A PHASE 1 STUDY OF PARSACLISIB IN COMBINATION WITH RITUXIMAB, BENDAMUSTINE + RITUXIMAB, OR IBRUTINIB IN PATIENTS WITH PREVIOUSLY TREATED B-CELL LYMPHOMA (CITADEL-112): PRELIMINARY SAFETY RESULTS

ABSTRACT

Background: Rituximab-based chemoimmunotherapy regimens are backbone treatment (Tmt) for both indolent (follicular [FL], marginal zone [MZL]) and aggressive (diffuse large B-cell [DLBCL], mantle cell [MCL]) B-cell lymphomas. Standard of care (SoC) for relapsed or refractory (R/R) disease includes anti-CD20 in combination with chemotherapy and targeted therapies, such as Bruton's tyrosine kinase inhibitors (eg, ibrutinib) and phosphoinositide 3-kinase (PI3K) inhibitors. Parsaclisib is a potent and highly selective next generation PI3Kδ inhibitor that is currently being investigated in hematological malignancies. Aims: CITADEL-112 (NCT03424122) is an open-label phase 1 study evaluating the safety and tolerability of adding parsaclisib to investigator choice SoC Tmt rituximab (RIT), RIT + bendamustine (BEN), or ibrutinib (IBR) in patients (pts) with R/R B-cell lymphoma. Methods: Enrolled pts were ≥18 years and had histologically confirmed DLBCL, FL, MCL, or MZL, ECOG PS 0-2, were R/R to ≥1 (≥2 for FL) prior systemic therapy, and ineligible for stem cell transplant. 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 (± cycle 2) (Tmt A);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 (Tmt B);or IBR 560 mg QD (Tmt C). Pts received treatment until disease progression, unacceptable toxicity, or withdrawal. Results: At data cutoff (May 14, 2021), 50 pts were treated (16 pts each in Tmt A and C, 18 pts in Tmt B) and 13 pts were ongoing treatment (3 pts in Tmt A, 8 pts in Tmt B, 2 pts in Tmt C). Most pts had received ≥2 prior systemic treatments (81.3%, 61.1%, and 68.8% in Tmt A [range 1-4], B [range 1-4], and C [range 1-7], respectively). The most common reasons for discontinuation were progressive disease (56.3%, 38.9%, and 50.0%) and adverse events (AEs) (12.5%, 11.1%, and 6.3% in Tmt A, B, and C, respectively). One pt in Tmt B experienced a dose-limiting toxicity of grade 4 neutropenia for >14 days. All pts experienced at least 1 treatment-emergent AE (TEAE);in Tmt A, 75.0% had grade ≥3 and 37.5% had serious TEAEs;Tmt B, 83.3% had grade ≥3 and 27.8% had serious TEAEs;and Tmt C, 62.5% had grade ≥3 and 43.8% had serious TEAEs. Common any-grade TEAEs (≥30%) included neutropenia (62.5%), diarrhea (37.5%), and anemia (31.3%) in Tmt A;neutropenia (50.0%), abdominal pain, asthenia, diarrhea, and nausea (each 33.3%) in Tmt B;neutropenia (50.0%) and increased ALT and increased AST (each 37.5%) in Tmt C. Most common grade ≥3 TEAEs (≥15%) were neutropenia (50.0%) and diarrhea (18.8%) in Tmt A, and neutropenia (38.9% and 25.0%) in Tmt B and Tmt C, respectively. Serious TEAEs occurring in >1 pt were COVID-19, diarrhea, and pneumonia (n = 2 each) in Tmt A, and atrial fibrillation (n = 2) in Tmt C. TEAEs with fatal outcome were reported in 2 pts in Tmt A (COVID-19 and COVID-19 pneumonia [n = 1], interstitial lung disease [n = 1]) and 1 pt in Tmt C (COVID-19, acute kidney injury). Parsaclisib dose interruption or dose reduction due to TEAEs occurred in 75.0% and 18.8% of pts, respectively, in Tmt A;66.7% and 27.8% of pts, respectively, in Tmt B;and 56.3% and 18.8% of pts, respectively, in Tmt C. Summary/Conclusion: Parsaclisib 20 mg QD for 8 weeks followed by 20 mg QW can be safely combined with RIT, RIT + BEN, or IBR in pts with R/R B-cell lymphomas. The tolerability profile of the combination regimens was manageable, with no unexpected safety concerns.