A Phase 1/1b Study of Parsaclisib Plus Standard Immunochemotherapy for Newly Diagnosed High-Risk Diffuse Large B-Cell Lymphoma

Background: Immunochemotherapy is the current standard-of-care frontline therapy for diffuse large B-cell lymphoma (DLBCL). Our group previously reported that addition of the mTOR inhibitor everolimus to R-CHOP resulted in excellent efficacy in the Alliance N1085 trial (Witzig TE et al, Blood Cancer J, 2017, 7(6):e576), with 23 of 24 patients achieving event-free survival at 24 months (EFS24), supporting further investigation of PI3K/mTOR targeting in DLBCL. New insights into molecular classification of DLBCL suggest that multiple genetic subtypes of DLBCL (eg, MCD, BN2, ST2, and EZB per LymphGen classification) may be susceptible to PI3K/mTOR targeting. Therefore, we conducted a phase 1/1b trial to investigate the safety and efficacy of combination therapy with a novel PI3K inhibitor parsaclisib and standard immunochemotherapy. Methods: Adult patients with newly diagnosed DLBCL were eligible if any of the following was present: 1) non-GCB subtype per the Hans algorithm; 2) protein expression of either MYC (≥40%) or BCL2 (≥50%) by immunohistochemistry; or 3) MYC rearrangement by FISH. Patients with high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements were also eligible. Phase 1 followed a 3+3 design to determine the maximum tolerated dose (MTD) of parsaclisib (plus R-CHOP) to be used in Phase 1b (dose expansion). The primary efficacy endpoint in phase 1/1b was complete response (CR) rate by PET. A polatuzumab vedotin (Pola) safety lead-in cohort was added later to explore the safety and efficacy of parsaclisib (at MTD) plus Pola-R-CHP. Results: From July 2020 to May 2023, 50 patients were enrolled; 1 patient withdrew consent before study treatment and was excluded from this analysis. Nine patients were treated in Phase 1, 33 in Phase 1b, and 7 in the Pola cohort. The median age at diagnosis was 66 years (range 20-86), and 20 (41%) were female. Two (4%) patients had ECOG PS ≥2, 26 (53%) had elevated LDH, 19 (39%) had >1 extranodal site, 37 (76%) had stage III/IV, and 25 (51%) had high-intermediate or high-risk International Prognostic Index (3-5). 23 (47%) had non-GCB subtype, 23 (46.9%) had MYC or BCL2 single expression, 21 (42.9%) had MYC/BCL2 double expression, and 6 (12%) had MYC rearrangement (2 with BCL2 and/or BCL6 rearrangements). In Phase 1, 3 patients were treated at dose level 1 (parsaclisib 20 mg QD, d1-10) and 6 at dose level 2 (parsaclisib 20 mg QD, d1-14). No dose limiting toxicity was observed. Therefore, dose level 2 for parsaclisib was the MTD and was used in Phase 1b. In the Pola cohort (n=7), only 1 of 6 evaluable patients experienced significant toxicity (grade 3 diarrhea). Among all 49 patients, the most common treatment-related adverse event (TRAE) of any grade included neutropenia (83.7%), thrombocytopenia (79.6%), leukopenia (77.6%), lymphopenia (71.4%), anemia (71.4%), nausea (63.3%), fatigue (40.8%), peripheral sensory neuropathy (36.7%), constipation (24.5%), and diarrhea (22.4%), and the most common grade ≥3 TRAE included neutropenia (71.4%), leukopenia (69.4%), lymphopenia (49.0%), thrombocytopenia (20.4%), anemia (16.3%), febrile neutropenia (6.1%), and diarrhea (6.1%). In Phase 1/1b (n=42), the overall response rate (ORR) to parsaclisib plus R-CHOP was 97.6%, and the CR rate was 90.5%. After a median follow-up of 28.5 months (95% CI 27.7-32.7), the estimated 2-year progression-free survival (PFS) rate was 84.6% (95% CI 73.9-96.8), and the estimated 2-year overall survival (OS) rate was 95.1% (95% CI 88.7-100.0). In the Pola cohort, the ORR to parsaclisib plus Pola-R-CHP was 100% and the CR rate was 100%. After a median follow-up of 15.6 months (95% CI 13.5-NE), 1 patient had disease relapse at 11.95 months, and all patients were alive. Conclusions: Addition of the PI3K inhibitor parsaclisib to R-CHOP or Pola-R-CHP immunochemotherapy is considered safe in patients with newly diagnosed DLBCL. Combination of parsaclisib and standard immunochemotherapy resulted in high ORR and CR rate and encouraging preliminary PFS and OS outcomes patients with high-risk DLBCL. These data support further investigation of PI3K/mTOR targeting in newly diagnosed DLBCL in future trials.