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Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL
Citation
Tam, CS and Trotman, J and Opat, S and Burger, JA and Cull, G and Gottlieb, D and Harrup, R and Johnston, PB and Marlton, P and Munoz, J and Seymour, JF and Simpson, D and Tedeschi, A and Elstrom, R and Yu, Y and Tang, Z and Han, L and Huang, J and Novotny, W and Wang, L and Roberts, AW, Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL, Blood, 134, (11) pp. 851-859. ISSN 0006-4971 (2019) [Refereed Article]
Copyright Statement
© 2019 by The American Society of Hematology
DOI: doi:10.1182/blood.2019001160
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 1 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 5 .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 mon
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ths was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities.
Item Details
| Item Type: | Refereed Article |
|---|---|
| Research Division: | Biomedical and Clinical Sciences |
| Research Group: | Oncology and carcinogenesis |
| Research Field: | Cancer therapy (excl. chemotherapy and radiation therapy) |
| Objective Division: | Health |
| Objective Group: | Clinical health |
| Objective Field: | Treatment of human diseases and conditions |
| UTAS Author: | Harrup, R (Dr Rosemary Harrup) |
| ID Code: | 151728 |
| Year Published: | 2019 |
| Web of Science® Times Cited: | 199 |
| Deposited By: | Medicine |
| Deposited On: | 2022-08-04 |
| Last Modified: | 2022-11-25 |
| Downloads: | 0 |
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