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

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

Research output: Contribution to journalArticle

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 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities.

Original languageEnglish (US)
Pages (from-to)851-859
Number of pages9
JournalBlood
Volume134
Issue number11
DOIs
StatePublished - Sep 12 2019

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B-Cell Chronic Lymphocytic Leukemia
Toxicity
B-Lymphocytes
Cells
Safety
Refractory materials
Neoplasms
Pharmacodynamics
Pharmacokinetics
Biopsy
Labels
Blood
Agammaglobulinaemia tyrosine kinase
Maximum Tolerated Dose
Neutropenia
Disease-Free Survival
Blood Cells
Lymph Nodes
Confidence Intervals
Hemorrhage

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Tam, C. S., Trotman, J., Opat, S., Burger, J. A., Cull, G., Gottlieb, D., ... Roberts, A. W. (2019). Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood, 134(11), 851-859. https://doi.org/10.1182/blood.2019001160

Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. / Tam, Constantine S.; Trotman, Judith; Opat, Stephen; Burger, Jan A.; Cull, Gavin; Gottlieb, David; Harrup, Rosemary; Johnston, Patrick B.; Marlton, Paula; Munoz, Javier; Seymour, John F.; Simpson, David; Tedeschi, Alessandra; Elstrom, Rebecca; Yu, Yiling; Tang, Zhiyu; Han, Lynn; Huang, Jane; Novotny, William; Wang, Lai; Roberts, Andrew W.

In: Blood, Vol. 134, No. 11, 12.09.2019, p. 851-859.

Research output: Contribution to journalArticle

Tam, CS, Trotman, J, Opat, S, Burger, JA, Cull, G, Gottlieb, D, Harrup, R, Johnston, PB, Marlton, P, Munoz, J, Seymour, JF, Simpson, D, Tedeschi, A, Elstrom, R, Yu, Y, Tang, Z, Han, L, Huang, J, Novotny, W, Wang, L & Roberts, AW 2019, 'Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL', Blood, vol. 134, no. 11, pp. 851-859. https://doi.org/10.1182/blood.2019001160
Tam, Constantine S. ; Trotman, Judith ; Opat, Stephen ; Burger, Jan A. ; Cull, Gavin ; Gottlieb, David ; Harrup, Rosemary ; Johnston, Patrick B. ; Marlton, Paula ; Munoz, Javier ; Seymour, John F. ; Simpson, David ; Tedeschi, Alessandra ; Elstrom, Rebecca ; Yu, Yiling ; Tang, Zhiyu ; Han, Lynn ; Huang, Jane ; Novotny, William ; Wang, Lai ; Roberts, Andrew W. / Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. In: Blood. 2019 ; Vol. 134, No. 11. pp. 851-859.
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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 months was 100{\%}. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities.",
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AU - Burger, Jan A.

AU - Cull, Gavin

AU - Gottlieb, David

AU - Harrup, Rosemary

AU - Johnston, Patrick B.

AU - Marlton, Paula

AU - Munoz, Javier

AU - Seymour, John F.

AU - Simpson, David

AU - Tedeschi, Alessandra

AU - Elstrom, Rebecca

AU - Yu, Yiling

AU - Tang, Zhiyu

AU - Han, Lynn

AU - Huang, Jane

AU - Novotny, William

AU - Wang, Lai

AU - Roberts, Andrew W.

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