Acalabrutinib (ACP-196), a second-generation BTK inhibitor, has demonstrated high response rates in patients with chronic lymphocytic leukemia (CLL) who have experienced relapse or refractory disease.
This was first reported in The New England Journal of Medicine (NEJM), and the results were discussed during a session at the American Society of Hematology's (ASH) 57th Annual Meeting, held December 5-8, 2015, in Orlando, Fla.
During the phase I/II, multicenter study, researchers administered oral acalabrutinib to 61 patients with CLL who experienced relapse to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of acalabrutinib. Patients were treated with 100 mg to 400 mg dose once daily in the dose-escalation (phase I) part of the study, and 100 mg twice daily in the expansion (phase II) portion.
At a median follow-up of 14.3 months, the overall response rate was 95%, including 85% with a partial response and 10% with a partial response with lymphocytosis (an increase in the number or proportion of lymphocytes in the blood). Of the remaining 5%, their disease burden was stable. Among patients with the chromosome 17p13.1 deletion, the overall response rate (ORR) was 100% (partial response in 89% and partial response with lymphocytosis in 11%).
Patients experienced some side effects, including headache (43% of the patients), diarrhea (39%), and increased weight (26%), pyrexia (23%), and upper respiratory tract infection (23%). Most adverse events were of grade 1 or 2.
According to the scientific abstract presented at the ASH meeting, ACP-196 has been well-tolerated with 93% of patients continuing to take the study drug. To date, no dose-related effect has been observed in frequency or severity of adverse events or serious adverse events. No major hemorrhage (including subdural hematomas), atrial fibrillation, tumor lysis syndrome, or pneumonitis have occurred, suggesting improved safety compared with other BCR and BCL-2-targeted therapies.
Leading this effort has been John C. Byrd, MD, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) hematology division director, D. Warren Brown Chair of Leukemia Research, and Amy J. Johnson, PhD, associate professor and OSUCCC – James leukemia researcher. The development of ACP-196 was done in close collaboration with investigators at Acerta Pharma, the University of California-Irvine, and Cornell Medical Center.
“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. What is particularly remarkable is how well patients are tolerating this therapy,” said Dr. Byrd in a James press release.
“BTK inhibitors are transforming CLL from an incurable to a chronic disease, especially considering that standard CLL therapies typically produce a 35-40 percent response rate in this disease setting,” Dr. Byrd said.
ACP-196 is currently in phase III trials, including a trial comparing ibrutinib and ACP-196.