Irinotecan Hydrochloride and Temozolomide With Temsirolimus or Dinutuximab in Treating Younger Patients With Refractory or Relapsed Neuroblastoma

PRIMARY OBJECTIVES:

I. To identify whether temsirolimus or ch14.18 (dinutuximab) is the optimal therapeutic agent
to consider for further testing in a future Phase III randomized trial for treatment of newly
diagnosed high-risk neuroblastoma.

II. To determine the response rate of patients with relapsed, refractory or progressive
neuroblastoma following treatment with irinotecan, temozolomide and ch14.18 (dinutuximab) and
to compare this with the known response rate of patients treated with irinotecan and
temozolomide alone.

EXPLORATORY OBJECTIVES:

I. To compare the response rates (RR) for patients receiving temsirolimus or ch14.18
(dinutuximab) in combination with irinotecan (irinotecan hydrochloride) and temozolomide.

II. To compare the progression free survival (PFS) and overall survival (OS) rates for
patients receiving temsirolimus or ch14.18 (dinutuximab) in combination with irinotecan and
temozolomide.

III. To compare the toxicities associated with temsirolimus or ch14.18 (dinutuximab) when
combined with irinotecan and temozolomide in patients with refractory, relapsed or
progressive neuroblastoma.

IV. To compare the ability to maintain intended dose intensity of all agents when
temsirolimus or ch14.18 (dinutuximab) is combined with irinotecan and temozolomide in
patients with refractory, relapsed or progressive neuroblastoma.

V. To determine the concordance between tumor responses as defined by standard International
Neuroblastoma Response Criteria (INRC) versus response per the revised INRC.

VI. To study the clinical relevance of naturally occurring anti-glycan antibodies in patients
receiving ch14.18 (dinutuximab) antibody.

VII. To study the clinical relevance of natural killer (NK) receptor natural cytotoxicity
triggering receptor 3 (NKp30) isoforms in patients receiving ch14.18 (dinutuximab) antibody
or temsirolimus.

VIII. To study the association between host factors and response to irinotecan, temozolomide
and ch14.18 (dinutuximab).

IX. To characterize the tumor immune-microenvironment (gene expression; immune effector
cells, activities and signaling molecules; immune target expression) following treatment with
irinotecan, temozolomide and ch14.18 (dinutuximab).

X. To study the association between changes in the tumor immune-microenvironment (gene
expression; immune effector cells, activities and signaling molecules; immune target
expression) with response following treatment with irinotecan, temozolomide and ch14.18
(dinutuximab).

XI. To study the association between tumor genomic and transcriptomic aberrations as well as
levels of circulating ganglioside (GD2) with response to irinotecan, temozolomide and ch14.18
(dinutuximab).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I (CLOSED TO ACCRUAL 06/17/2016): Patients receive temozolomide orally (PO) on days 1-5,
irinotecan hydrochloride intravenously (IV) over 90 minutes on days 1-5, and temsirolimus IV
over 30 minutes on days 1 and 8.

ARM II: Patients receive temozolomide PO on days 1-5, irinotecan hydrochloride over 90
minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim
subcutaneously (SC) or IV over 2 hours on days 6-12.

In both arms, treatment repeats every 21 days for up to 17 courses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- Patients must have had histologic verification of neuroblastoma or
ganglioneuroblastoma or demonstration of neuroblastoma cells in the bone marrow with
elevated urinary catecholamines (i.e., > 2 x upper limit of normal [ULN]), at the time
of initial diagnosis

- For the purposes of this study, aggressive multidrug chemotherapy is defined as
chemotherapy including 2 or more agents that must include an alkylating agent and a
platinum-containing compound; patients must have ONE of the following:

- First episode of recurrent disease following completion of aggressive multi-drug
frontline therapy

- First episode of progressive disease during aggressive multi-drug frontline
therapy

- Primary resistant/refractory disease (less than partial response by INRC)
detected at the conclusion of at least 4 cycles of aggressive multidrug induction
chemotherapy on or according to a high-risk neuroblastoma protocol (examples
include A3973, ANBL0532, ANBL09P1, etc.)

- Patients must have at least ONE of the following:

- Measurable tumor on magnetic resonance imaging (MRI), computed tomography (CT)
scan obtained within 3 weeks prior to study entry; measurable is defined as >= 10
mm in at least one dimension on spiral/helical CT that is metaiodobenzylguanidine
(MIBG) avid or demonstrates increased fludeoxyglucose (FDG) uptake on positron
emission tomography (PET) scan

- MIBG scan obtained within 3 weeks prior to study entry with positive uptake at a
minimum of one site; this site must represent disease recurrence after completion
of therapy, progressive disease on therapy, or refractory disease during
induction

- Patients with resistant/refractory soft tissue disease that is not MIBG avid or
does not demonstrate increased FDG uptake on PET scan must undergo biopsy to
document the presence of viable neuroblastoma; biopsy is not required for
patients who have new site of soft tissue disease (radiographic evidence of
disease progression) regardless of whether progression occurs while receiving
therapy or after completion of therapy

- Note: Patients with elevated catecholamines (i.e., > 2 x ULN) only or bone marrow
disease only are NOT eligible for this study

- Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1 or 2; use Karnofsky for patients > 16 years of age and
Lansky for patients =< 16 years of age

- Patients must have received frontline therapy (including surgery, chemotherapy,
autologous stem cell transplant [SCT] +/- MIBG, immunotherapy, radiotherapy, and
retinoids) but may NOT have received second line chemotherapy for
resistant/refractory, relapsed disease or progressive disease

- At least 14 days must have elapsed since completion of myelosuppressive therapy

- At least 7 days must have elapsed since the completion of therapy with a
non-myelosuppressive biologic agent or retinoid

- No interim time prior to study entry is required following prior radiation therapy
(RT) for non-target lesions; however, patients must not have received radiation for a
minimum of 4 weeks prior to study entry at the site of any lesion that will be
identified as a target lesion to measure tumor response; lesions that have been
previously radiated cannot be used as target lesions unless there is radiographic
evidence of progression at the site following radiation or a biopsy done following
radiation shows viable neuroblastoma; palliative radiation is allowed to sites that
will not be used to measure response during this study

- Patients are eligible >= 6 weeks after autologous stem cell transplants or stem cell
infusions as long as hematologic and other eligibility criteria have been met

- Patients are eligible >= 6 weeks after therapeutic 131I-MIBG provided that all other
eligibility criteria are met

- Subjects who have previously received anti-GD2 monoclonal antibodies for biologic
therapy or for tumor imaging are eligible unless they have had progressive disease
while receiving prior anti-GD2 therapy; subjects who have received autologous marrow
infusions or autologous stem cell infusions that were purged using monoclonal antibody
linked to beads, but no other form of anti-GD2 monoclonal antibody, are eligible

- Patients must not have received long-acting myeloid growth factors (e.g., Neulasta)
within 14 days of entry on this study; seven days must have elapsed since
administration of a short acting myeloid growth factor

- Peripheral absolute neutrophil count (ANC) >= 750/uL

- Platelet count >= 75,000/uL (transfusion independent)

- Patients known to have bone marrow involvement with neuroblastoma are eligible
provided that minimum ANC and platelet count criteria are met but are not evaluable
for hematological toxicity

- Creatinine clearance or estimated radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or

- A serum creatinine =< upper limit of normal (ULN) based on age/gender as follows:

- Age 1 month to < 6 months: 0.4 for males, 0.4 for females

- Age 6 months to < 1 year: 0.5 for males, 0.5 for females

- Age 1 to < 2 years: 0.6 for males, 0.6 for females

- Age 2 to < 6 years: 0.8 for males, 0.8 for females

- Age 6 to < 10 years: 1 for males, 1 for females

- Age 10 to < 13 years: 1.2 for males, 1.2 for females

- Age 13 to < 16 years: 1.5 for males, 1.4 for females

- Age >= 16 years: 1.7 for males, 1.4 for females

- Total bilirubin =< 1.5 x ULN for age AND

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5.0 x
ULN for age (=< 225 U/L); for the purpose of this study, the ULN for SGPT is 45 U/L

- Adequate central nervous system function defined as:

- Patients with a history of central nervous system (CNS) disease must have no
clinical or radiological evidence of CNS disease at the time of study enrollment

- Patients with seizure disorders may be enrolled if seizures are well controlled
on anticonvulsants

- CNS toxicity =< grade 2

- Shortening fraction of >= 27% by echocardiogram (ECHO) OR

- Ejection fraction >= 50% by ECHO or gated radionuclide study

- Adequate coagulation defined as:

- Prothrombin time (PT) =< 1.2 x upper limit of normal

- Adequate pulmonary function defined as:

- No evidence of dyspnea at rest, no exercise intolerance, no chronic oxygen
requirement, and room air pulse oximetry > 94% if there is a clinical indication
for pulse oximetry; normal pulmonary function tests in patients who are capable
of cooperating with testing (including diffusion capacity of the lung of carbon
monoxide [DLCO]) are required if there is a clinical indication for
determination; for patients who do not have respiratory symptoms, full pulmonary
function tests (PFTs) are NOT required

Exclusion Criteria:

- Men and women of childbearing potential and their partners must agree to use adequate
contraception while enrolled on this study; based on the established teratogenic
potential of alkylating agents, pregnant women will be excluded from this study;
female patients who are lactating must agree to stop breastfeeding or will otherwise
be excluded from this study; females of childbearing potential must have a negative
pregnancy test to be eligible for this study

- Patients with elevated catecholamines (i.e., > 2 x ULN) only or bone marrow disease
only are NOT eligible for this study

- Patients must have been off pharmacologic doses of systemic steroids for at least 7
days prior to enrollment; patients who require or are likely to require pharmacologic
doses of systemic corticosteroids while receiving treatment on this study are
ineligible; the only exception is for patients known to require 2 mg/kg or less of
hydrocortisone (or an equivalent dose of an alternative corticosteroid) as
premedication for blood product administration in order to avoid allergic transfusion
reactions; the use of conventional doses of inhaled steroids for the treatment of
asthma is permitted, as is the use of physiologic doses of steroids for patients with
known adrenal insufficiency

- Patients must not have received enzyme-inducing anticonvulsants including phenytoin,
phenobarbital, valproic acid, or carbamazepine for at least 7 days prior to study
enrollment; patients receiving non-enzyme inducing anticonvulsants such as gabapentin
or levetiracetam will be eligible

- Patients must not have been diagnosed with myelodysplastic syndrome or with any
malignancy other than neuroblastoma

- Patients with symptoms of congestive heart failure are not eligible

- Patients must not have >= grade 2 diarrhea

- Patients must not have uncontrolled infection

- Patients with a history of grade 4 allergic reactions to anti-GD2 antibodies or
reactions that required discontinuation of the anti-GD2 therapy are not eligible

- Patients with a significant intercurrent illness (any ongoing serious medical problem
unrelated to cancer or its treatment) that is not covered by the detailed exclusion
criteria and that is expected to interfere with the action of study agents or to
significantly increase the severity of the toxicities experienced from study treatment
are not eligible