Dr. Matthew Davids and colleagues presented this research at the American Society for Hematology annual meeting held in December 2021 (ASH 2021).
Background:
BCL2 is a protein that helps control whether a cell lives or dies by blocking a type of cell death called apoptosis. In chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), BCL2 is made in more significant amounts, which may keep cancer cells from dying. BCL2 inhibitors, such as venetoclax, bind to the BCL2 protein and block its action leading to cell death. BCL2 inhibition with venetoclax has proved to be a highly effective treatment for patients with CLL / SLL.
However, when administered to patients with CLL / SLL who have a high tumor burden, venetoclax is associated with an elevated risk of tumor lysis syndrome (TLS), which is when a large number of cancer cells die at once and spill their contents into the bloodstream. TLS can be very dangerous for the patient because it can cause heart, kidneys, and nervous system problems. Because of this risk, venetoclax is initiated with a gradual, 5-week dose ramp-up, requiring close laboratory monitoring over an extended period. Lisaftoclax (APG-2575) is a novel, potent, selective BCL2 inhibitor under clinical development for blood cancers, and it is designed to have a much shorter ramp-up period (5 days rather than 5 weeks). In addition, preliminary data in 18 patients with CLL treated in a first-in-human study suggested the feasibility of an abbreviated ramp-up of lisaftoclax. You can see our previous coverage here.
Takeaways:
- This study is a global, open-label, multicenter, two-part phase 1b dose-escalation and dose-expansion study to assess the safety and tolerability of lisaftoclax (Part 1) and lisaftoclax combined with rituximab or acalabrutinib (Part 2).
- Eligible patients are adults diagnosed with CLL / SLL whose disease is relapsed or refractory to ≥ 1 prior therapy and requires treatment. Researchers expect to enroll 144 patients in the study.
- You are not eligible for this study if you have any of the following:
- Received allogeneic stem cell transplantation or CAR T-cell therapy within the past 90 days
- Previous treatment with a BCL2 inhibitor
- Richter’s syndrome
- Infection
- In Part 1, lisaftoclax is administered orally once daily in a 28-day cycle, with full doses of 200 to 1,200 mg (by 200-mg increments at 4 dose levels (400, 600, 800, and 1,000 mg) in parallel. The ramp-up is performed in the hospital with close monitoring for TLS.
- Part 2 includes a further standard dose escalation of lisaftoclax combined with rituximab or acalabrutinib (in separate cohorts).
- The primary endpoints are (1) dose-limiting toxicities observed during cycle 1 and (2) maximum tolerated dose (measured over the same interval).
Conclusions:
Clinical trials are key for developing new therapies to treat CLL and SLL. While lisaftoclax is still early in development, the hope is that it will provide a less burdensome alternative to venetoclax. If you are interested in participating in this phase 1b study or lisaftoclax, more information can be found here
Here is the link to the ASH 2021 abstract for more details.
Take care of yourself first.
Ann Liu, PhD
