BACKGROUND: Parsaclisib is a potent and highly selective PI3Kδ inhibitor that has shown clinical benefit in patients with relapsed/refractory (R/R) B-cell malignancies. In this phase 2 study (CITADEL-205; NCT03235544, EudraCT 2017-003148-19), the efficacy and safety of parsaclisib was evaluated in patients with R/R mantle cell lymphoma (MCL). METHODS: Patients ≥18 years old with pathologically confirmed R/R MCL and prior treatment with 1-3 systemic therapies, with (cohort 1) or without (cohort 2) previous Bruton kinase inhibitor (BTKi) treatment, received oral parsaclisib 20 mg once-daily (QD) for 8 weeks, then either parsaclisib 20 mg once-weekly (weekly dosing group [WG]) or parsaclisib 2.5 mg QD (daily dosing group [DG]). The primary endpoint was objective response rate (ORR). FINDINGS: At the primary analysis data cutoff on January 15, 2021, 53 patients in cohort 1 (BTKi-experienced) (WG, n = 12; DG: n = 41) and 108 patients in cohort 2 (BTKi-naive) (WG, n = 31; DG: n = 77) had received parsaclisib monotherapy. The BTKi-experienced cohort was closed after an interim analysis demonstrated limited clinical benefit. In the BTKi-naive cohort, the ORR (95% CI) for DG (dosing selected for further study) was 70.1% (58.6%-80.0%), with a complete response rate (95% CI) of 15.6% (8.3%-25.6%) and a median duration of response (95% CI) of 12.1 (9.0-not evaluable) months. Treatment-emergent adverse events (TEAEs) occurred among 90.7% (98/108) of all treated patients in the BTKi-naive cohort. Grade ≥3 TEAEs occurred among 62.0% (67/108) of patients, including diarrhoea (13.9%, 15/108) and neutropenia (8.3%, 9/108). Parsaclisib interruption, reduction, or discontinuation due to TEAEs occurred among 47.2% (51/108), 8.3% (9/108), and 25.0% (27/108) of patients, respectively. Fatal TEAEs were experienced by six patients and determined to be treatment-related in one patient. INTERPRETATION: Parsaclisib, a potent, highly selective, PI3Kδ inhibitor demonstrated meaningful clinical benefits and a manageable safety profile (25.0% discontinuation rate, low incidences of individually reported grade ≥3 or serious adverse events) in R/R MCL patients with no prior BTKi therapy. Limited clinical benefit was observed with parsaclisib monotherapy in patients who had previously received BTKi treatment. Future development of PI3K inhibitors for NHL will require further investigation of dose optimisation to improve safety and long-term survival. FUNDING: Incyte Corporation.

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