title: A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies.
abstract: We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255.
authors.affiliation: Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom;
authors.forename: Harriet S
authors.identifier: http://orcid.org/0000-0003-2618-711X
authors.initials: HS
authors.lastname: Walter
authors.affiliation: Department of Haematology, Plymouth Hospitals NHS Trust, Plymouth, United Kingdom;
authors.forename: Simon A
authors.initials: SA
authors.lastname: Rule
authors.affiliation: Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom;
authors.forename: Martin J S
authors.identifier: http://orcid.org/0000-0002-5033-2236
authors.initials: MJ
authors.lastname: Dyer
authors.affiliation: Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Service d'Hématologie, Pierre-Bénite, Université Claude Bernard Lyon 1, Lyon, France;
authors.forename: Lionel
authors.initials: L
authors.lastname: Karlin
authors.affiliation: Cardiff CLL Research Group, School of Medicine, Heath Park, Cardiff, Wales, United Kingdom;
authors.forename: Ceri
authors.initials: C
authors.lastname: Jones
authors.affiliation: Department of Clinical Hematology, Centre Hospitalier Régional Universitaire (CHRU) de Lille, and Unité Groupe de Recherche sur les Formes Injectables et les Technologies Associées (GRITA), Université de Lille 2, Lille, France;
authors.forename: Bruno
authors.initials: B
authors.lastname: Cazin
authors.affiliation: Department of Clinical Hematology and Unité Mixte de Recherche (UMR)-Centre National de la Recherche Scientifique (CNRS) 5235, CHRU, Montpellier, France;
authors.forename: Philippe
authors.initials: P
authors.lastname: Quittet
authors.affiliation: Department of Haematology, Plymouth Hospitals NHS Trust, Plymouth, United Kingdom;
authors.forename: Nimish
authors.initials: N
authors.lastname: Shah
authors.affiliation: Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom; Department of Haematology, Plymouth Hospitals NHS Trust, Plymouth, United Kingdom;
authors.forename: Claire V
authors.initials: CV
authors.lastname: Hutchinson
authors.affiliation: ONO Pharmaceuticals Co Ltd, Osaka, Japan; and.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Honda
authors.affiliation: ONO Pharma UK Ltd, London, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Duffy
authors.affiliation: ONO Pharma UK Ltd, London, United Kingdom.
authors.forename: Joseph
authors.initials: J
authors.lastname: Birkett
authors.affiliation: ONO Pharma UK Ltd, London, United Kingdom.
authors.forename: Virginia
authors.initials: V
authors.lastname: Jamieson
authors.affiliation: ONO Pharma UK Ltd, London, United Kingdom.
authors.forename: Nigel
authors.initials: N
authors.lastname: Courtenay-Luck
authors.affiliation: ONO Pharmaceuticals Co Ltd, Osaka, Japan; and.
authors.forename: Toshio
authors.initials: T
authors.lastname: Yoshizawa
authors.affiliation: ONO Pharma UK Ltd, London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Sharpe
authors.affiliation: ONO Pharmaceuticals Co Ltd, Osaka, Japan; and.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Ohno
authors.affiliation: ONO Pharma UK Ltd, London, United Kingdom.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Abe
authors.affiliation: ONO Pharmaceuticals Co Ltd, Osaka, Japan; and.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Nishimura
authors.affiliation: Department of Clinical Hematology and Unité Mixte de Recherche (UMR)-Centre National de la Recherche Scientifique (CNRS) 5235, CHRU, Montpellier, France;
authors.forename: Guillaume
authors.initials: G
authors.lastname: Cartron
authors.affiliation: Department of Clinical Hematology, Centre Hospitalier Régional Universitaire (CHRU) de Lille, and Unité Groupe de Recherche sur les Formes Injectables et les Technologies Associées (GRITA), Université de Lille 2, Lille, France;
authors.forename: Franck
authors.initials: F
authors.lastname: Morschhauser
authors.affiliation: Cardiff CLL Research Group, School of Medicine, Heath Park, Cardiff, Wales, United Kingdom;
authors.forename: Christopher
authors.initials: C
authors.lastname: Fegan
authors.affiliation: Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Service d'Hématologie, Pierre-Bénite, Université Claude Bernard Lyon 1, Lyon, France;
authors.forename: Gilles
authors.identifier: http://orcid.org/0000-0002-9541-8666
authors.initials: G
authors.lastname: Salles
mesh_terms: D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000187:drug effects* / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000473:pathology; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000608238:tirabrutinib