Neuroblastoma Precision Trial

Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. High-risk NB is
highly lethal and responsible for over 15% of childhood cancer related deaths. The majority
of patients with metastatic NB respond to upfront cytotoxic chemotherapy, yet patients who
die of recurrent disease do so from tumor acquired resistance to treatment. Thus,
understanding the repertoire of tumor specific genomic alterations leading to tumor
progression and therapy resistance is critical to devising novel targeted therapy options for
patients with recurrent or refractory (r)NB. Limited data exists regarding the genetic and
immunologic predictive biomarkers in rNB, which can be used to direct targeted therapies.
Another barrier to clinical implementation of genetic testing of tumor samples from children
with rNB is obtaining sufficient number of tumor cells from bone marrow (BM) specimens, the
most easily accessible and common site of relapse. This proposal sets forth the platform for
a Precision Medicine clinical trial through the New Approaches to Neuroblastoma Therapy
(NANT) consortium. The plan is to utilize NANT's established multi-institutional
infrastructure and Translational Genomics Research Institute (TGen) GEMTM sequencing platform
for acquisition and gene panel sequencing of relapsed biological specimens in rNB including
those obtained from the bone, bone marrow or soft tissue. Our primary aim is to identify
subgroups of rNB patients who have potentially targetable genetic (ALK, MAPK pathway,
Metabolic-related genes) and/or immunologic (tumor-associated macrophage infiltration and/or
PD-L1 expression) biomarkers in rNB. Additional potential novel biomarkers will also be
evaluated and reported in this cohort of patients. This aim has immediate impact on the lives
of children with rNB as it provides a clinical report to patients and their physicians
detailing observed mutations and rNB subgroups and information on clinical trials that best
match them. Our second aim will assess a novel method for enriching tumor cells from bone
marrow aspirates containing less than 30% tumor involvement so that next generation
sequencing can be performed. Our bone marrow (BM) enrichment protocol has both methodological
and patient significance; 1) BM enrichment will allow a much larger group of rNB patients
access to future personalized medicine trials and 2) Successful confirmation that BM
enrichment can produce quality DNA for genetic analysis serves as proof of principal that
this method can be used for genetic testing of BM with evidence of metastasis in other adult
or pediatric solid tumors. In summary, our proposal will define the genetic and immunologic
landscape of rNB and contribute to our understanding and ability to therapeutically target
the dynamic alterations in tumor biology of children with rNB.

Inclusion Criteria:

- Patients must be ≥ 1 year and ≤ 30 years of age at study registration

- Patients must have had a diagnosis of neuroblastoma either by histological
verification of neuroblastoma and/or demonstration of tumor cells in the bone marrow
with increased urinary catecholamines.

- Patients must have a history of high-risk neuroblastoma according to

- COG risk classification at the time of study registration. Patients must have at least
one of the following: Recurrent/progressive disease, Refractory disease, Persistent
disease

- Patient must be willing to undergo a clinically indicated biopsy and meet at least one
of the following requirements: Bone biopsy, Soft tissue biopsy, Bone marrow biopsy and
aspirate

- Patients must not be receiving any other anti-cancer agents or radiotherapy during the
interval

Exclusion Criteria:

- Patients with disease of any major organ system that would compromise their ability to
withstand biopsy procedures of soft tissue, bone and/or bone marrow.

- Patients who enroll and successfully receive a NANT Precision Report may not re-enroll
at a future time.

- Patient declines participation in NANT 2004-05, the NANT Biology Study.