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

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%; 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 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.

Graphical abstract

Figure 1.

Plasma concentration-time profile of zanubrutinib after initial doses of 40, 80, 160, and 320 mg once daily and 160 mg twice daily in part 1 and cohort 2a patients. Lines represent mean plasma concentration and error bars indicate standard deviation. *For the 160-mg twice-daily dose group, patients received only the morning dose (one-half of the daily dose) for the 24-hour pharmacokinetic evaluation on day 1 of week 1. BID, twice daily; QD, once daily.

Figure 2.

BTK occupancy. In (A) PBMCs and (B) nodal tissue. Data for individual patients at each time point are shown. Patient numbers and the percentage of patients with >95% BTK occupancy are noted. Triangles indicate percentages of BTK occupancy in PBMCs of patients predose, at 4 and 24 hours after zanubrutinib treatment on day 1 of week 1 (W1D1), predose on day 3 of week 1 (W1D3), and day 1 of week 2 (W2D1). BTK occupancy in lymph node biopsy specimens was assessed at baseline and predose on W1D3 and calculated as 1 − ([free BTK on day 3 predose] × [total BTK at screening])/([free BTK at screening] × [total BTK on day 3 predose]). Median values are shown as lines through the individual triangles. DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MZL, marginal zone lymphoma.

Figure 3.

Reductions in the sum of the products of perpendicular diameters of target lymph nodes. In patients with (A) treatment-naive or (B) relapsed/refractory CLL/SLL; (C) kinetics of lymphocytosis. Data indicate median percentage change in lymphocyte counts and 95% CIs. ALC, absolute lymphocyte count; SD, stable disease; SPD, sum of the products of lymph node diameters as assessed by computed tomography scan.