Neuroblastoma Clinical Trials

Clinical trials are scientific studies conducted to learn more about a disease and find new or better treatments. Clinical trials are the standard of care for children with neuroblastoma: virtually all children treated for intermediate- and high-risk disease as well as many low-risk NB patients are enrolled on a clinical trial or treated “per” a clinical trial. The treatment is the same in either case, but only the outcomes of those enrolled are included in the final trial results.

Since neuroblastoma is a rare disease, clinical trials are planned and carried out either by large single institutions, small groups of institutions, or large, international cooperative groups such as the Children’s Oncology Group (COG). Clinical trials may study therapeutic results of patient treatment or examine non-therapeutic issues such as what causes a type of cancer, similarities and differences between tumors, or what late effects patients may experience as a result of cancer treatment.


The current focus of clinical trials for low- and intermediate-risk neuroblastoma is to reduce treatment toxicity while maintaining high survival rates, as well as to determine how to identify at diagnosis the small subset of those with higher risk of treatment failure or relapse. By contrast, the focus of trials for high-risk neuroblastoma is primarily to increase the survival rate.

There are four different types, or phases, of therapeutic clinical trials.

Phase I Clinical Trials

Phase I pediatric clinical trials are the initial attempt to use a drug or drug combination in children, and often enroll small numbers of patients (e.g., 10 to 30). Phase I trials are open only to children who have “refractory” disease that has not responded to other treatments or children who have relapsed. In addition to measurable or detectable disease, eligibility criteria usually include adequate organ function such as specified blood cell counts, and liver, kidney, and heart test values.

Phase I trials are not intended to cure a child of disease, but to learn more about potentially effective new agents. A child enrolled on a Phase I study often does not benefit directly from the drug (although individual beneficial results are hoped for and do happen), but other children may benefit from what researchers learn about the drug, its administration, and side effects.

The goals of a Phase I clinical trial will usually include one or more of the following:

  • Pediatric use: To determine whether a drug or drug combination can be used in children. Drugs or drug combinations in a Phase I trial have been shown to be effective against neuroblastoma cell lines in the laboratory — and usually have been previously studied in adults— but have not been tried in children.
  • Toxicity: To determine what side effects and toxicities the drug causes when used in children. Toxicity is quantified (grades 1, 2, 3, and 4) and reported according to NCI’s Common Toxicity Criteria.
  • Dosage: To determine the highest tolerated dose of the drug or drugs in children. You may hear such studies referred to as “dose escalation studies.” In these studies, a small number of children (usually three) are given the same dose and their response to the drug, including any adverse effects, are observed. If the first group of children tolerates the treatment well, the next group of children enrolled on the study will receive an increased dose, until the doctors determine the maximum tolerated dose (MTD) that can be given without serious side-effects. “Intrapatient dose escalation” design allows for the dose to be increased in each patient as tolerated.
  • Absorption (“pharmacokinetics”): To determine how well a new drug or a new method or formulation for delivering an old drug or combination of drugs is absorbed in the child’s system, and how long before it is eliminated.

The extent of a child’s disease is monitored periodically during the clinical trial and is reported commonly as reduced (response to treatment), stable, or progressive (disease is growing). Children who have progressive disease are removed from the trial and other treatment options are explored. Children who have severe adverse reactions will also be removed from the study. In some cases, studies have been closed when several children experienced very serious side effects.

Phase II Clinical Trials

Like Phase I trials, Phase II clinical trials are generally open to refractory or relapsed patients who have not responded to more conventional treatments. Drugs or drug combinations in a Phase II trial have undergone Phase I testing, so the recommended, maximum tolerated dose has been established and toxicities are known.

The primary goal of Phase II trials is to determine if the drug or drug combination is active against neuroblastoma—whether the drug will shrink tumors or, in some cases, prevent the cancer from recurring. In addition, researchers may learn more about side effects and toxicities associated with taking the drug. Phase II trials typically enroll more patients than Phase I, often 30-60 in the case of neuroblastoma.

Some Phase II trials are designed specifically to test new frontline treatment regimens on newly diagnosed patients. Such Phase II trials are available only at certain large institutions and are often referred to as “pilot” studies or protocols. These studies determine toxicity and survival rates for new treatment regimens for frontline therapy. If the results are promising, future Phase III trials may incorporate the new regimens to be verified as more effective.

Phase III Clinical Trials

Children newly diagnosed with high-risk neuroblastoma usually are enrolled on the current COG Phase III clinical trial, unless their hospital runs single-institution trials, which may be a Phase II trial. If your child is not either enrolled on a trial, or being treated “per” a trial, you should ask your doctor why your child is not receiving the newest treatments. It is worth noting that children are often treated on closed trials (Phase II or III protocols), so their data is not included in the results of the study.
Although they utilize some of the most effective treatments against neuroblastoma, enrollment on a Phase III trial does not guarantee a cure. Because the prognosis for high-risk disease is so poor, doctors and researchers are constantly working to find more effective treatments that pose fewer long-term risks to children.

Phase III clinical trials require enrollment of a large number of patients for increased statistical significance, usually in the 300-500 patient range. These studies compare two or more treatments that are specific to neuroblastoma and try to determine which one is more effective. Most Phase III studies are randomized—children in the “control group” receive the “standard” treatment, while other children receive a different drug or treatment designed to answer a specific research question. A computer is used to randomly select which children receive the experimental treatment and which receive the standard treatment.

For a history of Phase III trials for high-risk neuroblastoma, see Appendix to “Understanding the Basics of NB Treatment in the NB Parent Handbook.”

Phase IV Clinical Trials

These trials are to verify the safety of a newly approved treatment or drug. None of these “Post Marketing Surveillance Trials” are currently designed for neuroblastoma.

Single or Limited Institution Trials

Some institutions, such as St. Jude’s Children’s Research Hospital and Memorial Sloan-Kettering Cancer Center, conduct trials limited to patients at their facility. Other trials are conducted at only a few institutions. Single institution and limited institution trials may take the form of pilot studies or individual drug studies—i.e., the initial study examining a new method or treatment. These smaller trials allow researchers to answer critical questions before a drug or treatment is made available to more patients through a larger study.

Non-therapeutic Clinical Trials

Non-therapeutic clinical trials generally fall into one of four categories:

  • Biological studies—studies that examine the biology of tumor samples and identify prognostic variables;
  • Epidemiological studies—studies that look for the causes of a type of cancer and the frequency with which it occurs;
  • Cancer control studies—studies designed to find the best methods for dealing with side effects; and
  • Late effects studies—studies designed to identify and deal with the after-effects of treatment.

Patient Safety

Clinical trials are carefully planned and rigorously monitored. Each hospital must elect to open a study and enroll patients, which requires approval from the hospital’s Institutional Review Board (IRB). Because patient safety is such a concern with experimental treatments, there are strict guidelines for carrying out clinical trials. For example, there is no flexibility in eligibility criteria. If the study requires patients to have a platelet count of at least 100,000 no patient can be enrolled with less. Similarly, there are strict monitoring requirements for disease status and reporting toxicity.

Compassionate Use

Occasionally parents pursue “compassionate use” of “investigational new drugs” (INDs) from the FDA and manufacturers. Reasons for this may be that the drug is offered in an open study but the child does not meet eligibility criteria, or no study is currently open. The child’s oncologist, the principal investigator of the new drug, the manufacturer of the drug, and the FDA are all involved in getting compassionate use approved on a case-by-case basis. Approval is highly variable based on many factors.


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