A phase 1/2 clinical trial of acalabrutinib—a second-generation selective BTK inhibitor—showed a 95% overall response rate and few side effects in patients with relapsed chronic lymphocytic leukemia (CLL), investigators reported December 7, 2015 at the American Society of Hematology meeting in Orlando, FL.
Investigators reported that acalabrutinib (ACP-196) more selectively blocks the BTK pathway without disrupting other key pathways important for preserving platelet and immune function, which minimizes and avoids the adverse effects associated with first-generation agents. These results were simultaneously published online in The New England Journal of Medicine.
In this phase 1/2 multicenter trial, investigators enrolled 61 patients with relapsed CLL (the most prevalent leukemia in adults). In the phase 1 dose-escalation portion of the trial, researchers administered acalabrutinib to patients starting at a dose of 100 mg once daily and increased to a maximum of 400 mg. In the phase 2 expansion part of the study, researchers gave patients 100 mg of acalabrutinib twice daily.
At a median follow-up of 14.3 months, patients had an overall response rate of 95% (partial response in 85% and partial response with lymphocytosis in 10%). Disease was stable in the remaining 5% of patients, the researchers reported. Among patients with chromosome 17p13.1 deletion, the overall response rate was 100%.
“This data is very exciting because it illustrates that acalabrutinib is a highly potent and selective oral BTK inhibitor that can be given safely in patients with relapsed CLL,” said the study’s principal investigator John C. Byrd, MD, Chair of Leukemia Research at The Ohio State University Comprehensive Cancer Center/Arthur G. James Cancer Hospital, in Columbus, OH.
“What is particularly remarkable is how well patients are tolerating this therapy,” Dr. Byrd added. The type of bleeding effects that occurred with current BTK inhibitors did not occur with acalabrutinib in this trial. Averse events with acalabrutinib were mostly grade 1 or 2 and self-limiting, and most resolved over time. At a median follow-up of 14.3 months, only 8 of 61 patients (13%) had discontinued the study treatment.
“BTK inhibitors are transforming CLL from an incurable to a chronic disease, especially considering that standard CLL therapies typically produce a 35% to 40% response rate in this disease setting,” Dr. Byrd said.
Given these findings, the investigators have already begun a phase 3 trial that will compare acalabrutinib with ibrutinib—a first-generation BTK inhibitor—in high-risk patients with relapsed CLL.
The study was funded with support from Acerta Pharma (which is helping to develop the drug), the National Cancer Institute, The Leukemia & Lymphoma Society, and other foundations.