Iobenguane I-131 or Crizotinib and Standard Therapy in Treating Younger Patients With Newly-Diagnosed High-Risk Neuroblastoma or Ganglioneuroblastoma

This phase III trial studies iobenguane I-131 or crizotinib 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. Crizotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving iobenguane I-131 or crizotinib and standard therapy may work better compared to crizotinib and standard therapy alone in treating younger patients with neuroblastoma or ganglioneuroblastoma.

PRIMARY OBJECTIVES:

1. 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:

1. 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:

1. 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.

1. 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.

1. 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 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 IV over 30 minutes on days 1-5 of cycle 2 and cisplatin IV over 4 hours and etoposide IV over 2 hours on days 1-3 of cycles 3 and 5. Patients also receive vincristine IV over 1 minute on day 1 and dexrazoxane IV over 5-15 minutes, doxorubicin 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 IV over 30 minutes on days -7 to -5, and etoposide 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, cisplatin, and etoposide 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, dexrazoxane, doxorubicin, 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, and carboplatin as in Arm A.

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

ARM C:

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

CONSOLIDATION THERAPY: Patients receive busulfan IV over 3 hours on days -6 to -3 and melphalan 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, cisplatin, etoposide, vincristine, dexrazoxane, doxorubicin, 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, etoposide, 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.