Patient case: 4-year-old female with neuroblastoma; genetic feature: ALK

Clinical trial: Neuroblastoma Precision Trial

Summary: 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 GEM sequencing platform for acquisition and gene panel sequencing of relapsed biological specimens in relapsed/refractory neuroblastoma (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 programmed death ligand [PD-L1] expression) biomarkers in rNB. Additional potential novel biomarkers will also be evaluated and reported in this cohort of patients.

Detailed description: 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.

Eligibility: 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.

Relevance to patient case: definitely relevant