First-in-Human Trial Evaluates Novel BCL-2 Inhibitor in CLL, SLL

By Cecilia Brown - May 17, 2023

The novel BCL-2 inhibitor lisaftoclax “induced rapid clinical responses” in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), according to a recent study.

Sikander Ailawadhi, MD, of the Mayo Clinic in Jacksonville, Florida, and colleagues published results from the open-label study in Clinical Cancer Research.

Dr. Ailawadhi and colleagues conducted the global phase I trial to investigate the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax, also known as APG-2575, in patients with relapsed or refractory hematologic malignancies. They evaluated the maximum tolerated dose and recommended phase II dose. The primary outcome measures were safety and tolerability. The secondary outcome measures were pharmacokinetic variables and antitumor effects.

The maximum tolerated dose was not reached in the 52 patients who received lisaftoclax. Grade 3 or higher hematologic treatment-emergent adverse events (AEs) included neutropenia in 21.2% of patients, thrombocytopenia in 13.5%, and anemia in 9.6%. However, none of the grade 3 or higher hematologic treatment-emergent AEs resulted in treatment discontinuation, according to the study’s authors. See TABLE 1 for information on other treatment-emergent AEs.

TABLE 1. Treatment-Emergent AEs in Patients Receiving Lisaftoclax

Type of AE Frequency
Diarrhea 48.1%
Fatigue 34.6%
Nausea 30.8%
Anemia 28.8%
Thrombocytopenia 28.8%
Neutropenia 26.9%
Constipation 25%
Vomiting 23.1%
Headache 21.2%
Peripheral edema 17.3%
Hypokalemia 17.3%


“Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells,” Dr. Ailawadhi and colleagues wrote.

A partial response occurred in 14 of the 22 patients with relapsed or refractory CLL or SLL who were evaluable for efficacy at a median of 15 treatment cycles. The objective response rate was 63.6%, with a median of two cycles until response.

“Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome,” Dr. Ailawadhi and colleagues concluded. “Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs weekly) dose ramp-up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation.”


Ailawadhi S, Chen Z, Huang B, et al. Novel BCL-2 inhibitor lisaftoclax in relapsed or refractory chronic lymphocytic leukemia and other hematologic malignancies: first-in-human open-label trial. Clin Cancer Res. 2023. doi:10.1158/1078-0432.ccr-22-3321

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