Abstract
Inhibition of the B-cell receptor pathway, and specifically of Bruton tyrosine kinase (BTK), is a leading therapeutic strategy in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Target occupancy is a measure of covalent binding to BTK and has been applied as a pharmacodynamic parameter in clinical studies of BTK inhibitors. However, the kinetics of de novo BTK synthesis, which determines occupancy, and the relationship between occupancy, pathway inhibition and clinical outcomes remain undefined. This randomized phase 2 study investigated the safety, efficacy, and pharmacodynamics of a selective BTK inhibitor acalabrutinib at 100 mg twice daily (BID) or 200 mg once daily (QD) in 48 patients with relapsed/refractory or high-risk treatment-naïve CLL. Acalabrutinib was well tolerated and yielded an overall response rate (ORR) of partial response or better of 95.8% (95% confidence interval [CI], 78.9-99.9) and an estimated progression-free survival (PFS) rate at 24 months of 91.5% (95% CI, 70.0-97.8) with BID dosing and an ORR of 79.2% (95% CI, 57.9-92.9) and an estimated PFS rate at 24 months of 87.2% (95% CI, 57.2-96.7) with QD dosing. BTK resynthesis was faster in patients with CLL than in healthy volunteers. BID dosing maintained higher BTK occupancy and achieved more potent pathway inhibition compared with QD dosing. Small increments in occupancy attained by BID dosing relative to QD dosing compounded over time to augment downstream biological effects. The impact of BTK occupancy on long-term clinical outcomes remains to be determined. This trial was registered at www.clinicaltrials.gov as #NCT02337829.
Publication types
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Clinical Trial, Phase II
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Comparative Study
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Randomized Controlled Trial
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors*
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Agammaglobulinaemia Tyrosine Kinase / biosynthesis
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Agammaglobulinaemia Tyrosine Kinase / genetics
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Aged
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Aged, 80 and over
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / adverse effects
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Antineoplastic Agents / therapeutic use*
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Benzamides / administration & dosage
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Benzamides / adverse effects
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Benzamides / therapeutic use*
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Drug Administration Schedule
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Enzyme Induction
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Female
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Headache / chemically induced
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Hematologic Diseases / chemically induced
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Humans
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Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
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Leukemia, Lymphocytic, Chronic, B-Cell / enzymology
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics
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Male
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Middle Aged
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Pain / chemically induced
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Progression-Free Survival
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / adverse effects
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Protein Kinase Inhibitors / therapeutic use*
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Pyrazines / administration & dosage
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Pyrazines / adverse effects
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Pyrazines / therapeutic use*
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Neoplasm / biosynthesis
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RNA, Neoplasm / genetics
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RNA-Seq
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Transcriptome
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Treatment Outcome
Substances
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Antineoplastic Agents
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Benzamides
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Neoplasm Proteins
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Protein Kinase Inhibitors
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Pyrazines
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RNA, Messenger
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RNA, Neoplasm
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Agammaglobulinaemia Tyrosine Kinase
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BTK protein, human
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acalabrutinib
Associated data
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ClinicalTrials.gov/NCT02337829