THE PI3Kδ INHIBITOR ME‐401 ± RITUXIMAB IN RELAPSED/REFRACTORY (R/R) FOLLICULAR LYMPHOMA (FL), CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), AND SMALL LYMPHOCYTIC LYMPHOMA (SLL)

Background: ME-401, a potent and selective oral PI3kδ inhibitor, is being evaluated in a Phase 1b study in patients (pts) with R/R B-cell malignancies (NCT02914938). 70 pts were treated as of January 2019 and we report here results in pts with FL and CLL/SLL. Methods: Adult pts with ECOG performance status ≤2, no prior PI3K therapy, and progression of disease (POD) after ≥1 prior therapy were initially enrolled in a dose escalation phase (60-180 mg) then in 60 mg expansion cohorts 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 POD or unacceptable toxicity. Patients on CS were switched to an intermittent schedule (IS) on days 1-7 of a 28-day cycle in Cycle 3 (n = 20) or in Cycles ≥4 (n = 18) of CS. Toxicity on CS was managed by switch to IS and POD on IS was managed by switch to CS. Results: 61 pts, 48 with FL and 13 with CLL/SLL received ME-401 alone (n = 48) or with rituximab (n = 13). Median age 65 yrs. (range: 38-81), median prior therapies 2 (range: 1-10), 33 pts had ≥2 prior therapies, and 25 FL pts were POD24. In CLL/SLL pts, IgVH was unmutated in 7, mutated in 2, and not evaluated in 4. 39 pts (64%) remain on therapy with a median follow-up of 12.3 months (range: 1.6-25.1) and 22 pts discontinued: 9 POD, 5 adverse events (AEs), 5 withdrew consent, and 3 were referred to stem cell transplant in CR. Delayed (i.e., Cycle >2) grade 3 immune related AEs (irAEs), primarily diarrhea/colitis and rash, were reported in 13/41 pts (31.7%) on CS and 2/20 pts (10%) who had switched to IS in Cycle 3, with irAEs noted 15 and 18 days after switch to IS. 6 pts with grade 3 irAEs had a drug holiday and corticosteroid therapy then resumed ME-401 on IS without recurrence of the irAE. Objective responses were achieved in 33/43 evaluable FL pts (77%) and 11/11 evaluable CLL/SLL pts (100%). In FL, response rate was 77% with ME-401 alone (including 29% CR by Lugano criteria), 78% with ME-401 plus rituximab, 91% in POD24, and 75% in pts who had ≥2 prior therapies. Of 38 pts switched to IS, 33 (87%) remain on therapy (median: 14.5 months), 26 on IS and 7 who switched back to CS due to POD on IS, 3 pts discontinued due to persistent POD after switch to CS, and 2 pts withdrew. Conclusions: ME-401 achieves a high rate of durable responses in R/R FL and CLL/SLL. IS appears to reduce the incidence of irAEs and maintain responses. POD on IS can be successfully retreated by reverting to CS. A global study is enrolling pts with R/R FL randomized to ME-401 by IS or CS after 2 cycles of CS, with switch to IS for irAEs and switch to CS if POD on IS (NCT03768505). Keywords: chronic lymphocytic leukemia (CLL); follicular lymphoma (FL); PI3K/AKT/mTOR. Disclosures: Zelenetz, A: Consultant Advisory Role: MEI Pharma, Amgen, Astra-Zeneca, Bayer, Celgene, DAVA oncology, Genentech/Roche, Gilead, Janssen, Karyopharm, Morphosys, Novartis, Pharmacyclics/AbbVie, Pfizer, Verastem. Reddy, N: Research Funding: AbbVie, BMS, Adaptive Biotechnoligies, Gilead, Genentech. Stathis, A: Research Funding: Amgen, Bayer, Novartis, Pfizer, Roche, MEI Pharma. Soumerai, J: Consultant Advisory Role: Verastem; Research Funding: Roche/Genentech, BeiGene, TG Therapeutics. LLorin-Sangalang, J: Employment Leadership Position: MEI Pharma. Pagel, J: Consultant Advisory Role: Pharmacyclics, Gilead, Astra Zeneca.