Monoclonal Antibody Therapy for Relapsed or Treatment-Resistant Neuroblastoma

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Name of the Trials

Study 1: Lenalidomide and Monoclonal Antibody with or without Isotretinoin in Treating Younger Patients with Refractory or Recurrent Neuroblastoma (NANT-2011-04). See the protocol summary.

Study 2: Irinotecan Hydrochloride and Temozolomide with Temsirolimus or Monoclonal Antibody Ch14.18 in Treating Younger Patients with Refractory or Relapsed Neuroblastoma (COG-ANBL1221). See the protocol summary.

Principal Investigators

Study 1: Dr. Araz Marachelian, New Approaches to Neuroblastoma Treatment (NANT)

Study 2: Dr. Rajen Mody, Children's Oncology Group (COG)

Why These Trials Are Important

Neuroblastoma is a cancer of immature nerve cells that occurs most often in and around the adrenal glands, which sit atop the kidneys. However, it can also occur in other areas of the abdomen and in the chest, neck, and near the spine. Neuroblastoma usually affects infants and young children, with approximately 90 percent of cases diagnosed in children younger than 5 years of age. The remaining cases are diagnosed in older children, adolescents, and even young adults. Older age at diagnosis is generally associated with poorer outcomes.

Neuroblastoma is a disease that can show diverse clinical behaviors, ranging from a localized tumor with benign features to widespread disease with highly aggressive features. Based on considerations such as tumor histology, biological and molecular characteristics of the tumor cells, extent of disease spread, and age, patients are often categorized into one of three risk groups—low-risk, intermediate-risk, or high-risk—in terms of their prognosis. These risk-based categories help doctors decide how to treat patients.

In very young children with low-risk disease, active treatment may be deferred in favor of observation because spontaneous regressions have been noted in patients with certain favorable characteristics. In contrast, patients with high-risk neuroblastoma are treated very aggressively, often with chemotherapy, surgery, radiation therapy, stem-cell transplantation, and/or biological therapy. Despite aggressive treatment, some high-risk patients will have cancer that fails to respond to treatment (refractory disease) or comes back after initially showing signs of response (recurrent disease). The outlook for these patients is poor. New treatments are desperately needed to help extend the lives of children with recurrent or refractory neuroblastoma.

A chimeric antibody called ch14.18 (also known as dinutuximab) might offer some hope for patients with high-risk neuroblastoma. Ch14.18 binds to a molecule called GD2 that is commonly overexpressed by neuroblastoma cells, but its expression by normal cells is limited. In a Children’s Oncology Group phase III clinical trial, the addition of ch14.18, along with an immunostimulant, to standard maintenance therapy with isotretinoin improved both event-free survival and overall survival in patients with high-risk neuroblastoma who had responded to induction therapy and stem-cell transplantation.

NCI is now sponsoring additional trials of ch14.18, in combination with other drugs, to see if the antibody may be helpful for children or young adults (up to age 21) with relapsed or refractory neuroblastoma.

In a phase I trial being conducted by the New Approaches to Neuroblastoma Treatment (NANT) consortium, patients with relapsed or refractory neuroblastoma will be assigned to receive different doses of the drug lenalidomide and ch14.18 with or without isotretinoin. Researchers want to determine how much lenalidomide can be given safely with ch14.18 and isotretinoin and see how the combination affects the immune system.

“Currently, ch14.18 is administered with immune stimulating agents like interleukin-2 or granulocyte-macrophage colony-stimulating factor in an effort to enhance the immune response,” Dr. Marachelian said. “We are trying to determine if the antibody can be given safely with lenalidomide, an immunomodulating agent, rather than an immune stimulator like IL-2, which is known to cause toxic side effects.”

“If co-administration of ch14.18 and lenalidomide proves safe, our study could lead to a head-to-head comparison with the standard way ch14.18 is given now with cytokines,” she added.

In a phase II trial, member sites of the Children’s Oncology Group will treat patients with a combination of the drugs irinotecan and temozolomide and randomly assign them to receive either ch14.18 or the drug temsirolimus in combination with their chemotherapy. Doctors want to see if one combination leads to a better response rate and compare the toxicity of the interventions.  

“If one arm of the study proves better than the other and the combination is well tolerated, it may be used in a future phase III trial for patients with newly diagnosed neuroblastoma,” said Dr. Mody. “This is an exciting study in that it is testing the chimeric antibody [ch14.18], a biologic agent that has already proven to be beneficial to patients by preventing relapses, to see if it can actually help improve the survival of patients with relapsed disease.”

For More Information

See the lists of eligibility criteria (study 1; study 2) and trial contact information (study 1; study 2) or call the NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). The toll-free call is confidential.

  • Posted: September 9, 2014

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