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.
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.
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 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 1-28 of cycles 1-6 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.
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.