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

Constantine Si Lun Tam, Judith Trotman, Stephen Opat, Jan A Burger, Gavin Cull, David J Gottlieb, Rosemary Anne Harrup, Patrick Johnston, Paula Marlton, Javier Munoz, John F. Seymour, David R Simpson, Alessandra Tedeschi, Rebecca Elstrom, Yiling Yu, Zhiyu Tang, Lynn Han, Jane Huang, William Novotny, Lai Wang and Andrew W. Roberts

Key Points

  • Zanubrutinib is a potent and selective BTK inhibitor with greater selectivity and potentially fewer off-target effects than ibrutinib

  • In this study zanubrutinib was tolerable and demonstrated encouraging activity in patients with relapsed/refractory or treatment-naïve CLL

Abstract

Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-­label, multicenter, phase1 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-naïve 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%; P=.0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5), 89 (94.7%) CLL/SLL patients 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, overall response rate was 96.2% (95% CI, 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 study is registered with www.clinicaltrials.gov as #NCT02343120.

  • Submitted January 2, 2019.
  • Revision received July 22, 2019.
  • Accepted June 24, 2019.