Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Follicular Lymphoma: Primary Analysis from a Phase 2 Study (CITADEL-203)
Authors: Lynch Ryan C. , Avigdor Abraham , McKinney Matthew S , Paneesha Shankara , Wahlin Björn , Hrom John S , Cunningham David , Morley Nicholas , Canales Miguel , Bastos-Oreiro Mariana , Belada David , Devizzi Liliana , Zheng Fred , DeMarini Douglas J , Jiang Wei , Trněný Marek 
Published: November 2021

Abstract
Background: Follicular lymphoma (FL) is the second most common form of non-Hodgkin lymphoma (NHL) in Western countries, accounting for 20-30% of all NHLs (Hübel K. Hemasphere. 2020;4:e317). While most patients (pts) respond well to first-line therapy, they typically experience frequent relapses and progressively shorter duration of response with subsequent lines of therapy (Batlevi CL. Blood Cancer J. 2020;10:74; Rivas-Delgado A. Br J Haematol. 2019;184:753-9), and increasingly refractory disease with limited treatment options. Thus, there is an unmet need for effective treatment options for pts with relapsed or refractory (R/R) FL. Parsaclisib is a potent, highly selective, next-generation phosphatidylinositol 3-kinase (PI3K)δ inhibitor. Here we report results of the primary analysis of CITADEL-203 (NCT03126019, EudraCT 2017-001624-22), a phase 2, multicenter, open-label study of parsaclisib monotherapy in R/R FL.
Methods: Eligible pts were ≥18 years of age, had histologically confirmed R/R FL (grade 1, 2, or 3a), had received ≥2 prior systemic therapies (not including PI3K inhibitors or Bruton's kinase inhibitors), had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, and were ineligible for hematopoietic stem cell therapy. Pts were allocated to receive 20 mg parsaclisib once daily (QD) for 8 weeks, followed by parsaclisib either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg QD (daily-dosing group [DG]). Prophylaxis for Pneumocystis jirovecii pneumonia was required. The primary endpoint was objective response rate (ORR) as determined by an independent review committee (IRC); secondary endpoints included complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability. All radiology-based endpoints were confirmed by an IRC.
Results: At data cutoff for the primary analysis (Jan 15, 2021), 126 pts (WG, n=23; DG, n=103) had been treated. The median (range) age was 67.5 (40-88) years, 55.6% of pts were male, and majority (93.7%) of pts had an ECOG PS ≤1. The median (range) time since initial diagnosis was 5.95 (0.2-32.2) years. 54.0% of pts had received 2 lines and 27.8% had received 3 lines of prior systemic therapy (median [range], 2 [1-8]); 41.3% of pts had relapsed disease and 49.2% were refractory to their most recent prior therapy. 87 pts (69.0%) had discontinued treatment, primarily due to progressive disease (36.5%) or adverse events (21.4%). The median (range) treatment duration and follow-up from first dose to data cutoff were 8.5 (0.5-27.2) and 20.6 (5.7-34.1) months for all treated pts, and 8.4 (0.8-27.2) and 17.6 (5.7-33.1) months for the DG. The ORR (95% CI) was 75.4% (66.9-82.6) for all treated pts and 77.7% (68.4-85.3) for the DG (Table 1); CRR (95% CI) was 18.3% (11.9-26.1) for all pts and 19.4% (12.3-28.4) for the DG. Among all treated pts with complete or partial response, 73.7% of responses occurred at the first disease assessment. Median (95% CI) DOR was 14.7 (12.0-20.3) months for all pts and 14.7 (10.4-not estimable [NE]) months for the DG. Median (95% CI) PFS was 14.0 (11.3-19.6) months for all pts and 15.8 (11.0-NE) months for the DG. Median OS was not reached.
Among 126 treated pts, treatment-emergent adverse events (TEAEs) occurred in 97.6% (n=123) of pts (grade ≥3 in 58.7% [n=74]). The most common TEAEs were diarrhea (38.1%), nausea (24.6%), and cough (22.2%); most common grade ≥3 TEAEs included diarrhea (11.9%) and neutropenia (10.3%). TEAEs leading to dose interruption or dose reduction occurred in 46.8% and 17.5% of pts, respectively. TEAEs led to treatment discontinuation in 23.8% of all pts; the most common were diarrhea (7.1%), colitis (4.0%), pneumonitis, and rash (2.4% each). Serious TEAEs were experienced by 45.2% (n=57) of pts overall; the most common reported among all pts were diarrhea (7.1%), colitis (6.3%), and pneumonitis (2.4%). Two pts (1.6%) overall experienced a fatal TEAE.
Conclusions: Parsaclisib monotherapy demonstrated a rapid and durable response, had an acceptable safety profile, and was generally well tolerated in pts with R/R FL. These data suggest that parsaclisib could be a favorable treatment option for pts with R/R FL.
Figure 1 Figure 1.

Disclosures
Lynch: Morphosys: Consultancy; Takeda: Research Funding; Incyte: Research Funding; TG Therapeutics: Research Funding; Rhizen: Research Funding; Bayer: Research Funding; Juno: Research Funding; Cyteir: Research Funding; Genentech: Research Funding. Avigdor: Pfizer: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; BMS: Research Funding; Janssen: Research Funding; Takeda: Consultancy, Honoraria. McKinney: ADC Therapeutics: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy; Novartis: Research Funding; Nordic Nanovector: Research Funding; Molecular Templates: Consultancy, Research Funding; Kite/Gilead: Honoraria, Speakers Bureau; Incyte: Research Funding; Genetech: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Epizyme: Consultancy; BTG: Consultancy; Beigene: Research Funding; Verastem: Consultancy. Paneesha: AbbVie: Honoraria; Bristol Myers Squibb: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria. Wahlin: Gilead Sciences: Research Funding; Roche: Consultancy, Research Funding. Cunningham: Celgene: Research Funding; OVIBIO: Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; 4SC: Research Funding; Eli Lilly: Research Funding; Clovis Oncology: Research Funding; MedImmune: Research Funding; AstraZeneca: Research Funding; Roche: Research Funding. Morley: AbbVie; Takeda: Other: Conference support; Janssen: Honoraria; Kite: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference support. Canales: Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Sandoz: Honoraria, Speakers Bureau; Sanofi: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy; Gilead/Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Eusa Pharma: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; iQone: Honoraria. Bastos-Oreiro: Takeda: Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Kite: Speakers Bureau; Gilead: Honoraria; BMS-Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Honoraria, Research Funding, Speakers Bureau. Belada: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Celgene: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses, Research Funding. Zheng: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. DeMarini: Incyte: Current Employment, Current equity holder in publicly-traded company. Jiang: Incyte: Current Employment, Current equity holder in publicly-traded company. Trněný: Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Amgen: Consultancy, Honoraria; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Celgene: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure:
Investigational PI3K delta inhibitor (parsaclisib) for patients with FL