sargramostim	See Arm E in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Thiotepa	See Arm E in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Dexrazoxane Hydrochloride	See Arm E in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Dinutuximab	See Arm E in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	External Beam Radiation Therapy	See Arm E in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Multigated Acquisition Scan	See Arm E in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Positron Emission Tomography	See Arm E in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Topotecan Hydrochloride	See Arm E in detailed description.
Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)	Thiotepa	See Arm C in detailed description. Closed to accrual as of 12/17/20.
Arm D (chemotherapy, HSCT, EBRT)	Cisplatin	See Arm D in detailed description.
Arm D (chemotherapy, HSCT, EBRT)	Cyclophosphamide	See Arm D in detailed description.
Arm D (chemotherapy, HSCT, EBRT)	Thiotepa	See Arm D in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Carboplatin	See Arm E in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Cisplatin	See Arm E in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Cyclophosphamide	See Arm E in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Doxorubicin Hydrochloride	See Arm E in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Isotretinoin	See Arm E in detailed description.
Arm E (lorlatinib, chemotherapy, HSCT, EBRT)	Lorlatinib	See Arm E in detailed description.

Primary Outcome Measures

Name	Time	Method
Event free survival (EFS) (Arm A, B, D, and E)	3 years	EFS time is calculated from date of randomization or assignment to first episode of disease relapse or progression, second malignancy, or death, or until last contact if no event has occurred.

Secondary Outcome Measures

Name	Time	Method
Incidence of adverse events	Up to 18 months for Arms A-D and 28 months for Arm E	The proportion of patients with at least one Grade 3 or higher toxicity during protocol therapy, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, will be reported.
Overall survival (OS)	3 years	OS time is calculated from date of randomization or assignment until death, or until last contact if patient is alive.
Response rate	Up to 6 months	The response rate will be calculated among all evaluable patients at end-Induction. Responders are defined as patients who achieve a \>= partial response (PR) per the revised International Neuroblastoma Response Criteria (INRC).
EFS (Arm C)	3 years	EFS time is calculated from date of randomization to first episode of disease relapse or progression, second malignancy, or death, or until last contact if no event has occurred.

Trial Locations

Locations (161)

Children's Hospital of Alabama; 🇺🇸 Birmingham, Alabama, United States

Phoenix Childrens Hospital; 🇺🇸 Phoenix, Arizona, United States

Arkansas Children's Hospital; 🇺🇸 Little Rock, Arkansas, United States

Kaiser Permanente Downey Medical Center; 🇺🇸 Downey, California, United States

Loma Linda University Medical Center; 🇺🇸 Loma Linda, California, United States

Children's Hospital Los Angeles; 🇺🇸 Los Angeles, California, United States

Mattel Children's Hospital UCLA; 🇺🇸 Los Angeles, California, United States

Valley Children's Hospital; 🇺🇸 Madera, California, United States

Kaiser Permanente-Oakland; 🇺🇸 Oakland, California, United States

Children's Hospital of Orange County; 🇺🇸 Orange, California, United States

Lucile Packard Children's Hospital Stanford University; 🇺🇸 Palo Alto, California, United States

University of California Davis Comprehensive Cancer Center; 🇺🇸 Sacramento, California, United States

Rady Children's Hospital - San Diego; 🇺🇸 San Diego, California, United States

Naval Medical Center -San Diego; 🇺🇸 San Diego, California, United States

UCSF Medical Center-Mission Bay; 🇺🇸 San Francisco, California, United States

Children's Hospital Colorado; 🇺🇸 Aurora, Colorado, United States

Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center; 🇺🇸 Denver, Colorado, United States

Connecticut Children's Medical Center; 🇺🇸 Hartford, Connecticut, United States

Yale University; 🇺🇸 New Haven, Connecticut, United States

Alfred I duPont Hospital for Children; 🇺🇸 Wilmington, Delaware, United States

Children's National Medical Center; 🇺🇸 Washington, District of Columbia, United States

Golisano Children's Hospital of Southwest Florida; 🇺🇸 Fort Myers, Florida, United States

University of Florida Health Science Center - Gainesville; 🇺🇸 Gainesville, Florida, United States

Memorial Regional Hospital/Joe DiMaggio Children's Hospital; 🇺🇸 Hollywood, Florida, United States

Nemours Children's Clinic-Jacksonville; 🇺🇸 Jacksonville, Florida, United States

University of Miami Miller School of Medicine-Sylvester Cancer Center; 🇺🇸 Miami, Florida, United States

Nicklaus Children's Hospital; 🇺🇸 Miami, Florida, United States

AdventHealth Orlando; 🇺🇸 Orlando, Florida, United States

Nemours Children's Hospital; 🇺🇸 Orlando, Florida, United States

Johns Hopkins All Children's Hospital; 🇺🇸 Saint Petersburg, Florida, United States

Saint Mary's Medical Center; 🇺🇸 West Palm Beach, Florida, United States

Children's Healthcare of Atlanta - Arthur M Blank Hospital; 🇺🇸 Atlanta, Georgia, United States

Memorial Health University Medical Center; 🇺🇸 Savannah, Georgia, United States

Kapiolani Medical Center for Women and Children; 🇺🇸 Honolulu, Hawaii, United States

Saint Luke's Cancer Institute - Boise; 🇺🇸 Boise, Idaho, United States

Lurie Children's Hospital-Chicago; 🇺🇸 Chicago, Illinois, United States

University of Illinois; 🇺🇸 Chicago, Illinois, United States

University of Chicago Comprehensive Cancer Center; 🇺🇸 Chicago, Illinois, United States

Advocate Children's Hospital-Oak Lawn; 🇺🇸 Oak Lawn, Illinois, United States

Advocate Children's Hospital-Park Ridge; 🇺🇸 Park Ridge, Illinois, United States

Saint Jude Midwest Affiliate; 🇺🇸 Peoria, Illinois, United States

Southern Illinois University School of Medicine; 🇺🇸 Springfield, Illinois, United States

Riley Hospital for Children; 🇺🇸 Indianapolis, Indiana, United States

Blank Children's Hospital; 🇺🇸 Des Moines, Iowa, United States

University of Iowa/Holden Comprehensive Cancer Center; 🇺🇸 Iowa City, Iowa, United States

University of Kentucky/Markey Cancer Center; 🇺🇸 Lexington, Kentucky, United States

Children's Hospital New Orleans; 🇺🇸 New Orleans, Louisiana, United States

Ochsner Medical Center Jefferson; 🇺🇸 New Orleans, Louisiana, United States

Eastern Maine Medical Center; 🇺🇸 Bangor, Maine, United States

Maine Children's Cancer Program; 🇺🇸 Scarborough, Maine, United States

Sinai Hospital of Baltimore; 🇺🇸 Baltimore, Maryland, United States

Johns Hopkins University/Sidney Kimmel Cancer Center; 🇺🇸 Baltimore, Maryland, United States

Walter Reed National Military Medical Center; 🇺🇸 Bethesda, Maryland, United States

Tufts Children's Hospital; 🇺🇸 Boston, Massachusetts, United States

Massachusetts General Hospital Cancer Center; 🇺🇸 Boston, Massachusetts, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

C S Mott Children's Hospital; 🇺🇸 Ann Arbor, Michigan, United States

Children's Hospital of Michigan; 🇺🇸 Detroit, Michigan, United States

Wayne State University/Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

Henry Ford Health Saint John Hospital; 🇺🇸 Detroit, Michigan, United States

Michigan State University Clinical Center; 🇺🇸 East Lansing, Michigan, United States

Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital; 🇺🇸 Grand Rapids, Michigan, United States

Bronson Methodist Hospital; 🇺🇸 Kalamazoo, Michigan, United States

Corewell Health Children's; 🇺🇸 Royal Oak, Michigan, United States

Children's Hospitals and Clinics of Minnesota - Minneapolis; 🇺🇸 Minneapolis, Minnesota, United States

University of Minnesota/Masonic Cancer Center; 🇺🇸 Minneapolis, Minnesota, United States

Mayo Clinic in Rochester; 🇺🇸 Rochester, Minnesota, United States

University of Mississippi Medical Center; 🇺🇸 Jackson, Mississippi, United States

University of Missouri Children's Hospital; 🇺🇸 Columbia, Missouri, United States

Children's Mercy Hospitals and Clinics; 🇺🇸 Kansas City, Missouri, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

Mercy Hospital Saint Louis; 🇺🇸 Saint Louis, Missouri, United States

Children's Hospital and Medical Center of Omaha; 🇺🇸 Omaha, Nebraska, United States

University of Nebraska Medical Center; 🇺🇸 Omaha, Nebraska, United States

University Medical Center of Southern Nevada; 🇺🇸 Las Vegas, Nevada, United States

Sunrise Hospital and Medical Center; 🇺🇸 Las Vegas, Nevada, United States

Alliance for Childhood Diseases/Cure 4 the Kids Foundation; 🇺🇸 Las Vegas, Nevada, United States

Summerlin Hospital Medical Center; 🇺🇸 Las Vegas, Nevada, United States

Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center; 🇺🇸 Lebanon, New Hampshire, United States

Hackensack University Medical Center; 🇺🇸 Hackensack, New Jersey, United States

Morristown Medical Center; 🇺🇸 Morristown, New Jersey, United States

Saint Peter's University Hospital; 🇺🇸 New Brunswick, New Jersey, United States

Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital; 🇺🇸 New Brunswick, New Jersey, United States

Newark Beth Israel Medical Center; 🇺🇸 Newark, New Jersey, United States

Saint Joseph's Regional Medical Center; 🇺🇸 Paterson, New Jersey, United States

University of New Mexico Cancer Center; 🇺🇸 Albuquerque, New Mexico, United States

Albany Medical Center; 🇺🇸 Albany, New York, United States

Montefiore Medical Center - Moses Campus; 🇺🇸 Bronx, New York, United States

Maimonides Medical Center; 🇺🇸 Brooklyn, New York, United States

Roswell Park Cancer Institute; 🇺🇸 Buffalo, New York, United States

NYU Langone Hospital - Long Island; 🇺🇸 Mineola, New York, United States

The Steven and Alexandra Cohen Children's Medical Center of New York; 🇺🇸 New Hyde Park, New York, United States

Laura and Isaac Perlmutter Cancer Center at NYU Langone; 🇺🇸 New York, New York, United States

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center; 🇺🇸 New York, New York, United States

University of Rochester; 🇺🇸 Rochester, New York, United States

Stony Brook University Medical Center; 🇺🇸 Stony Brook, New York, United States

State University of New York Upstate Medical University; 🇺🇸 Syracuse, New York, United States

New York Medical College; 🇺🇸 Valhalla, New York, United States

Mission Hospital; 🇺🇸 Asheville, North Carolina, United States

UNC Lineberger Comprehensive Cancer Center; 🇺🇸 Chapel Hill, North Carolina, United States

Carolinas Medical Center/Levine Cancer Institute; 🇺🇸 Charlotte, North Carolina, United States

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States

East Carolina University; 🇺🇸 Greenville, North Carolina, United States

Wake Forest University Health Sciences; 🇺🇸 Winston-Salem, North Carolina, United States

Sanford Broadway Medical Center; 🇺🇸 Fargo, North Dakota, United States

Cincinnati Children's Hospital Medical Center; 🇺🇸 Cincinnati, Ohio, United States

Rainbow Babies and Childrens Hospital; 🇺🇸 Cleveland, Ohio, United States

Cleveland Clinic Foundation; 🇺🇸 Cleveland, Ohio, United States

Nationwide Children's Hospital; 🇺🇸 Columbus, Ohio, United States

Dayton Children's Hospital; 🇺🇸 Dayton, Ohio, United States

ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital; 🇺🇸 Toledo, Ohio, United States

University of Oklahoma Health Sciences Center; 🇺🇸 Oklahoma City, Oklahoma, United States

Legacy Emanuel Children's Hospital; 🇺🇸 Portland, Oregon, United States

Lehigh Valley Hospital-Cedar Crest; 🇺🇸 Allentown, Pennsylvania, United States

Geisinger Medical Center; 🇺🇸 Danville, Pennsylvania, United States

Penn State Children's Hospital; 🇺🇸 Hershey, Pennsylvania, United States

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh of UPMC; 🇺🇸 Pittsburgh, Pennsylvania, United States

Rhode Island Hospital; 🇺🇸 Providence, Rhode Island, United States

Medical University of South Carolina; 🇺🇸 Charleston, South Carolina, United States

Prisma Health Richland Hospital; 🇺🇸 Columbia, South Carolina, United States

BI-LO Charities Children's Cancer Center; 🇺🇸 Greenville, South Carolina, United States

Sanford USD Medical Center - Sioux Falls; 🇺🇸 Sioux Falls, South Dakota, United States

East Tennessee Childrens Hospital; 🇺🇸 Knoxville, Tennessee, United States

Saint Jude Children's Research Hospital; 🇺🇸 Memphis, Tennessee, United States

The Children's Hospital at TriStar Centennial; 🇺🇸 Nashville, Tennessee, United States

Vanderbilt University/Ingram Cancer Center; 🇺🇸 Nashville, Tennessee, United States

Dell Children's Medical Center of Central Texas; 🇺🇸 Austin, Texas, United States

Driscoll Children's Hospital; 🇺🇸 Corpus Christi, Texas, United States

Medical City Dallas Hospital; 🇺🇸 Dallas, Texas, United States

UT Southwestern/Simmons Cancer Center-Dallas; 🇺🇸 Dallas, Texas, United States

El Paso Children's Hospital; 🇺🇸 El Paso, Texas, United States

Cook Children's Medical Center; 🇺🇸 Fort Worth, Texas, United States

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center; 🇺🇸 Houston, Texas, United States

Covenant Children's Hospital; 🇺🇸 Lubbock, Texas, United States

UMC Cancer Center / UMC Health System; 🇺🇸 Lubbock, Texas, United States

Children's Hospital of San Antonio; 🇺🇸 San Antonio, Texas, United States

Methodist Children's Hospital of South Texas; 🇺🇸 San Antonio, Texas, United States

University of Texas Health Science Center at San Antonio; 🇺🇸 San Antonio, Texas, United States

Primary Children's Hospital; 🇺🇸 Salt Lake City, Utah, United States

University of Vermont and State Agricultural College; 🇺🇸 Burlington, Vermont, United States

Virginia Commonwealth University/Massey Cancer Center; 🇺🇸 Richmond, Virginia, United States

Seattle Children's Hospital; 🇺🇸 Seattle, Washington, United States

Providence Sacred Heart Medical Center and Children's Hospital; 🇺🇸 Spokane, Washington, United States

Mary Bridge Children's Hospital and Health Center; 🇺🇸 Tacoma, Washington, United States

Madigan Army Medical Center; 🇺🇸 Tacoma, Washington, United States

West Virginia University Healthcare; 🇺🇸 Morgantown, West Virginia, United States

Saint Vincent Hospital Cancer Center Green Bay; 🇺🇸 Green Bay, Wisconsin, United States

University of Wisconsin Carbone Cancer Center - University Hospital; 🇺🇸 Madison, Wisconsin, United States

Marshfield Medical Center-Marshfield; 🇺🇸 Marshfield, Wisconsin, United States

Children's Hospital of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States

British Columbia Children's Hospital; 🇨🇦 Vancouver, British Columbia, Canada

CancerCare Manitoba; 🇨🇦 Winnipeg, Manitoba, Canada

Janeway Child Health Centre; 🇨🇦 Saint John's, Newfoundland and Labrador, Canada

IWK Health Centre; 🇨🇦 Halifax, Nova Scotia, Canada

McMaster Children's Hospital at Hamilton Health Sciences; 🇨🇦 Hamilton, Ontario, Canada

Kingston Health Sciences Centre; 🇨🇦 Kingston, Ontario, Canada

Children's Hospital; 🇨🇦 London, Ontario, Canada

Children's Hospital of Eastern Ontario; 🇨🇦 Ottawa, Ontario, Canada

Hospital for Sick Children; 🇨🇦 Toronto, Ontario, Canada

HIMA San Pablo Oncologic Hospital; 🇵🇷 Caguas, Puerto Rico