Rapid Administration Pilot for Infusing Dinutuximab

Neuroblastoma is the most common extracranial solid tumor of childhood. While it comprises only 8% of all childhood cancer cases, neuroblastoma is responsible for 12% of cancer deaths in children under 15 years of age. Approximately 50% of neuroblastoma patients are classified as high-risk, and over half of these children succumb to their disease despite intensive multi-modal therapy. The prognosis is worse for patients whose disease is refractory to initial therapy or who experience a recurrence of their tumor, as the majority of these patients cannot be cured of their disease. However, rates of event free survival and overall survival have improved over the past decades with the introduction of dinutuximab.

Dinutuximab is a chimeric monoclonal antibody that targets disialoganglioside (GD2) receptors. It has become an integral modality in the treatment of high-risk neuroblastoma (HR NBL) in up-front therapy and in the setting of relapsed or refractory disease. Additionally, there are numerous ongoing trials that include dinutuximab as part of the backbone therapy or in combination with other agents to improve tumor response in HR NBL patients.

A limiting factor for the use of dinutuximab has been the management of infusion-related toxicities. GD2 is expressed on neurons, skin melanocytes, and peripheral pain fibers of human tissues, which is evident in the common manifestation of pain during infusions. Other most common adverse effects include hypotension, capillary leak syndrome, and infusion-related reactions. These toxicities typically last during the standardized infusion duration of 10-20 hours but typically do not correlate with plasma levels. Pain that occurs during the infusion typically resolves shortly after the infusion is completed, despite the fact that dinutuximab persists in the circulation, which suggests that pain may be related to infusion rate rather than drug exposure (AUC). Due to the lengthy infusion duration and high frequency of side effects, dinutuximab infusions currently require significant hospital resources including nursing care, opioid infusions, around the clock supportive care medications, and a hospital stay for a minimum of 4-5 days.

With the expectation of repeated cycles of dinutuximab for different protocols in HR NBL treatment and with the expansion of dinutuximab studies in other GD2 positive tumors, there is a need to improve the administration and management of dinutuximab for future practicality and patient durability. A different anti-GD2 antibody naxitamab with a similar side effect profile to dinutuximab has been FDA approved for administration in the outpatient setting. Therefore, there is potential for dinutuximab to be administered in the outpatient setting. Although some studies have attempted to modify the administration of dinutuximab dosing and infusion durations, none have focused on shortening infusion time in the pediatric setting.