Safety, tolerability, and pharmacokinetics of lisaftoclax (APG-2575)-based therapy in patients with chronic lymphocytic leukemia: Phase 1b/2 study.

BACKGROUND

Despite recent chronic lymphocytic leukemia (CLL) treatment advances, resistance and intolerance are challenges. Lisaftoclax is a selective, small-molecule oral BCL-2 inhibitor.

METHODS

Lisaftoclax was administered with initial daily dose ramp-up (5-7 days depending on the target dose), followed by daily dosing as monotherapy, plus six 28-day cycles of rituximab or continuous acalabrutinib (ClinicalTrials.gov: NCT04215809). The primary endpoints comprised safety/tolerability (phases 1b and 2) and efficacy (phase 2), while the pharmacokinetic profile was a secondary endpoint.

FINDINGS: Of 176 patients, 154 (87.5%) had relapsed/refractory and 22 (12.5%) treatment-naive CLL. Five patients (2.8%) experienced tumor lysis syndrome (TLS) (2 clinical and 3 laboratory). Any-grade treatment-emergent adverse events (TEAEs) included neutropenia in 67 patients (38.1%), diarrhea or anemia in 51 (29.0%), and COVID-19 in 63 (35.8%). Grade ≥3 cytopenias occurred in 53 patients (30.1%) with neutropenia and 15 (8.5%) with thrombocytopenia. No treatment-related discontinuations or deaths occurred. The overall response rate (ORR) was 67.4% (29/43) with lisaftoclax monotherapy, 84.6% (33/39) with lisaftoclax-rituximab, and 97.7% (85/87) with lisaftoclax-acalabrutinib. In the lisaftoclax-acalabrutinib cohort, this included 22 patients who were treatment naive and 65 relapsed/refractory, among whom 14 patients had prior venetoclax exposure. In these patients, the ORR was 92.9% (13/14); 100% (8/8) of these patients were Bruton tyrosine kinase inhibitor (BTKi) naive, 83.3% (5/6) had prior BTKi exposure, and 64.3% (9/14) were venetoclax refractory. Rituximab or acalabrutinib did not alter the pharmacokinetic profile of lisaftoclax.

CONCLUSIONS

Daily ramp-up over 5-7 days (to 400 or 800 mg) with continuous treatment with lisaftoclax alone or plus rituximab or acalabrutinib was well tolerated and led to responses in patients with CLL without clinically significant pharmacokinetic interactions.

FUNDING: Ascentage Pharma Group Corp Ltd. (Hong Kong).