1206 - First-in-human open-label study of lisaftoclax (APG-2575), a novel BCL-2 inhibitor, in patients with relapsed/refractory chronic lymphocytic leukemia and other hematologic malignancies

Background: Many B-cell malignancies evade apoptosis by overexpressing BCL-2 proteins.
The BCL-2 inhibitor venetoclax is active in certain hematologic malignancies but can increase the risk of tumor lysis syndrome, requiring a 5-week dose ramp-up for patients with chronic lymphocytic leukemia (CLL). Cases of severe neutropenia with venetoclax treatment have also been reported. Investigational lisaftoclax (APG-2575) is a novel, potent, selective BCL-2 inhibitor that is active against hematologic malignancies and is under clinical development (Ailawadhi S et al. Clin Cancer Res 2023; In press:OF1-OF9. doi:10.1158/1078-0432.CCR-22-3321).

Methods: This first-in-human global phase 1 dose escalation and expansion study assessed the safety, pharmacokinetics, pharmacodynamics, efficacy, and maximum tolerated or recommended phase 2 dose of lisaftoclax in patients with relapsed/refractory CLL and other hematologic malignancies. Lisaftoclax was orally administered daily in a 28-day cycle. Patients with CLL or intermediate-high tumor lysis syndrome risk were initiated on a daily ramp-up schedule until the assigned dose was reached.

Results: As of October 22, 2022, 52 patients were enrolled and treated with lisaftoclax at doses ranging from 20 to 1,200 mg, with a median (range) of 2 (1-13) prior lines of treatment. Patients had diagnoses of relapsed/refractory CLL or small lymphocytic lymphoma (SLL; n = 23), non-Hodgkin lymphoma (n = 14), multiple myeloma (n = 11), and either acute myeloid leukemia, myelodysplastic syndrome, hairy cell leukemia, or Castleman disease (n = 1 each). No dose-limiting toxicity was observed even at 1,200 mg, the highest treatment dose. The maximum tolerated dose was not reached, and no laboratory or clinical tumor lysis syndrome was reported. The median (range) of treatment duration was 7 (1-43) cycles. Any grade treatment-emergent adverse events (TEAEs) in ≥ 20% of patients included anemia (28.8%), thrombocytopenia (28.8%), neutropenia (26.9%; hematologic), diarrhea (48.1%), fatigue (34.6%), nausea (30.8%), constipation (25.0%), vomiting (23.1%), and headache (21.2%; nonhematologic). Grade 3-4 TEAEs in ≥ 5% of patients included neutropenia (21.2%), thrombocytopenia (13.5%), and anemia (9.6%). In patients with CLL/SLL, grade 3-4 TEAEs included neutropenia (26.1%), increased lipase (13.0%), and thrombocytopenia (8.7%), which did not cause treatment-related discontinuation. Of 22 evaluable patients with relapsed/refractory CLL/SLL, 14 achieved partial responses, for an overall response rate of 63.6% (95% CI: [41%, 83%]) and median (range) time to response of 2 (2-8) cycles. Among 28 evaluable patients without CLL/SLL, clinical benefit was observed in 14 (50.0%). The pharmacokinetic profile showed that exposures increased with lisaftoclax doses from 20 to 1,200 mg (average half-life: 3-5 hours). BH3 profiling demonstrated that lisaftoclax rapidly induced changes in BCL-2 complex and triggered cytochrome c release in CLL/SLL patient samples, which were consistent with rapid clinical reductions in absolute lymphocyte counts.

Conclusions: Lisaftoclax was well tolerated up to 1,200 mg/day. No tumor lysis syndrome was observed even with the daily ramp-up schedule. There were no significant new or unmanageable safety findings, and the overall response rate in patients with relapsed/refractory CLL/SLL was 63.6%. Grade 3-4 TEAEs were infrequent even at dose levels of 800 mg and above. Thus, the BCL-2 inhibitor lisaftoclax offers a potential treatment alternative for patients with relapsed/refractory CLL/SLL and other hematologic malignancies, with a daily ramp-up schedule that may be more patient “user friendly” and a favorable preliminary safety profile. Internal study identifier: APG-2575-001; clinical trial registration: NCT03537482.