Lisaftoclax Granted FDA Clearance for Phase 3 Trial in Patients With Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma

Lisaftoclax (APG-2575) combined with a BTK inhibitor was granted FDA clearance for a global, registrational, phase 3 study (APG2575CG301) among patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who were previously treated with a Bruton’s tyrosine kinase (BTK) inhibitor.¹

“Lisaftoclax, a key drug candidate of our apoptosis-targeted pipeline with global best-in-class potential, has shown promising efficacy and favorable safety in earlier studies. We are very encouraged by the FDA’s clearance for the global registrational phase 3 study as it marks a major milestone in the development of lisaftoclax,” said Yifan Zhai, MD, PhD, chief medical officer of Ascentage Pharma, in a statement. “Fulfilling the mission of addressing unmet clinical needs in China and around the world, we will press ahead with the global registrational phase III study of lisaftoclax to allow patients around the world to benefit from this novel therapeutic as soon as possible.”

The multicenter, randomized, controlled trial is anticipated begin in the second half of this year. Lisaftoclax is a novel, oral, small-molecule, BCL-2 selective inhibitor that was previously evaluated as monotherapy and in combination with acalabrutinib (Calquence) or rituximab (Rituxan) in patients with R/R or treatment-naïve CLL/SLL as part of a phase 1/2 trial (NCT04215809).

Prior research found that previously untreated patients with CLL/SLL administered lisaftoclax with acalabrutinib (n = 16) experienced an overall response rate (ORR) of 100%, according to data presented at the 2022 ASH Annual Meeting. The results also showed that ORR was 98% among patients with R/R CLL/SLL administered the lisaftoclax combination (n = 57).^2,3

In the phase 1/2 study, lisaftoclax was administered at doses of 400 mg, 600 mg, or 800 mg alone or combined with continuous acalabrutinib or rituximab for six 28-day cycles. The study’s primary objectives were to establish the recommended phase 2 dose and to evaluate safety and efficacy.

Ramp-up dosing of lisaftoclax was completed over 4 to 6 days to monitor for tumor lysis syndrome, with a target dose administered on day 1 of cycle 1. In patients administered the combination, lisaftoclax was received for 7 additional days alone before acalabrutinib or rituximab were started on day 8 of cycle 1.³

Lisaftoclax alone or in combination with acalabrutinib or rituximab showed a manageable safety profile. Across the 3 patient cohorts evaluated, the most common any-grade adverse effects (AEs) included neutropenia, diarrhea, and infections.

Among patients administered the acalabrutinib combination, grade 3 or higher AEs were neutropenia (23%), COVID-19 infections (11.5%), anemia (10%), and thrombocytopenia (6.4%). There were no observed dose-limiting toxicities or drug-to-drug interactions in either combination cohort.

References

1. Ascentage Pharma received clearance from US FDA to proceed with global registrational phase III clinical trial for lisaftoclax (APG-2575) in previously treated patients with CLL/SLL. News release. Ascentage Pharma. August 6, 2023. Accessed August 7, 2023. https://ascentage.com/ascentage-pharma-received-clearance-from-u-s-fda-to-proceed-with-global-registrational-phase-iii-clinical-trial-for-lisaftoclax-apg-2575-in-previously-treated-patients-with-cll-sll/
2. Davids MS, Chanan-Khan A, Mudenda B, et al. Lisaftoclax (APG-2575) safety and activity as monotherapy or combined with acalabrutinib or rituximab in patients (pts) with treatment-naïve, relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (R/R CLL/SLL): initial data from a phase 2 global study. Blood. 2022;140(suppl 1):2326-2328. doi:10.1182/blood-2022-160386
3. Live from ASH 2022 | Ascentage Pharma presents latest data of APG-2575, including encouraging results of the combination with BTKi in patients with R/R CLL/SLL. News release. Ascentage Pharma. December 14, 2022. Accessed August 7, 2023. https://ascentage.com/live-from-ash-2022-ascentage-pharma-presents-latest-data-of-apg-2575-including-encouraging-results-of-the-combination-with-btki-in-patients-with-r-r-cll-sll/