Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Mantle Cell Lymphoma Not Previously Treated with a BTK Inhibitor: Primary Analysis from a Phase 2 Study (CITADEL-205)
Authors: Mehta Amitkumar , Trněný Marek , Walewski Jan , Ribrag Vincent , Dartigeas Caroline , Christensen Jacob Haaber , Pane Fabrizio , Rodriguez Guillermo , Taszner Michal , Venugopal Parameswaran , Zilioli Vittorio Ruggero , Zheng Fred , DeMarini Douglas J , Jiang Wei , Zinzani Pier Luigi Luigi 
Published: November 2021

Abstract
Background: Mantle cell lymphoma (MCL) is an aggressive type of non-Hodgkin lymphoma (NHL) and accounts for 6% of all NHL cases in Western countries (Thandra KC. Med Sci. 2021;9:5). First-line treatment options are not curative and most patients (pts) experience relapse (Wu H. Front Oncol. 2020:10:588314; Kumar A. Blood Cancer J. 2019;9:50). Targeted therapies, including Bruton's tyrosine kinase (BTK) inhibitors, are used as second- and later-lines; however, treatment intolerance and failure are common with poor survival outcomes (Epperla N. Hematol Oncol. 2017;35:528-35; Jain P. Br J Haematol. 2018;182:404-11). Thus, novel therapies are needed for pts with relapsed or refractory (R/R) MCL. Parsaclisib is a potent, highly selective, next-generation inhibitor of phosphatidylinositol 3-kinase (PI3K) δ. Here, we report results of the primary analysis of the cohort of BTK inhibitor-naive pts with R/R MCL treated with parsaclisib monotherapy in the open-label, phase 2 study CITADEL-205 (NCT03235544, EudraCT 2017-003148-19).
Methods: Eligible pts were ≥18 years old, had pathologically confirmed MCL with documented cyclin D1 overexpression or t(11;14) translocation, and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Pts must have received 1-3 prior systemic therapies and not had any prior treatment with a BTK and/or PI3K inhibitor. Pts were allocated to receive parsaclisib 20 mg once daily (QD) for 8 weeks followed by 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), overall survival (OS), progression-free survival (PFS), and safety and tolerability. All radiology-based endpoints were confirmed by an IRC.
Results: At data cutoff for the primary analysis (Jan 15, 2021), 108 pts naive to prior BTK inhibitor had been treated (WG, n=31; DG, n=77). Median (range) age was 72.0 (43-90) years, 79.6% of pts were male, 92.6% had ECOG PS ≤1, and median (range) time since initial diagnosis was 3.6 (0.1-20.9) years. Among all pts, 63.9% had received 1 line and 25.9% had received 2 lines of prior systemic therapy (median [range], 1 [1-3]); 31.5% of pts had prior hematopoietic stem cell transplant, and 50.0% had relapsed and 43.5% were refractory to their most recent prior therapy. 78 pts (72.2%) had discontinued treatment; primary reasons were progressive disease in 49 (45.4%) and adverse events in 25 (23.1%) pts. Median (range) treatment duration and follow-up from first dose to data cutoff were 8.3 (0.1-30.0) and 22.9 (11.6-35.9) months for all pts, and 7.9 (1.7-27.4) and 18.2 (11.6-35.9) months for DG, respectively. The ORR (95% CI) was 68.5% (58.9-77.1) for all pts and 70.1% (58.6-80.0) for the DG (Table 1); CRR (95% CI) was 17.6% (10.9-26.1) for all pts and 15.6% (8.3-25.6) for the DG. Among all treated pts with complete or partial response, 89.2% of responses occurred at the first disease assessment. Median (95% CI) DOR was 13.7 (9.0-19.9) months for all pts and 12.1 (9.0-not estimable) months for the DG. Median (95% CI) PFS was 11.99 (8.3-16.9) months for all pts and 13.6 (10.0-16.9) months for the DG. Median OS was not reached.
Among 108 treated pts, treatment-emergent adverse events (TEAEs) occurred in 90.7% (n=98) pts (grade ≥3 in 62.0% [n=67]). The most common TEAEs were diarrhea (34.3%), pyrexia (17.6%), and constipation (13.0%); most common grade ≥3 TEAEs were diarrhea (13.9%) and neutropenia (8.3%). TEAEs leading to dose interruption or dose reduction occurred in 47.2% and 8.3% of all pts, respectively. TEAEs led to treatment discontinuation in 25.0% of all pts; the most common were diarrhea (11.1%), colitis (4.6%), and hypokalemia (2.8%). Serious TEAEs occurred in 42.6% (n=46) of all pts; the most common were diarrhea (9.3%) and colitis (4.6%). Six pts (5.6%) overall experienced fatal TEAEs.
Conclusion: Parsaclisib monotherapy demonstrated a rapid and durable response, had an acceptable safety profile, and was generally well tolerated in BTK inhibitor-naive pts with R/R MCL. These data suggest that parsaclisib could be a potential treatment option for pts with R/R MCL.
Figure 1 Figure 1.

Disclosures
Mehta: Seattle Genetics; Incyte; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics; Incyte; TG Therapeutics: Consultancy; Affirmed; Kite/Gilead; Roche-Genetech; Celgene/BMS; Oncotartis; Innate Pharmaceuticals; Seattle Genetics; Incyte; Takeda; Fortyseven Inc/Gilead; TG Therapeutics; Merck; Juno Pharmaceuticals/Bristol Myers Squibb: Research Funding. Trněný: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; 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; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Walewski: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria; Takeda: Consultancy, 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, Research Funding; roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Servier: Consultancy, Honoraria. Ribrag: Incyte: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Pane: AbbVie; Amgen; Novartis: Other: Travel, accommodation, expenses; Novartis Pharma SAS;: Research Funding; AbbVie; Amgen; Novartis, GSK , Incyte: Consultancy; AbbVie; Amgen; Novartis, GSK, Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, ; Janssen: Other: Travel, Accommodations, ; Jazz Pharmaceuticals: Consultancy, Other: Travel, Accommodations, Speakers Bureau. Rodriguez: Bristol-Myers Squibb; Celgene; EUSA Pharma; Janssen; Roche; Takeda: Consultancy; Bristol-Myers Squibb; Celgene; Janssen; Roche; Takeda: Speakers Bureau. Taszner: Roche, Takeda: Consultancy, Other: Travel. Zilioli: Takeda: Other: travel expenses, accommodation; Roche, Italfarmaco: Consultancy, Honoraria; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau. 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. Zinzani: Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

OffLabel Disclosure:
Investigational PI3Kdelta inhibitor (parsaclisib) for patients with MCL