{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T19:26:08Z","timestamp":1792697168033,"version":"4.5.0"},"reference-count":28,"publisher":"American Society of Hematology","issue":"11","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,9,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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\u2009+\u20093 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 &amp;gt;95% at all doses. Sustained complete (&amp;gt;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 &amp;gt;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.<\/jats:p>","DOI":"10.1182\/blood.2019001160","type":"journal-article","created":{"date-parts":[[2019,7,24]],"date-time":"2019-07-24T21:25:19Z","timestamp":1564003519000},"page":"851-859","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":340,"title":["Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL"],"prefix":"10.1182","volume":"134","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9759-5017","authenticated-orcid":false,"given":"Constantine S.","family":"Tam","sequence":"first","affiliation":[{"name":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;"},{"name":"Department of Medicine, University of Melbourne, Parkville, VIC, Australia;"},{"name":"St Vincent\u2019s Hospital, Fitzroy, VIC, Australia;"},{"name":"Royal Melbourne Hospital, Parkville, VIC, Australia;"},{"name":"Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8009-4593","authenticated-orcid":false,"given":"Judith","family":"Trotman","sequence":"additional","affiliation":[{"name":"Department of Haematology, Concord Repatriation General Hospital, Concord, NSW, Australia;"},{"name":"Haematology Department, University of Sydney, Concord, NSW, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Opat","sequence":"additional","affiliation":[{"name":"Clinical Haematology, Monash Health, Clayton, VIC, Australia;"},{"name":"School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6177-7572","authenticated-orcid":false,"given":"Jan A.","family":"Burger","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin","family":"Cull","sequence":"additional","affiliation":[{"name":"Haematology Department, Sir Charles Gairdner Hospital, Nedlands, WA, Australia;"},{"name":"PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA, Australia;"},{"name":"University of Western Australia, Perth, WA, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Gottlieb","sequence":"additional","affiliation":[{"name":"Department of Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia;"},{"name":"Department of Haematology, Westmead Hospital, Westmead, NSW, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosemary","family":"Harrup","sequence":"additional","affiliation":[{"name":"Department of Clinical Haematology, Royal Hobart Hospital, Hobart, TAS, Australia;"},{"name":"Department of Medical Oncology, University of Tasmania, Hobart, TAS, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick B.","family":"Johnston","sequence":"additional","affiliation":[{"name":"Division of Hematology, Mayo Clinic, Rochester, MN;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Marlton","sequence":"additional","affiliation":[{"name":"Princess Alexandra Hospital, Brisbane, QLD, Australia;"},{"name":"School of Medicine, University of Queensland, Brisbane, QLD, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Munoz","sequence":"additional","affiliation":[{"name":"Banner MD Anderson Cancer Center, Gilbert, AZ;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2188-6835","authenticated-orcid":false,"given":"John F.","family":"Seymour","sequence":"additional","affiliation":[{"name":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;"},{"name":"Department of Medicine, University of Melbourne, Parkville, VIC, Australia;"},{"name":"Royal Melbourne Hospital, Parkville, VIC, Australia;"},{"name":"Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9768-7413","authenticated-orcid":false,"given":"David","family":"Simpson","sequence":"additional","affiliation":[{"name":"North Shore Hospital, Auckland, New Zealand;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Tedeschi","sequence":"additional","affiliation":[{"name":"ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Elstrom","sequence":"additional","affiliation":[{"name":"BeiGene USA, Inc, San Mateo, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiling","family":"Yu","sequence":"additional","affiliation":[{"name":"BeiGene Shanghai, Ltd, Shanghai, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyu","family":"Tang","sequence":"additional","affiliation":[{"name":"BeiGene USA, Inc, San Mateo, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn","family":"Han","sequence":"additional","affiliation":[{"name":"BeiGene USA, Inc, San Mateo, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Huang","sequence":"additional","affiliation":[{"name":"BeiGene USA, Inc, San Mateo, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Novotny","sequence":"additional","affiliation":[{"name":"BeiGene USA, Inc, San Mateo, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lai","family":"Wang","sequence":"additional","affiliation":[{"name":"BeiGene Beijing, Ltd, Beijing, China; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7341-5720","authenticated-orcid":false,"given":"Andrew W.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;"},{"name":"Department of Medicine, University of Melbourne, Parkville, VIC, Australia;"},{"name":"Royal Melbourne Hospital, Parkville, VIC, Australia;"},{"name":"Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia;"},{"name":"Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"12","key":"2020021109181697700_B1","doi-asserted-by":"crossref","first-page":"2761","DOI":"10.1002\/ijc.29326","article-title":"Inhibitors of BCR signalling interrupt the survival signal mediated by the micro-environment in mantle cell lymphoma","volume":"136","author":"Bernard","year":"2015","journal-title":"Int J Cancer"},{"issue":"11","key":"2020021109181697700_B2","doi-asserted-by":"crossref","first-page":"2590","DOI":"10.1182\/blood-2011-11-390989","article-title":"The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia","volume":"119","author":"de Rooij","year":"2012","journal-title":"Blood"},{"issue":"17","key":"2020021109181697700_B3","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1200\/JCO.2013.53.1046","article-title":"Bruton\u2019s tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell malignancies","volume":"32","author":"Ponader","year":"2014","journal-title":"J Clin Oncol"},{"issue":"6","key":"2020021109181697700_B4","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.semcancer.2013.09.001","article-title":"B-cell receptor signaling as a driver of lymphoma development and evolution","volume":"23","author":"Niemann","year":"2013","journal-title":"Semin Cancer Biol"},{"issue":"25","key":"2020021109181697700_B5","doi-asserted-by":"crossref","first-page":"2425","DOI":"10.1056\/NEJMoa1509388","article-title":"Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia","volume":"373","author":"Burger","year":"2015","journal-title":"N Engl J Med"},{"issue":"3","key":"2020021109181697700_B6","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1056\/NEJMoa1400376","article-title":"Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia","volume":"371","author":"Byrd","year":"2014","journal-title":"N Engl J Med"},{"issue":"1","key":"2020021109181697700_B7","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1056\/NEJMoa1215637","article-title":"Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia","volume":"369","author":"Byrd","year":"2013","journal-title":"N Engl J Med"},{"issue":"2","key":"2020021109181697700_B8","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S1470-2045(16)30632-5","article-title":"Ibrutinib for patients with rituximab-refractory Waldenstr\u00f6m\u2019s macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial","volume":"18","author":"Dimopoulos","year":"2017","journal-title":"Lancet Oncol"},{"issue":"2","key":"2020021109181697700_B9","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S1470-2045(14)71182-9","article-title":"Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial","volume":"16","author":"Farooqui","year":"2015","journal-title":"Lancet Oncol"},{"issue":"2","key":"2020021109181697700_B10","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1053\/j.seminoncol.2016.02.008","article-title":"Bruton tyrosine kinase inhibition in chronic lymphocytic leukemia","volume":"43","author":"Maddocks","year":"2016","journal-title":"Semin Oncol"},{"issue":"1","key":"2020021109181697700_B11","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1200\/JCO.2012.42.7906","article-title":"Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed\/refractory B-cell malignancies","volume":"31","author":"Advani","year":"2013","journal-title":"J Clin Oncol"},{"issue":"4","key":"2020021109181697700_B12","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1056\/NEJMoa1509981","article-title":"Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia","volume":"374","author":"Byrd","year":"2016","journal-title":"N Engl J Med"},{"issue":"23","key":"2020021109181697700_B13","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1182\/blood.V126.23.832.832","article-title":"The BTK inhibitor, Bgb-3111, is safe, tolerable, and highly active in patients with relapsed\/ refractory B-cell malignancies: initial report of a phase 1 first-in-human trial [abstract]","volume":"126","author":"Tam","year":"2015","journal-title":"Blood"},{"issue":"7","key":"2020021109181697700_B14","doi-asserted-by":"crossref","first-page":"e295","DOI":"10.3324\/haematol.2015.140806","article-title":"Phase I study of single-agent CC-292, a highly selective Bruton\u2019s tyrosine kinase inhibitor, in relapsed\/refractory chronic lymphocytic leukemia","volume":"101","author":"Brown","year":"2016","journal-title":"Haematologica"},{"issue":"4","key":"2020021109181697700_B15","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1182\/blood-2015-08-664086","article-title":"A phase 1 clinical trial of the selective BTK inhibitor ONO\/GS-4059 in relapsed and refractory mature B-cell malignancies","volume":"127","author":"Walter","year":"2016","journal-title":"Blood"},{"issue":"4","key":"2020021109181697700_B16","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1038\/leu.2014.247","article-title":"Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation","volume":"29","author":"Kamel","year":"2015","journal-title":"Leukemia"},{"issue":"26","key":"2020021109181697700_B17","doi-asserted-by":"crossref","first-page":"3991","DOI":"10.1182\/blood-2014-06-583294","article-title":"Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions","volume":"124","author":"Levade","year":"2014","journal-title":"Blood"},{"issue":"25","key":"2020021109181697700_B18","doi-asserted-by":"crossref","first-page":"3829","DOI":"10.1182\/blood-2014-10-604272","article-title":"Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling","volume":"124","author":"McMullen","year":"2014","journal-title":"Blood"},{"issue":"3","key":"2020021109181697700_B19","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1111\/bjh.14324","article-title":"Atrial fibrillation in CLL patients treated with ibrutinib. An international retrospective study","volume":"175","author":"Thompson","year":"2016","journal-title":"Br J Haematol"},{"issue":"12","key":"2020021109181697700_B20","doi-asserted-by":"crossref","first-page":"5446","DOI":"10.1182\/blood-2007-06-093906","article-title":"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","volume":"111","author":"Hallek","year":"2008","journal-title":"Blood"},{"issue":"23","key":"2020021109181697700_B21","first-page":"5348","article-title":"Response assessment in chronic lymphocytic leukemia treated with novel agents causing an increase of peripheral blood lymphocytes [abstract]","volume":"119","author":"Hallek","year":"2012","journal-title":"Blood"},{"issue":"27","key":"2020021109181697700_B22","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.1200\/JCO.2013.54.8800","article-title":"Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification","volume":"32","author":"Cheson","year":"2014","journal-title":"J Clin Oncol"},{"issue":"16","key":"2020021109181697700_B23","doi-asserted-by":"crossref","first-page":"2497","DOI":"10.1182\/blood-2014-10-606038","article-title":"Three-year follow-up of treatment-na\u00efve and previously treated patients with CLL and SLL receiving single-agent ibrutinib","volume":"125","author":"Byrd","year":"2015","journal-title":"Blood"},{"issue":"5","key":"2020021109181697700_B24","doi-asserted-by":"crossref","first-page":"874","DOI":"10.3324\/haematol.2017.182907","article-title":"Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis","volume":"103","author":"Mato","year":"2018","journal-title":"Haematologica"},{"key":"2020021109181697700_B25","volume-title":"Summary of product characteristics","author":"IMBRUVICA","year":"2018"},{"issue":"26","key":"2020021109181697700_B26","doi-asserted-by":"crossref","first-page":"2610","DOI":"10.1182\/bloodadvances.2017011999","article-title":"Severe platelet dysfunction in NHL patients receiving ibrutinib is absent in patients receiving acalabrutinib","volume":"1","author":"Bye","year":"2017","journal-title":"Blood Adv"},{"issue":"5","key":"2020021109181697700_B27","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1111\/ejh.13148","article-title":"The effect of Bruton\u2019s tyrosine kinase (BTK) inhibitors on collagen-induced platelet aggregation, BTK, and tyrosine kinase expressed in hepatocellular carcinoma (TEC)","volume":"101","author":"Chen","year":"2018","journal-title":"Eur J Haematol"},{"issue":"1","key":"2020021109181697700_B28","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1080\/13543784.2018.1404027","article-title":"Bruton\u2019s tyrosine kinase inhibitors: first and second generation agents for patients with chronic lymphocytic leukemia (CLL)","volume":"27","author":"Thompson","year":"2018","journal-title":"Expert Opin Investig Drugs"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/134\/11\/851\/1554545\/bloodbld2019001160.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/134\/11\/851\/1554545\/bloodbld2019001160.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,2,11]],"date-time":"2020-02-11T09:51:23Z","timestamp":1581414683000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/134\/11\/851\/273871\/Phase-1-study-of-the-selective-BTK-inhibitor"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,12]]},"references-count":28,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2019,9,12]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2019001160","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.736262333.793582417","asserted-by":"object"}]},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,12]]}}}