Initial results of a dose escalation study of a selective and structurally differentiated PI3Kδ inhibitor, ME-401, in relapsed/refractory (R/R) follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

7519 Background: ME-401, an oral tyrosine kinase inhibitor highly selective for PI3Kδ was studied in a phase 1b trial for patients (pts) with R/R FL or CLL/SLL. The starting dose was based on pharmacokinetic and pharmacodynamic data from a study in healthy volunteers. Methods: Eligible adult pts had ECOG ≤2, no prior PI3K therapy, and no prior progression of disease (POD) on BTK therapy. ME-401 was given once daily on days 1-28 of 28-day cycle until POD or unacceptable toxicity. All pts received PJP prophylaxis and CMV monitoring was mandatory. At least 6 evaluable pts were treated at each dose level, with option to expand to 12 pts for efficacy assessment. Dose limiting toxicities (DLT) were assessed up to Day 56. Response was assessed after Cycles 2 and 6. Results: 31 pts (21 FL, 10 CLL/SLL) received ME-401 and 30 were evaluable for DLT: 12 at 60 mg, 12 at 120 mg, and 6 at 180 mg. Median age was 65 (range: 47-79), 14/30 (47%) pts received ≥2 prior therapies, and 9/21 (43%) pts with FL had POD < 24 months after initial chemoimmunotherapy (POD24). Of 29 pts evaluable for response, the overall objective response rate was 83% (24/29), with 75% (15/20) in FL, including 9/9 (100%) with POD24, and 100% (9/9) in CLL/SLL, occurring by Cycle 2 in 20/24 responders. No DLTs were reported and escalation above 180 mg was closed given frequent responses across lower dose levels. With a median follow-up of 20 weeks (range: 2-53 weeks) 3 pts had POD at 8, 14 and 17 weeks after starting therapy. Five pts discontinued MEI-401 due to adverse events (AEs): rash (n = 3), colitis (n = 1), and cardiomyopathy (n = 1), and 2 pts discontinued for personal reasons. Most common AEs (all grades/grade ≥3) were diarrhea (32%/16%), fatigue (29%/0%), cough (29%/0%), rash (29%/10%), and nasal congestion (26%/0%). All grade ≥3 AEs were reported in Cycle 3 or later. Conclusions: ME-401 was well tolerated with high early response rates among R/R FL and CLL/SLL pts. No DLTs were reported. An alternative dosing (ME-401 days 1-7 of 28-day cycle starting with Cycle 3) is being evaluated, including dosing ME-401 at 45 mg and at 60 mg in combination with rituximab. Clinical trial information: NCT02914938.