FDA Grants Clearance for Phase 3 Study of Lisaftoclax in Previously Treated CLL/SLL

The FDA has granted clearance for a global, registrational, phase 3 study (APG2575CG301) examining lisaftoclax (APG-2575) in combination with a BTK inhibitor in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who received prior treatment with a BTK inhibitor.¹

The global, multicenter, randomized, controlled trial will begin in the second half of 2023.

“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,” Yifan Zhai, MD, PhD, chief medical officer of Ascentage Pharma, stated in a news release. “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 novel, oral, small-molecule, BCL-2 selective inhibitor, lisaftoclax, was previously studied alone and in combination with acalabrutinib (Calquence) or rituximab (Rituxan) in patients with relapsed/refractory or treatment-naïve CLL/SLL as part of a phase 1/2 trial (NCT04215809). In data presented at the 2022 ASH Annual Meeting, previously untreated patients with CLL/SLL who received lisaftoclax plus acalabrutinib (n = 16) experienced an overall response rate (ORR) of 100%. Among those with relapsed/refractory disease treated with this combination (n = 57), the ORR was 98%.^2,3

During the phase 1/2 study, lisaftoclax was administered at 400 mg, 600 mg, or 800 mg alone or in combination with continuous acalabrutinib or rituximab for six 28-day cycles. Ramp-up dosing of lisaftoclax was done over 4 to 6 days to monitor for tumor lysis syndrome, and the target dose was given on day 1 of cycle 1. In patients who received a combination, lisaftoclax was given for 7 additional days alone before acalabrutinib or rituximab were started on day 8 of cycle 1.³

Establishing the recommended phase 2 dose, as well as evaluating safety and efficacy, served as the study’s primary objectives. 

Regarding safety, lisaftoclax alone or in combination with acalabrutinib or rituximab demonstrated a manageable safety profile. Across the phase 1/2 trial’s 3 cohorts, the most common any-grade adverse effects (AEs) included neutropenia, diarrhea, and infections.

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

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/