The PI3K Inhibitor ME-401 ± Rituximab in Relapsed/Refractory (R/R) Follicular Lymphoma (FL), Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Purpose of the Study: ME-401, a potent and selective oral PI3k inhibitor, is being evaluated in a Phase 1b study in patients (pts) with R/R B-cell malignancies (NCT02914938). 101 pts were treated as of August 2019. We report here preliminary results of the safety and efficacy of 71 pts with FL and CLL/SLL.

Summarized Description of the Project: Adults with ECOG perfor- mance status 2, no prior PI3K therapy and  disease  progression (PD) after 1 prior therapy were initially enrolled in a dose escalation phase (60-180 mg ME-401), and at 60 mg daily as monotherapy or in combination with rituximab (375 mg/m2 x 8 doses in 6 months). ME- 401 was given initially on a daily continuous schedule (CS) until PD or unacceptable toxicity. An intermittent schedule (IS) was subsequently developed with daily continuous dosing for  2 cycles, followed by 7 days on and 21 days off therapy every 28-day cycle. Toxicity on CS was managed by a switch to IS. Patients who developed PD on IS could switch to CS.

Results: 71 pts, 54 with FL (CS=31, IS=23) and 17 with CLL/SLL (CS=9, IS=8) received ME-401  alone  (n  =  52)  or  with rituximab (n = 19). Median age was 65 years (range 38-82), median number of prior therapies 2 (range 1-10), 40 (56%) pts had 2 prior therapies. In CLL/SLL pts, IgVH was unmutated in 9/11 (82%). 45 pts (63%) remain on therapy with a median follow-up of 7 months (range 0.9-26.9+) and 26 pts discontinued: 10 (14%) due to PD, 6 (8%) due to adverse events (AEs), 4 (6%) were referred to stem cell transplant and 6 (8%) withdrew consent. The incidence of grade 3 adverse events of special interest (AESI) was: diarrhea 8/40 pts (20.0%) in CS and 3/31 pts (9.7%) in IS, rash 4/40 pts (10%) in CS and 0/31 (0%) in IS, AST/ALT increased 3/40 pts (7.5%) in CS and 1/31 pts (3.2%) in IS, pneumonia 5/40 (12.5%) in CS and 1/31 (3.2%) in IS and mucositis 1/40 (2.3%) in CS and none in IS. Objective responses achieved in 40/50 evaluable FL pts (80%), 79% with ME-401 alone, 83% with ME-401 plus rituximab. Objective responses in 14/14 evaluable pts (100%) with CLL/SLL, observed in monotherapy and in combination with rituximab. The ORR was 80% in FL (75% IS, 83% CS) and 100% CLL/SLL. 55 pts received ME-401 on intermittent dosing (31 IS and 24 CS switched to IS in cycle 4). 20/55 pts (36%) lost tumor control while on IS and switched back to daily dosing: 14/20 (70%) were able to continue treatment on CS with a median follow up of 3 months (range 1-14+), 5 (25%) discontinued due to PD, and 1 (5%) was referred to transplant.

Conclusion: ME-401 achieved a high rate of response in R/R FL and CLL/SLL. IS appears to reduce the incidence of AESI by more than 50% and response to therapy is maintained. PD on IS can be sal- vaged by reverting to CS. A global study is currently enrolling pts with R/R FL randomized to ME-401 evaluating the CS and IS (NCT03768505).