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Title: | Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. | Authors: | Trotman J.;Marlton P.;Munoz J.;Seymour J.F.;Simpson D.;Tedeschi A.;Elstrom R.;Yu Y.;Tang Z.;Han L.;Huang J.;Novotny W.;Wang L. ;Harrup R.;Roberts A.W.;Gottlieb D.;Burger J.A.;Opat S. ;Tam C.S.;Johnston P.B.;Cull G. | Institution: | (Tam, Seymour, Roberts) Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (Tam, Seymour, Roberts) Department of Medicine, University of Melbourne, Parkville, VIC, Australia (Tam) St Vincent's Hospital, Fitzroy, VIC, Australia (Tam, Seymour, Roberts) Royal Melbourne Hospital, Parkville, VIC, Australia (Tam, Seymour, Roberts) Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia (Trotman) Department of Haematology, Concord Repatriation General Hospital, Concord, NSW, Australia (Trotman) Haematology Department, University of Sydney, Concord, NSW, Australia (Opat) Clinical Haematology, Monash Health, Clayton, VIC, Australia (Opat) School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia (Burger) Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, United States (Cull) Haematology Department, Sir Charles Gairdner Hospital, Nedlands, WA, Australia (Cull) PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA, Australia (Cull) University of Western Australia, Perth, WA, Australia (Gottlieb) Department of Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia (Gottlieb) Department of Haematology, Westmead Hospital, Westmead, NSW, Australia (Harrup) Department of Clinical Haematology, Royal Hobart Hospital, Hobart, TAS, Australia (Harrup) Department of Medical Oncology, University of Tasmania, Hobart, TAS, Australia (Johnston) Division of Hematology, Mayo Clinic, Rochester, MN, United States (Marlton) Princess Alexandra Hospital, Brisbane, QLD, Australia (Marlton) School of Medicine, University of Queensland, Brisbane, QLD, Australia (Munoz) Banner MD Anderson Cancer Center, Gilbert, AZ, United States (Simpson) North Shore Hospital, Auckland, New Zealand (Tedeschi) ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy (Elstrom, Tang, Han, Huang, Novotny) BeiGene USA, Inc, San Mateo, CA, United States (Yu) BeiGene Shanghai, Ltd, Shanghai, China (Wang) BeiGene Beijing, Ltd, Beijing, China (Roberts) Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia | Issue Date: | 26-Sep-2019 | Copyright year: | 2019 | Publisher: | American Society of Hematology (E-mail: publishing@hematology.org) | Place of publication: | United States | Publication information: | Blood. 134 (11) (pp 851-859), 2019. Date of Publication: 12 Sep 2019. | Journal: | Blood | 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.Copyright © 2019 by The American Society of Hematology | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1182/blood.2019001160 | PubMed URL: | 31340982 [http://www.ncbi.nlm.nih.gov/pubmed/?term=31340982] | ISSN: | 0006-4971 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/35986 | Type: | Article | Subjects: | herpes zoster/si [Side Effect] human human cell hypertension/si [Side Effect] *leukemia relapse limb injury/si [Side Effect] limit of quantitation liquid chromatography mass spectrometry lymph node biopsy lymphadenopathy lymphocyte count *lymphocytic lymphoma/dt [Drug Therapy] lymphocytosis major clinical study male maximum plasma concentration maximum tolerated dose multicenter study muscle spasm/si [Side Effect] nausea/si [Side Effect] neutropenia/si [Side Effect] open study peripheral blood mononuclear cell peripheral edema/si [Side Effect] petechia/si [Side Effect] pharmacodynamics pharmacokinetic parameters phase 1 clinical trial plasma concentration-time curve pneumonia/si [Side Effect] priority journal progression free survival purpura/si [Side Effect] rash/si [Side Effect] rhinopharyngitis/si [Side Effect] sinusitis/si [Side Effect] squamous cell skin carcinoma/si [Side Effect] subcutaneous hemorrhage/si [Side Effect] therapeutic dose therapy delay thrombocytopenia/si [Side Effect] upper respiratory tract infection/si [Side Effect] urinary tract infection/si [Side Effect] very elderly X-ray computed tomography xerostomia/si [Side Effect] acetylsalicylic acid alemtuzumab bendamustine chlorambucil clopidogrel cyclophosphamide doxorubicin duvelisib fludarabine heparin idelalisib lenalidomide low molecular weight heparin navitoclax nonsteroid antiinflammatory agent obinutuzumab ofatumumab pentostatin prednisone rituximab thrombin inhibitor venetoclax vincristine *zanubrutinib/ae [Adverse Drug Reaction] *zanubrutinib/ct [Clinical Trial] *zanubrutinib/dt [Drug Therapy] *zanubrutinib/to [Drug Toxicity] *zanubrutinib/po [Oral Drug Administration] *zanubrutinib/pk [Pharmacokinetics] *zanubrutinib/pd [Pharmacology] postprocedural contusion/si [Side Effect] drug half life abdominal pain/si [Side Effect] acute kidney failure/si [Side Effect] adult aged anemia/si [Side Effect] area under the curve arthralgia/si [Side Effect] article backache/si [Side Effect] basal cell carcinoma/si [Side Effect] cancer patient cancer survival cellulitis/si [Side Effect] *chronic lymphatic leukemia/dt [Drug Therapy] clinical outcome cohort analysis constipation/si [Side Effect] contusion/si [Side Effect] coughing/si [Side Effect] diarrhea/si [Side Effect] disease exacerbation dizziness/si [Side Effect] drug blood level drug dose escalation *drug efficacy *drug safety drug tolerability fatigue/si [Side Effect] febrile neutropenia/si [Side Effect] female follow up headache/si [Side Effect] hematuria/si [Side Effect] cancer survival cellulitis / side effect *chronic lymphatic leukemia / *drug therapy clinical outcome cohort analysis constipation / side effect contusion / side effect coughing / side effect diarrhea / side effect disease exacerbation dizziness / side effect drug blood level drug dose escalation *drug efficacy drug half life *drug safety drug tolerability fatigue / side effect febrile neutropenia / side effect female follow up headache / side effect hematuria / side effect herpes zoster / side effect human human cell hypertension / side effect *leukemia relapse limb injury / side effect limit of quantitation liquid chromatography-mass spectrometry lymph node biopsy lymphadenopathy lymphocyte count *lymphocytic lymphoma / *drug therapy lymphocytosis major clinical study male maximum plasma concentration maximum tolerated dose multicenter study muscle spasm / side effect nausea / side effect neutropenia / side effect open study peripheral blood mononuclear cell peripheral edema / side effect petechia / side effect acute kidney failure / side effect pharmacokinetic parameters phase 1 clinical trial plasma concentration-time curve pneumonia / side effect priority journal progression free survival purpura / side effect rash / side effect rhinopharyngitis / side effect sinusitis / side effect squamous cell skin carcinoma / side effect subcutaneous hemorrhage / side effect therapeutic dose therapy delay thrombocytopenia / side effect upper respiratory tract infection / side effect urinary tract infection / side effect very elderly x-ray computed tomography xerostomia / side effect abdominal pain / side effect pharmacodynamics adult aged anemia / side effect area under the curve arthralgia / side effect Article backache / side effect basal cell carcinoma / side effect cancer patient |
Type of Clinical Study or Trial: | Observational study (cohort, case-control, cross sectional or survey) |
Appears in Collections: | Articles |
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