First Patient Enrolled in Trial Testing Defitelio to Prevent Neurotoxicity in DLBCL Patients Receiving CAR T-cell Therapy

Jazz Pharmaceuticals has enrolled the first participant in a Phase 2 trial assessing the efficacy of Defitelio (defibrotide) to prevent nerve cell toxicity in people with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are receiving chimeric antigen receptor (CAR) T-cell therapy.

The multicenter open-label trial (NCT03954106) is recruiting up to 35 adult participants at six medical centers across the U.S. It will evaluate the safety and efficacy of Defitelio as a preventive treatment against CAR T-cell therapy-related neurotoxicity in patients receiving Yescarta (axicabtagene ciloleucel).

The study will first evaluate two doses of Defitelio (2.5 and 6.25 mg/kg) to establish a recommended dosage. The second part will assess the safety and efficacy of the recommended dose at preventing CAR-T associated neurotoxicity.

CAR T-cell therapy consists of taking T-cells (a type of immune cell) from a person and modifying them to target and kill cancer cells, before infusing the T-cells back into the patient. These therapies have proven particularly useful for advanced blood cancers such as relapsed or refractory non-Hodgkin’s lymphoma.

However, CAR T-cell therapy can cause side effects, including cytokine release syndrome and neurotoxicity. While the mechanisms underlying these side effects remain unknown, they seem to be related.

Recent studies suggested that during cytokine release syndrome, excessive amounts of cytokines — molecules that regulate the immune system and inflammation — accumulate in the blood and fluid that surrounds the brain and spine (cerebrospinal fluid). This leads to damage in the cells that line the blood vessels, called endothelial cells, disrupting their ability to create a tight, protective barrier in the brain, and causing neurotoxicity.

Defitelio (marketed by Jazz) was approved in the U.S and Europe as a treatment for adults and children who develop hepatic veno-occlusive disease (VOD) — a condition in which blood clots obstruct blood vessels that feed the liver — after receiving a bone marrow transplant.

The therapy acts by protecting the endothelial cells, thus avoiding damage to the blood vessels and preventing blood clots.

Researchers at Jazz hypothesized that Diftelio could also prevent CAR T-cell-related neurotoxicity by avoiding damage to the endothelial cells that protect the central nervous system.

“The introduction of CAR-T therapies to the oncology treatment landscape is groundbreaking but can be associated with serious complications such as neurotoxicity,” Robert Iannone, MD, executive vice president of research and development at Jazz, said in a news release.

“At Jazz, we strive to improve outcomes for patients, and we are committed through our development program to explore the potential of defibrotide, including as a preventive treatment for neurotoxicity in patients receiving CAR-T therapy,” he added.