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 crizotinib to intensive multimodality therapy for
      patients with high-risk NBL whose tumors harbor activating point mutations in or
      amplification of the ALK gene results in superior EFS compared to a contemporaneously treated
      cohort of patients whose tumors lack these ALK aberrations.

      SECONDARY OBJECTIVES:

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

      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
      crizotinib.

      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 crizotinib.

      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 determine whether the efficacy (end-induction response, EFS, and OS) of crizotinib is
      associated with specific ALK mutations or ALK amplification.

      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 crizotinib 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.

      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.

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

      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.

      ARM D: Patients receive treatment identical to Arm A.

      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 crizotinib PO BID on
      days 1-21 of cycles 2-4 and days 1-8 of cycle 5 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
      crizotinib PO BID 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. Crizotinib is restarted when external beam radiation is initiated, provided there is no
      evidence 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 crizotinib PO BID on days 1-28 of cycles 1-6 in the absence of disease progression or
      unacceptable toxicity.

      CONTINUATION THERAPY: Patients receive crizotinib PO BID on days 1-28. Cycles repeat every 28
      days for 1 year in the absence of disease progression or unacceptable toxicity.

      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.