A two-part, single-arm, multicentre, phase I study of zanubrutinib, a selective Bruton tyrosine kinase inhibitor, in Chinese patients with relapsed/refractory B-cell malignancies

Yuqin Song, Mingyuan Sun, Junyuan Qi, Wei Xu, Jianfeng Zhou, Dengju Li, Jianyong Li, Lugui Qiu, Chenmu Du, Haiyi Guo, Jane Huang, Zhiyu Tang, Ying Ou, Binghao Wu, Yiling Yu, Jun Zhu, Yuqin Song, Mingyuan Sun, Junyuan Qi, Wei Xu, Jianfeng Zhou, Dengju Li, Jianyong Li, Lugui Qiu, Chenmu Du, Haiyi Guo, Jane Huang, Zhiyu Tang, Ying Ou, Binghao Wu, Yiling Yu, Jun Zhu

Abstract

This single-arm, multicentre, phase I study is the first study of zanubrutinib, a potent, specific, irreversible Bruton tyrosine kinase (BTK) inhibitor, in Chinese patients with relapsed/refractory B-cell malignancies. The objectives were to evaluate safety and preliminary anti-tumour activity. Forty-four patients received zanubrutinib 320 mg once daily (QD) (n = 10) or 160 mg twice daily (BID) (n = 34) until disease progression or unacceptable toxicity. 29.5% of patients received zanubrutinib for at least two years. The most common adverse event (AE) and the most common grade 3 or higher AE was neutrophil count decreased (54.5% and 25.0% respectively). Two patients (4.5%) discontinued treatment due to AEs and one treatment-emergent AE led to death. All haemorrhagic events were grade 1-2 (except for one non-serious grade 3 purpura). No second primary malignancies, tumour lysis syndrome, or atrial fibrillation/flutter occurred. The overall response rate was 52.3% (complete response rate, 18.2%). Patients with all cancer subtypes benefited from treatment. BTK C481S/R or L528W mutations were found in zanubrutinib-progressive patients. The safety/efficacy profiles of patients treated with 320 mg QD and 160 mg BID were comparable and similar daily area under the curve (AUC) was achieved. Overall, zanubrutinib was well tolerated and either of these two regimens is clinically practical. Registered at ClinicalTrials.gov (NCT03189524, on 16 June 2017, https://ichgcp.net/clinical-trials-registry/NCT03189524).

Keywords: B-cell malignancies; efficacy; phase I; safety; zanubrutinib.

Conflict of interest statement

Chenmu Du, Haiyi Guo, Jane Huang, Zhiyu Tang, Ying Ou, Binghao Wu, and Yiling Yu are employees of and own stock in BeiGene. The other authors declare that they have no competing interests.

© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
Study design. In part I, three patients (or six patients if one of the first three patients experienced a DLT) were randomly assigned to one of the two treatment arms. If two or more patients experienced a DLT, the dosage was to be reduced by half and three patients were then enrolled at that dose. If zero or one patient experienced a DLT, 10 patients in total were to be enrolled in the arm to further assess the safety, tolerability, PK, and preliminary PD of the study drug and to determine the RP2D. DLT, dose‐limiting toxicity; RP2D, recommended phase II dose
FIGURE 2
FIGURE 2
Progression‐free survival in Chinese patients with relapsed/refractory (R/R) B‐cell malignancies receiving zanubrutinib by dose regimen. There was no significant difference between the two dose groups as indicated by the log‐rank test (p = 0.25)
FIGURE 3
FIGURE 3
Progression‐free survival in Chinese patients with relapsed/refractory (R/R) B‐cell malignancies receiving zanubrutinib by disease type
FIGURE 4
FIGURE 4
Duration of response [partial response with lymphocytosis (PR‐L) or better] in Chinese patients with relapsed/refractory (R/R) B‐cell malignancies receiving zanubrutinib. Response was defined as PR‐L or better
FIGURE 5
FIGURE 5
Plasma concentration–time profile of zanubrutinib on day 1 of week 2 after multiple doses in Chinese patients with relapsed/refractory B‐cell malignancies

References

    1. Guo Y, Liu Y, Hu N, Yu D, Zhou C, Shi G, et al. Discovery of zanubrutinib (BGB‐3111), a novel, potent, and selective covalent inhibitor of Bruton's tyrosine kinase. J Med Chem. 2019;62:7923–40.
    1. Tam CS, Trotman J, Opat S, Burger JA, Cull G, Gottlieb D, et al. Phase 1 study of the selective BTK inhibitor zanubrutinib in B‐cell malignancies and safety and efficacy evaluation in CLL. Blood. 2019;134:851–9.
    1. National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 [Internet]. National Cancer Institute; c2009. [updated June 14, 2010]. Available from:
    1. Hallek M, Cheson BD, Catovsky D, Caligaris‐Cappio F, Dighiero G, Döhner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the international workshop on chronic lymphocytic leukemia updating the National Cancer Institute‐working group 1996 guidelines. Blood. 2008;111:5446–56.
    1. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non‐Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32:3059–68.
    1. Owen RG, Kyle RA, Stone MJ, Rawstron AC, Leblond V, Merlini G, et al. Response assessment in Waldenström macroglobulinaemia: update from the VIth international workshop. Br J Haematol. 2013;160:171–6.
    1. National Comprehensive Cancer Network (NCCN) . NCCN guidelines insights: Waldenström's macroglobulinaemia/lymphoplasmacytic lymphoma, version 2.2013. J Natl Compr Canc Netw. 2012;10:1211–8.
    1. Chakravarty D, Gao J, Phillips S, Kundra R, Zhang H, Wang J, et al. OncoKB: a precision oncology knowledge base. JCO Precis Oncol, published online May 16, 2017.
    1. Tam CS, Opat S, D'Sa S, Jurczak W, Lee H‐P, Cull G, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinaemia: the ASPEN study. Blood. 2020;136:2038–50.
    1. Tam CS, Simpson D, Opat S, Kim WS, Wang M, Cull G, et al. Safety and activity of the highly specific BTK inhibitor BGB‐3111 in patients with indolent and aggressive non Hodgkin's lymphoma. Blood. 2017;130:152.
    1. Cull G, Simpson D, Opat S, Burger JA, Trotman J, Marlton P, et al. Treatment with the Bruton tyrosine kinase inhibitor zanubrutinib (BGB‐3111) demonstrates high overall response rate and durable responses in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): updated results from a phase 1/2 trial. Blood. 2019;134(Supplement_1):500.
    1. Ou YC, Tang Z, Novotny W, Cohen A, Wang K, Liu L, et al. Rationale for once‐daily or twice‐daily dosing of zanubrutinib in patients with mantle cell lymphoma. Leuk Lymphoma. 2021;62:2612–24.
    1. Tam CS, Ou YC, Trotman J, Opat S. Clinical pharmacology and PK/PD translation of the second‐generation Bruton's tyrosine kinase inhibitor, zanubrutinib. Expert Rev Clin Pharmacol. 2021;14:1329–44.
    1. Mu S, Tang Z, Novotny W, Tawashi M, Li T‐K, Ou Y, et al. Effect of rifampin and itraconazole on the pharmacokinetics of zanubrutinib (a Bruton's tyrosine kinase inhibitor) in Asian and non‐Asian healthy subjects. Cancer Chemother Pharmacol. 2020;85:391–9.
    1. Ou YC, Liu L, Tariq B, Wang K, Jindal A, Tang Z, et al. Population pharmacokinetic analysis of the BTK inhibitor zanubrutinib in healthy volunteers and patients with B‐cell malignancies. Clin Transl Sci. 2021;14:764–72.
    1. Woyach JA, Furman RR, Liu T‐M, Ozer HG, Zapatka M, Ruppert AS, et al. Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370:2286–94.
    1. Handunnetti SM, Tang CPS, Nguyen T, Zhou X, Thompson E, Sun H, et al. BTK Leu528Trp – a potential secondary resistance mechanism specific for patients with chronic lymphocytic leukemia treated with the next generation BTK inhibitor zanubrutinib. Blood. 2019;134(Supplement_1):170.
    1. Maddocks KJ, Ruppert AS, Lozanski G, Heerema NA, Zhao W, Abruzzo L, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1:80–7.
    1. Bartlett NL, Costello BA, LaPLant BR, Ansell SM, Kuruvilla JG, Reeder CB, et al. Single‐agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial. Blood. 2018;131:182–90.
    1. Bruscaggin A, di Bergamo LT, Spina V, Hodkinson B, Forestieri G, Bonfiglio F, et al. Circulating tumor DNA for comprehensive noninvasive monitoring of lymphoma treated with ibrutinib plus nivolumab. Blood Adv. 2021;5:4674–85.
    1. Du MQ, Peng H, Liu H, Hamoudi RA, Diss TC, Willis TG, et al. BCL10 gene mutation in lymphoma. Blood. 2000;95:3885–90.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir