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Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. | LitMetric

AI Article Synopsis

  • Zanubrutinib is a selective Bruton tyrosine kinase (BTK) inhibitor tested in a phase 1 study on patients with relapsed/refractory B-cell malignancies, focusing on safety, tolerability, and maximum tolerated dose.
  • Results from 144 patients showed that no dose-limiting toxicities occurred, with the most effective dosing identified as 160 mg twice daily, achieving over 95% BTK occupancy in blood cells and higher occupancy in lymph nodes.
  • The trial reported a high overall response rate of 96.2% in chronic lymphocytic leukemia/small lymphocytic lymphoma patients, with excellent progression-free survival and minimal serious side effects.

Article Abstract

Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in >2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742923PMC
http://dx.doi.org/10.1182/blood.2019001160DOI Listing

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