Background: B-cell malignancies evade apoptosis by overexpressing BCL-2 proteins. Approved BCL-2i venetoclax requires a slow dose ramp-up to limit risk of tumor lysis syndrome (TLS) and has been associated with severe neutropenia. Investigational single-agent lisaftoclax is a novel, oral BCL-2i active against hematologic malignancies (HMs), with potentially synergistic antitumor effects when combined with other agents in B-cell malignancies. Methods: The aim of this multicenter open-label study was to evaluate dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), efficacy, pharmacokinetics (PK), and pharmacodynamics of lisaftoclax in pts with R/R CLL/SLL (per 2008 iwCLL NCI-WG guidelines). Lisaftoclax was administered orally once daily at 3 dose cohorts (400, 600, or 800 mg) every 28 days, with 15 pts in each cohort. Results: As of the data cutoff date of January 25, 2022, 45 pts had been enrolled, with a median (range) age of 58 (38-80) years. DLT and MTD were not observed. The preliminary PK profile showed that exposures increased with lisaftoclax doses from 400 to 800 mg (average half-life: 4.2-6.6 hours). A total of 42 pts experienced any-grade treatment-related adverse events (AEs), including neutropenia (55.6%); anemia (42.2%); decreased leukocyte count (40%); thrombocytopenia (37.8%); lowered lymphocyte count (17.8%); hyperuricemia (31.1%); hypokalemia (24.4%); increased blood bilirubin (22.2%); hypertriglyceridemia (20%); diarrhea (20%); hyperphosphatemia, hypocalcemia, and decreased weight (15.6% each); increased AST (15.6%) and blood LDH (13.3%); pyrexia; and increased ALT and blood creatinine (11.1% each). A total of 28 (62.2%) pts experienced grade ≥ 3 AEs and 13 (28.9%) serious AEs. Of these, 25 (55.6% of total) and 9 (20%) were related to lisaftoclax, and 14 (31.1%) led to treatment discontinuation. One clinical TLS was reported. With a median (range) treatment of 7 (1-17) cycles and median (range) time to response of 1 (1-13) cycles, 1 of 41 evaluable pts with CLL experienced complete response (CR) and 27 with CLL/SLL achieved partial response (PR), for an objective response rate (ORR) of 68.29%. The RP2D of lisaftoclax as monotherapy was determined as 600 mg. Conclusions: BCL-2i lisaftoclax was well tolerated up to 800 mg/day. There were no significant new or unmanageable safety findings, and the ORR was 68.29%. Lisaftoclax may offer a treatment alternative for pts with R/R HMs, with a daily ramp-up schedule that may be more convenient and “user friendly.”Clinical trial information: NCT04494503.