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

Autor:	Tam CS; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Department of Medicine, University of Melbourne, Parkville, VIC, Australia.; St Vincent's Hospital, Fitzroy, VIC, Australia.; Royal Melbourne Hospital, Parkville, VIC, Australia.; Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia., Trotman J; Department of Haematology, Concord Repatriation General Hospital, Concord, NSW, Australia.; Haematology Department, University of Sydney, Concord, NSW, Australia., Opat S; Clinical Haematology, Monash Health, Clayton, VIC, Australia.; School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia., Burger JA; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX., Cull G; Haematology Department, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.; PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA, Australia.; University of Western Australia, Perth, WA, Australia., Gottlieb D; Department of Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.; Department of Haematology, Westmead Hospital, Westmead, NSW, Australia., Harrup R; Department of Clinical Haematology, Royal Hobart Hospital, Hobart, TAS, Australia.; Department of Medical Oncology, University of Tasmania, Hobart, TAS, Australia., Johnston PB; Division of Hematology, Mayo Clinic, Rochester, MN., Marlton P; Princess Alexandra Hospital, Brisbane, QLD, Australia.; School of Medicine, University of Queensland, Brisbane, QLD, Australia., Munoz J; Banner MD Anderson Cancer Center, Gilbert, AZ., Seymour JF; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Department of Medicine, University of Melbourne, Parkville, VIC, Australia.; Royal Melbourne Hospital, Parkville, VIC, Australia.; Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia., Simpson D; North Shore Hospital, Auckland, New Zealand., Tedeschi A; ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy., Elstrom R; BeiGene USA, Inc, San Mateo, CA., Yu Y; BeiGene Shanghai, Ltd, Shanghai, China., Tang Z; BeiGene USA, Inc, San Mateo, CA., Han L; BeiGene USA, Inc, San Mateo, CA., Huang J; BeiGene USA, Inc, San Mateo, CA., Novotny W; BeiGene USA, Inc, San Mateo, CA., Wang L; BeiGene Beijing, Ltd, Beijing, China; and., Roberts AW; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Department of Medicine, University of Melbourne, Parkville, VIC, Australia.; Royal Melbourne Hospital, Parkville, VIC, Australia.; Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia.; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2019 Sep 12; Vol. 134 (11), pp. 851-859. Date of Electronic Publication: 2019 Jul 24.
DOI:	10.1182/blood.2019001160
Abstrakt:	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. (© 2019 by The American Society of Hematology.)
Databáze:	MEDLINE
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