Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia

Abstract

Background: Irreversible inhibition of Bruton's tyrosine kinase (BTK) by ibrutinib represents an important therapeutic advance for the treatment of chronic lymphocytic leukemia (CLL). However, ibrutinib also irreversibly inhibits alternative kinase targets, which potentially compromises its therapeutic index. Acalabrutinib (ACP-196) is a more selective, irreversible BTK inhibitor that is specifically designed to improve on the safety and efficacy of first-generation BTK inhibitors.

Methods: In this uncontrolled, phase 1-2, multicenter study, we administered oral acalabrutinib to 61 patients who had relapsed CLL to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of acalabrutinib. Patients were treated with acalabrutinib at a dose of 100 to 400 mg once daily in the dose-escalation (phase 1) portion of the study and 100 mg twice daily in the expansion (phase 2) portion.

Results: The median age of the patients was 62 years, and patients had received a median of three previous therapies for CLL; 31% had chromosome 17p13.1 deletion, and 75% had unmutated immunoglobulin heavy-chain variable genes. No dose-limiting toxic effects occurred during the dose-escalation portion of the study. The most common adverse events observed were headache (in 43% of the patients), diarrhea (in 39%), and increased weight (in 26%). Most adverse events were of grade 1 or 2. 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; the remaining 5% of patients had stable disease. Among patients with chromosome 17p13.1 deletion, the overall response rate was 100%. No cases of Richter's transformation (CLL that has evolved into large-cell lymphoma) and only one case of CLL progression have occurred.

Conclusions: In this study, the selective BTK inhibitor acalabrutinib had promising safety and efficacy profiles in patients with relapsed CLL, including those with chromosome 17p13.1 deletion. (Funded by the Acerta Pharma and others; ClinicalTrials.gov number, NCT02029443.).

Figures

Figure 1. Acalabrutinib Pharmacokinetics and Pharmacodynamics

Panel A shows mean acalabrutinib plasma concentrations over time for the once daily (QD) and twice daily (BID) cohorts. Panel B shows Btk occupancy for each cohort before (pre) and 4 hours after (post) dosing on Day 8 (steady-state). For the BID cohort, Btk occupancy was evaluated for the morning dose only. Box extends from the 25th to 75th percentiles and whiskers go 1.5 times the interquartile distance per Tukey method. Panel C shows Btk occupancy over time for the 100-mg BID cohort (n=28). Panel D shows change in phosphorylated Btk levels over time for all patients. Btk denotes Bruton tyrosine kinase.

Figure 2

Response to Acalabrutinib. Panel A shows the median percent change from baseline in absolute lymphocyte count (ALC) and the sum of products of lymph node diameters (SPD) in all patients. The bars represent 95% confidence intervals of the median change from baseline. Panel B shows greatest change from baseline in lymphadenopathy for patients with baseline lymphadenopathy and at least one on treatment measurement. All measurements were based on radiologic assessments. Panel C and D provide investigator-assessed best response by cohort and over time, respectively. In Panel D responses are depicted for all available patients at each timepoint. BID denotes twice daily; QD denotes once daily

Figure 3

Kaplan-Meier Curve for Progression-free Survival