| Reference | 1. Leuk Lymphoma. 2017 Mar;58(3):699-707. doi: 10.1080/10428194.2016.1201567. Epub
2016 Aug 9.
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Anti-tumor efficacy study of the Bruton/’s tyrosine kinase (BTK) inhibitor,
ONO/GS-4059, in combination with the glycoengineered type II anti-CD20 monoclonal
antibody obinutuzumab (GA101) demonstrates superior in vivo efficacy compared to
ONO/GS-4059 in combination with rituximab.
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Yasuhiro T(1), Sawada W(1), Klein C(2), Kozaki R(1), Hotta S(1), Yoshizawa T(1).
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Author information: <br>
(1)a Ono Pharmaceutical Co, Ltd , Osaka , Japan.
(2)b Roche Pharmaceutical Research & Early Development, Roche Innovation Center
Zurich , Schlieren , Switzerland.
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The activated B-cell diffuse large B-cell-like lymphoma (ABC-DLBCL) correlates
with poor prognosis. The B-cell receptor signaling pathway is known to be
dysregulated in NHL/CLL and given BTK is a downstream mediator of BCR signaling,
BTK constitutes an interesting and obvious therapeutic target. Given the high
potency and selectivity of the BTK inhibitor, ONO/GS-4059, it was hypothesized
that, the anti-tumor activity of ONO/GS-4059 could be further enhanced by
combining it with the anti-CD20 Abs, rituximab (RTX) or obinutuzumab (GA101).
ONO/GS-4059 combined with GA101 or RTX was significantly better than the
respective monotherapy with tumor growth inhibition (TGI) of 90% for the GA101
combination and 86% for the RTX combination. In contrast, ibrutinib (PCI-32765)
combined with RTX did not result in improved efficacy compared with respective
monotherapy. Taken together these data indicate that the combination of
ONO/GS-4059 with rituximab and particularly obinutuzumab may be an effective
treatment for ABC-DLBCL.
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2. Oncotarget. 2017 Jan 24;8(4):7201-7207. doi: 10.18632/oncotarget.12786.
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Bruton tyrosine kinase inhibitor ONO/GS-4059: from bench to bedside.
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Wu J(1), Zhang M(1), Liu D(1).
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Author information: <br>
(1)Department of Oncology, The first Affiliated Hospital of Zhengzhou University,
Zhengzhou, China.
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The Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has been approved for the
treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and
Waldenstrom/’s macroglobulinemia. Acquired resistance to ibrutinib due to BTK
C481S mutation has been reported. Mutations in PLCγ2 can also mediate resistance
to ibrutinib. Untoward effects due to off-target effects are also disadvantages
of ibrutinib. More selective and potent BTK inhibitors (ACP-196, ONO/GS-4059,
BGB-3111, CC-292) are being investigated. This review summarized the preclinical
research and clinical data of ONO/GS-4059.
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3. Blood. 2016 Jan 28;127(4):411-9. doi: 10.1182/blood-2015-08-664086. Epub 2015 Nov
5.
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A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed
and refractory mature B-cell malignancies.
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Walter HS(1), Rule SA(2), Dyer MJ(1), Karlin L(3), Jones C(4), Cazin B(5),
Quittet P(6), Shah N(2), Hutchinson CV(7), Honda H(8), Duffy K(9), Birkett J(9),
Jamieson V(9), Courtenay-Luck N(9), Yoshizawa T(8), Sharpe J(9), Ohno T(8), Abe
S(9), Nishimura A(8), Cartron G(6), Morschhauser F(5), Fegan C(4), Salles G(3).
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Author information: <br>
(1)Ernest and Helen Scott Haematological Research Institute, University of
Leicester, Leicester, United Kingdom;
(2)Department of Haematology, Plymouth Hospitals NHS Trust, Plymouth, United
Kingdom;
(3)Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Service d/’Hématologie,
Pierre-Bénite, Université Claude Bernard Lyon 1, Lyon, France;
(4)Cardiff CLL Research Group, School of Medicine, Heath Park, Cardiff, Wales,
United Kingdom;
(5)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;
(6)Department of Clinical Hematology and Unité Mixte de Recherche (UMR)-Centre
National de la Recherche Scientifique (CNRS) 5235, CHRU, Montpellier, France;
(7)Ernest and Helen Scott Haematological Research Institute, University of
Leicester, Leicester, United Kingdom; Department of Haematology, Plymouth
Hospitals NHS Trust, Plymouth, United Kingdom;
(8)ONO Pharmaceuticals Co Ltd, Osaka, Japan; and.
(9)ONO Pharma UK Ltd, London, United Kingdom.
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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.
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