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 and are then randomized to 1 of 2 treatment
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 2-5: 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 2 hours on days 1-3 of cycles 3 and 5, and vincristine
IV on day 1, doxorubicin IV over 15 minutes, and cyclophosphamide IV over 1 hour on days
1-2 of cycle 4 in the absence of unacceptable toxicity. Patients undergo primary tumor
resection after Induction cycle 4 or 5. Following Induction cycle 5, patients undergo
testing to determine response to Induction therapy. Patients with a good tumor response
proceed to Consolidation, while patients with a poor tumor response proceed to Extended
Induction.
EXTENDED INDUCTION: Patients with a poor tumor response or progression during Induction
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 dinutuximab IV over 10 hours.
Treatment repeats every 21 days for up to a maximum of 6 cycles in the absence of disease
progression or unacceptable toxicity. If at any time during Extended Induction testing
shows a good tumor response, patients proceed to Consolidation. If after 6 cycles of
Extended Induction or if at any time progression is noted, patients are removed from the
study.
CONSOLIDATION: Patients undergo two autologous hematopoietic stem cell transplantations
(HSCTs) during Consolidation. Patients receive thiotepa IV over 2 hours on days -7 to -5
and cyclophosphamide IV over 1 hour on days -5 to -2 during HSCT 1. 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 during HSCT 2. Patients receive
stem cell infusion IV on day 0. Between day +42 and day +80 after HSCT 2. 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 cycles 1-5. 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, cycle 6.
Patients undergo bone marrow aspiration and/or biopsy, computed tomography (CT) scan,
magnetic resonance imaging (MRI), iodine-123 meta-iodobenzylguanidine (I-MIBG) scan and
possible fluorodeoxyglucose position emission tomography (FDG-PET) scan throughout the
study.
ARM B:
INDUCTION CYCLES 2-5: 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 2 hours on
days 1-3 and dinutuximab IV over 10 hours on days 2-5 of cycles 3 and 5, and vincristine
IV on day 1, doxorubicin IV over 15 minutes, and cyclophosphamide IV over 1 hour on days
1-2, and dinutuximab IV over 10 hours on days 2-5 of cycle 4 in the absence of
unacceptable toxicity. Patients undergo primary tumor resection after Induction cycle 4
or 5. Following Induction cycle 5, patients undergo testing to determine response to
Induction therapy. Patients with a good tumor response proceed to Consolidation, while
patients with a poor tumor response proceed to Extended Induction.
EXTENDED INDUCTION: Patients with a poor tumor response or progression during Induction
receive temozolomide PO, via NG tube, or via G-tube on days 1-5, irinotecan IV over 90
minutes on days 1-5, and dinutuximab IV over 10 hours. Treatment repeats every 21 days
for up to a maximum of 6 cycles in the absence of disease progression or unacceptable
toxicity. If at any time during Extended Induction testing shows a good tumor response,
patients proceed to Consolidation. If after 6 cycles of Extended Induction or if at any
time progression is noted, patients are removed from the study.
CONSOLIDATION: Patients undergo two autologous HSCTs during Consolidation. Patients
receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 1 hour on
days -5 to -2 during HSCT 1. 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 during HSCT 2. Patients receive stem cell infusion IV on
day 0. Between day +42 and day +80 after HSCT 2, 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 cycles 1-5. 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, cycle 6.
Patients undergo bone marrow aspiration and/or biopsy, CT scan, MRI, I-MIBG scan and
possible 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.