Clinical Trial FAQ

What is neuroblastoma?

Neuroblastoma is the second most common solid tumor and the third most common cancer in children. Neuroblastoma has a unique biology. In children with high-risk disease the tumor is usually metastatic (spread to bones, bone marrow, lymph nodes) and can become resistant to the best available standard therapy. In approximately one-third of children with high-risk neuroblastoma, gene analysis reveals the presence of abnormal genes (MYCN, ALK). However, genes that are frequently abnormal have not been identified in the other two-thirds of these children. The neuroblastoma tumor cells also enlist normal cells in their environment (the tumor microenvironment) to help them grow, spread, and resist treatments.  The patient’s own immune system has also been shown to be important in controlling the growth of neuroblastoma.  Current approaches to therapy include targeting the tumor cells themselves, identifying and targeting abnormal tumor genes, targeting normal cells in the tumor microenvironment, and immunotherapy.

How has NANT impacted the therapy of neuroblastoma?

NANT has played an essential role in establishing MIBG therapy across North America, and optimizing this therapy with the addition of other agents.  NANT performed multiple pilot studies showing the activity, safety, and feasibility of 131 I-MIBG therapy given alone or with chemotherapy and/or biologics in several multi-site clinical trials.   These pilot studies made possible the first Children’s Oncology Group randomized Phase 3 COG ANBL1531 trial to evaluate the role of the addition of 131 I-MIBG therapy to frontline therapy for patients with newly diagnosed neuroblastoma in changing patient outcome, opened in 2018.  NANT also completed the only randomized trial of MIBG given alone or with chemotherapy or biologics (N11-01) which found that MIBG with vorinostat had the highest response rate.  The successor N17-01 trial  showed the safety of MIBG with vorinostat and dinutuximab.

Based on compelling pre-clinical data from the lab of NANT investigator Dr. Yael Mosse which showed  the ALK inhibitor lorlatinib was active against neuroblastoma tumors resistant to the ALK Inhibitor crizotinib, NANT conducted the first Phase 1 study in children of lorlatinib to determine its safety and recommended dose alone or with chemotherapy, and to provide preliminary tumor response data. Based on impressive data from the NANT Phase 1 trial, COG study Phase 3 ANBL1531 was amended to replace the original ALK inhibitor crizotinib with lorlatinib.  Lorlatinib is also being studied in a European SIOPEN trial based on NANT results.

The completed NANT 2012-01 study (Chair, Dr. Mike Hogarty) of DFMO combined with chemotherapy provided the scientific rationale and safety data to support the development of a Children’s Oncology Group randomized Phase 2 trial of dinutuximab plus chemotherapy with or without the addition of DFMO.

The novel NB5 assay,  a very sensitive method that can detect minimal amounts of tumor in blood and bone marrow, was developed in a NANT collaborating laboratory.  The NB5 assay detected residual minimal tumor in 62% of newly diagnosed patients with high-risk neuroblastoma at the end of frontline therapy (including transplant and immunotherapy). Detection of tumor was correlated with poorer outcome. 

NANT developed novel response criteria to better define tumor response for patients with neuroblastoma. These NANT Response Criteria made a major contribution to the amendment of the International Neuroblastoma Response Criteria (INRC) in 2017, which will be used worldwide.

How are NANT clinical trials developed?

The development of a NANT clinical trial begins in a research laboratory, where neuroblastoma tumor cells from patients that have failed standard treatments are used to test the effectiveness of new treatments and how they work. When this laboratory data shows promise for activity against neuroblastoma, the investigator proposes a clinical trial to the NANT Executive Committee, composed of the NANT Leadership. Executive Committee performs a thorough review of the laboratory data, clinical data, and the proposed trial design to evaluate its scientific merit and prioritize the trial for development.  Trials are then reviewed and approved by the Scientific Review Committee (SRC). SRC members  include the lead pediatric oncologists from NANT sites, collaborating lab investigators, NANT Operations Center leadership, statisticians,  parent advisory representatives, NANT external clinical advisor, and the chair of the COG Neuroblastoma Committee.

After SRC approval of a new trial, the study chair works closely with NANT Leadership and the Operations Center to develop and implement the trial.  After a trial is opened to patient enrollment, its conduct is overseen by the NANT Operations Center.  NANT trials may be done in collaboration with a pharmaceutical company and/or the FDA.  This extensive multi-level review and infrastructure ensures that trials are selected based on scientific data of the highest merit, that patient safety is maximized, that all clinical trials standards are met, and that trials are run efficiently to maximize generation of new information for the neuroblastoma community.

How does NANT collaborate with the Children’s Oncology Group?

The NANT leadership are all members of the Neuroblastoma Committee in the Children’s Oncology Group (COG), and the Chair of this COG committee is also a member of the NANT Scientific Review Committee.  This collaboration is essential to provide a path forward for the novel therapies developed in NANT collaborating laboratories that are found to be effective in early phase trials to become standard therapy for patients with high-risk neuroblastoma. NANT provides an update on its Phase 1/2 clinical trials at each COG meeting.  These interactions promote rapid development of successor Phase 2/3 trials in COG with larger numbers of patients to establish the potential role of novel NANT therapies for newly diagnosed patients with high risk neuroblastoma.  Some examples of our successful collaboration are listed in the question above: How has NANT impacted the therapy of neuroblastoma?

Why aren’t more hospitals members of NANT?

NANT is a consortium of sites that have demonstrated significant expertise in neuroblastoma, and in the conduct of clinical and biology trials; have the resources to conduct complex trials of new therapies; and see sufficient numbers of neuroblastoma patients to allow efficient completion of NANT trials. NANT requires close communication and collaboration of all its sites. Each site is monitored by the Operations Center and reviewed annually by the Executive Committee to ensure they are meeting all safety and clinical trials conduct standards. NANT sites are chosen to achieve broad geographic distribution that will foster patient access to our clinical trials. NANT also has guest member sites that may participate in a specific clinical trial, for which they provide scientific and/or clinical expertise.  NANT has international sites in the United Kingdom, France, Netherlands, and Australia which further extends the impact of NANT research and clincial trials.

Why aren’t NANT treatments available to all children with neuroblastoma, on or off study?

Most NANT trials are “Phase 1”, which means the goal is to learn what is the best tolerated dose and schedule of the new treatment The dose chosen for further trials is based on observed side effects, drug levels in the blood, and additional biology tests that help determine how the treatment works.  Phase 1 clinical trials include therapies that have not yet been given to children or combinations of therapies that have not yet been given to any patient with cancer. 

Some of the new therapies given in NANT trials use treatments that have not yet been approved by the United States Food and Drug Administration (FDA), or are new combinations of drugs that may be FDA approved but have not been studied in children or adults. To ensure the highest safety for patients, these new treatments are only allowed to be given on study to patients who meet eligibility criteria that have been approved by the FDA or other regulatory bodies.  In addition, patients who receive these new therapies must be closely followed by the clinical trial team for side effects. Physicians are not allowed to waive these rules which protect patient safety. Phase I trials are designed so that we treat only a few patients at each dose level of the treatment at a time, so that side effects can be carefully monitored and fully evaluated before entering more patients at the next highest dose level.

Up to date information about each trial is shared with all NANT sites so that patients/families can be given the most current information about the trial, and the treating physician is aware of side effects that may have occurred in other patients on the trial.  This information may also be used to modify treatment for an individual patient on a clinical trial if needed. NANT sites are chosen because they have physicians and clinical research staff that have the experience and expertise to administer these new therapies safely, and to perform the required tests and data collection for NANT trials.

How are NANT Trials funded?

A clinical trials consortium requires significant funding, with a cost of approximately $30,000 USD for each child enrolled on a clinical trial. NANT funding has included grants from federal sources (including the FDA, National Institute of Health, and the Department of Defense), grants from philanthropic foundations, funding from pharmaceutical industry partners, and individual philanthropic donations.  If you would like to make a donation to NANT, you can contact the NANT Operations Center (323-361-5687) or you may donate online.

For more information about clinical trials through NANT, please see our NANT Clinical Trials page.