Phase I Study of Duvelisib Study for Cytokine Release Syndrome Prophylaxis in Patients Receiving Chimeric Antigen Receptor T Cell Treatment for Non-Hodgkin Lymphoma

CAR T-cell therapy toxicities, including CRS and immune cell-associated neurotoxicity syndrome (ICANS), can be significant and effective prophylactic strategies are needed. Duvelisib is an oral inhibitor of phosphoinositide 3-kinases (PI3K)-γ/δ and is FDA-approved therapy for CLL/NHL with an established safety profile. Pre-clinical work from our group has demonstrated that PI3K inhibition may prevent CRS.We are conducting a Phase I, 3 + 3 dose escalation and two-arm dose expansion, trial of duvelisib for CRS prophylaxis in patients (pts) undergoing standard-of-care (SoC) CAR T-cell therapy for non-Hodgkin lymphoma (NHL) (NCT05044039). Herein, we report data from the dose escalation cohort and the first dose expansion cohort, treated with duvelisib BID from day -2 to +28. The primary outcome was safety and tolerability. Secondary outcomes included the incidence and severity of CRS and ICANS, overall response rate (ORR), and progression-free survival (PFS).18 pts are included in this analysis, including 6 pts in dose escalation and 12 of 14 planned pts in dose expansion cohort A, with full enrollment of cohort A expected prior to presentation. Median age was 69 years (range: 28 – 79). Diagnoses included DLBCL (14), MCL (2), FL (1) and PBMCL (1). Delivered CAR-T cell therapies included: axi-cel (10), liso-cel (5), brexu-cel (2) and tisa-cel (1). 3 pts were enrolled on dose level 1 (15 mg BID) and 3 on dose level 2 (25 mg BID). No pts experienced a dose-limiting toxicity (DLT) during dose escalation and 25 mg BID was selected as the recommended dose for expansion. 78% of pts experienced CRS at a median of 5 days following cell infusion (range: 2 – 9) (Figure 1A). All CRS was grade 1 (86%) or 2 (14%), with no grade 3 – 4. The median duration of CRS was 1 day (range: 1 – 7). ICANS occurred in 44% of pts at a median of 7 days (range: 4 – 10). 11% of pts experienced grade 3-4 ICANS. The median duration of ICANS was 5 days (range: 1 – 11). 3 pts with ICANS received prolonged courses of steroids for recurrent weakness, failure to thrive and/or worsening psychiatric symptoms. Toclizumab was given to 77% of pts for treatment of CRS and 50% received steroids for CRS and/or ICANS. All 18 pts were evaluable for disease response to CAR T-cell therapy. At day +30, ORR was 72% (13/18) with 50% achieving complete response (CR). At day 180, Best response was CR in 72% of pts and stable disease in 17% of pts. Median PFS was 144 days, with 59% progressing during follow-up. In 17 evaluated pts, CAR T-cell expansion by flow cytometry was robust at all dose levels, consistent with prior reports (Figure 1B).Preliminary data from this phase I study suggests that duvelisib as CRS prophylaxis after SoC CAR T-cell therapy is safe and tolerable and may prevent grade 3-4 CRS and delay the onset of CRS.