A phase 2 study of the PI3Kδ inhibitor parsaclisib in relapsed and refractory marginal zone lymphoma (CITADEL-204)

Parsaclisib, a potent and highly selective PI3Kδ inhibitor, has shown clinical benefit in patients with relapsed or refractory (R/R) B-cell lymphomas. The phase 2 CITADEL-204 study (NCT03144674, EudraCT 2017-000970-12) assessed efficacy and safety of parsaclisib in BTK inhibitor-experienced (cohort 1) or BTK inhibitor-naive (cohort 2) patients with R/R marginal zone lymphoma (MZL). Patients aged ≥18 years with histologically confirmed R/R MZL, treated with ≥1 prior systemic therapy (including ≥1 anti-CD20 antibody) received parsaclisib 20 mg once daily (QD) for 8 weeks then 20 mg once weekly (weekly dosing group [WG]) or parsaclisib 20 mg QD for 8 weeks then 2.5 mg QD (daily dosing group [DG]); DG was selected for further assessment. Primary endpoint of the study was objective response rate (ORR). Owing to slower than expected recruitment, cohort 1 was closed with 10 patients (WG: n = 4; DG: n = 6) enrolled. Based on a planned interim analysis in cohort 2, the futility boundary was not crossed and enrollment continued to study completion. At data cut-off (Jan 15, 2021), 100 patients were enrolled and treated in cohort 2 (WG: n = 28; DG: n = 72). In the DG, the ORR (95% confidence interval [CI]) was 58.3% (46.1-69.8), with a complete response rate (95% CI) of 4.2% (0.9-11.7); the lower bound of the ORR 95% CI exceeded the protocol defined threshold of 40%. The median (95% CI) duration of response was 12.2 months (8.1-17.5) and progression-free survival was 16.5 months (11.5-20.6); median overall survival was not reached. The most common treatment-emergent adverse events (TEAEs) among all patients were diarrhea (47.0%), cough (23.0%), and rash (18.0%); the most common grade ≥3 TEAEs included diarrhea (12.0%), neutropenia, and pneumonia (9.0% each). TEAEs led to dose interruptions, reductions, and discontinuations in 56.0%, 16.0%, and 29.0% of all patients, respectively. Durable responses and overall manageable safety profile were demonstrated in patients with R/R MZL treated with parsaclisib monotherapy.