A phase 2 trial of defibrotide for the prevention of chimeric antigen receptor T-cell-associated neurotoxicity syndrome.

Chimeric antigen receptor T-cell (CAR-T) therapy is one of the most noteworthy advances in cancer immunotherapy; however, it can be associated with life-threatening neurotoxicity linked to blood-brain barrier disruption and endothelial activation. Defibrotide has been shown to reduce endothelial cell activation in vitro and is approved in the US for treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients with renal or pulmonary dysfunction post-HCT, and in the EU for treatment of severe VOD/SOS post-HCT in patients aged >1 month. It was hypothesized that defibrotide may stabilize the endothelium during CAR-T therapy and reduce the rate of CAR-T-associated neurotoxicity. This open-label, single-arm, phase 2 study evaluated safety and efficacy of defibrotide for prevention of CAR-T-associated neurotoxicity in patients with relapsed/refractory large B-cell lymphoma receiving axicabtagene ciloleucel. In Part 1, the recommended phase 2 dose (RP2D; 6.25 mg/kg) was established. Overall, 20 patients (from Parts 1 and 2) receiving the RP2D were evaluable for efficacy. The rate of CAR-T-associated neurotoxicity by day 30 (primary endpoint) was ~50%, lower than the 64% reported in ZUMA-1. The median event duration of grade ≥3 neurotoxicity was 7 days. There were no unexpected defibrotide-related safety findings, and no defibrotide-related treatment-emergent adverse events or deaths. Results showed a modest reduction in the rate of CAR-T-associated neurotoxicity and high-grade neurotoxicity event duration relative to historical data; however, the reduction was unlikely to meet the primary endpoint, so the study was terminated early. Nevertheless, results contribute valuable data for potential therapeutic insight on the management of CAR-T-associated neurotoxicity. Trial registration: ClinicalTrials.gov identifier: NCT03954106.