Safety and Efficacy of Parsaclisib in Combination with Rituximab, Bendamustine + Rituximab, or Ibrutinib in Patients with Previously Treated B-Cell Lymphoma: Analysis of a Phase 1 Dose-Finding Study (CITADEL-112)

Background: Rituximab (RIT)-based chemoimmunotherapy regimens are backbone treatment for indolent (follicular, marginal zone) and aggressive (diffuse large B-cell, mantle cell) B-cell lymphomas. For relapsed or refractory (R/R) disease, anti-CD20 antibodies can be combined with chemotherapy or targeted therapies, such as inhibitors of Bruton's tyrosine kinase (eg, ibrutinib) and phosphoinositide 3-kinase (PI3K). Parsaclisib is a potent and highly selective next-generation PI3Kδ inhibitor. In a preliminary safety analysis of CITADEL-112 (NCT03424122), an open-label phase 1 study of parsaclisib plus investigator choice standard of care (RIT, RIT + bendamustine [BEN], or ibrutinib [IBR]) in patients (pts) with R/R B-cell lymphoma, manageable tolerability was observed (Sancho JM, et al. HemaSphere 2022;6 Suppl 3:P1102). Here we present updated safety and initial efficacy data from CITADEL-112.

Methods: Enrolled pts were ≥18 years and had histologically confirmed DLBCL, FL, MCL, or MZL, ECOG performance status of 0-2, were R/R to ≥1 (≥2 for FL) prior systemic therapy, and ineligible for stem cell transplantation. Pts received parsaclisib 20 mg orally once daily (QD) for 8 weeks then 20 mg once weekly (QW) in combination with either RIT 375 mg/m² IV QW for 4 doses in cycle 1 (± an additional 4 QW doses) in Cohort A, or RIT 375 mg/m² IV on day 1 + BEN 90 mg/m² on day 1 and day 2 of each 28-day cycle for ≤6 cycles in Cohort B, or IBR 560 mg QD in Cohort C. A 3+3 design with dose de-escalation identified the maximum tolerated dose of QD parsaclisib within each treatment regimen independently. Pts received treatment until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was safety and tolerability. Investigator-determined objective response rate (ORR) and duration of response (DOR) were exploratory endpoints.

Results: At data cutoff (January 14, 2022), 50 pts were treated (16 pts each in Cohorts A and C, 18 pts in Cohort B) and 5 pts were ongoing treatment (all in Cohort B). Most pts had received ≥2 prior systemic treatments; the most common disease subtypes were FL in Cohort A and DLBCL in Cohorts B and C (Table 1). Median (range) dose of QD parsaclisib was 20.0 (13.3-20.0), 17.9 (2.8-20.0), and 20.0 (7.1-20.0) mg/day in Cohorts A, B, and C, respectively, and median (range) overall duration (QD+QW) of parsaclisib treatment was 5.1 (0.5-22.9), 9.3 (0.5-33.7), and 9.3 (0.6-37.7) months. The most common reasons for discontinuation were progressive disease (75.0%, 44.4%, and 56.3% in Cohorts A, B, and C, respectively) and adverse events (AEs; 12.5%, 16.7%, and 6.3%, respectively).

One pt in Cohort B experienced a dose-limiting toxicity of grade 4 neutropenia for 14 days. All pts experienced ≥1 treatment-emergent AE (TEAE); most common any-grade and grade ≥3 TEAEs are shown in Table 2. Grade ≥3 and serious TEAEs were experienced by 75.0% and 37.5% of pts, respectively, in Cohort A, 88.9% and 33.3% of pts in Cohort B, and 62.5% and 50.0% of pts in Cohort C. Serious TEAEs occurring in >1 pt were COVID-19, diarrhea, and pneumonia (n=2 each) in Cohort A, and atrial fibrillation (n=2) in Cohort C. TEAEs with fatal outcome occurred in 2 pts in Cohort A (COVID-19 and COVID-19 pneumonia [n=1], interstitial lung disease [n=1]) and 1 pt in Cohort C (COVID-19 pneumonia, septic shock, acute kidney injury, respiratory failure). TEAEs leading to discontinuation of parsaclisib occurred in 2 pts in Cohort A (diarrhea, streptococcal pneumonia [n=1 each]), 3 pts in Cohort B (neutropenia, maculopapular rash [n=1 each], diarrhea and renal failure [n=1]), and 1 pt in Cohort C (thrombocytopenia). TEAEs leading to parsaclisib dose interruption or reduction occurred in 75.0% and 18.8% of pts, respectively, in Cohort A, 66.7% and 27.8% of pts in Cohort B, and 56.3% and 18.8% of pts in Cohort C.

ORRs (95% confidence interval [CI]) were 81.3% (54.4-96.0), 55.6% (30.8-78.5), and 50.0% (24.7-75.3) for Cohorts A, B, and C, respectively; 18.8%, 33.3%, and 12.5% of pts had a complete metabolic response/complete response, respectively (Table 1). Median (95% CI) DOR was 5.2 months (1.7-15.8) for Cohort A, not reached (12.1-not evaluable [NE]) for Cohort B, and 13.4 months (0.7-NE) for Cohort C.

Conclusion: Parsaclisib 20 mg QD for 8 weeks followed by 20 mg QW in combination with RIT, RIT+BEN, or IBR in pts with R/R B-cell lymphomas had a manageable tolerability profile with no unexpected safety concerns, and demonstrated promising efficacy.

Sancho:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eli Lilly & Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi Biomedicine: Consultancy, 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; Kern Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees. Abrisqueta:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: 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; Sandoz: Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cordoba:Celgene: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Research Funding; Kite: Consultancy, Speakers Bureau; Takeda: Consultancy; GenMab: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Honoraria, Speakers Bureau; BeiGene: Consultancy; Lilly: Consultancy; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau. Liu:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Rappold:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Langmuir:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Lopez-Guillermo:Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Celgene, Gilead Sciences, Roche, Incyte: Membership on an entity's Board of Directors or advisory committees.

Parsaclisib is an investigational drug being evaluated in patients with B-cell lymphomas.