A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies

Walter, Harriet S.; Rule, Simon; Dyer, Martin J. S.; Karlin, Lionel; Jones, Ceri; Cazin, Bruno; Quittet, Philippe; Shah, Nimish; Hutchinson, Claire V.; Honda, Hideyuki; Duffy, Kevin J.; Birkett, Joseph; Jamieson, Virginia; Courtenay-Luck, Nigel; Yoshizawa, Toshio; Sharpe, John C.; Ohno, Tomoya; Abe, Shin‐ichiro; Nishimura, Akira; Cartron, Guillaume; Morschhauser, Franck; Fegan, Christopher; Salles, Gilles

doi:10.1182/blood-2015-08-664086

Cited by 231 publications

(191 citation statements)

References 28 publications

(35 reference statements)

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“…Clinical trials are currently evaluating second-generation BTK inhibitors (for example, acalabrutinib 148 , ONO/GS-4059 (REF. 149) or BGB-3111) to determine whether any one of these drugs has a superior therapeutic index than that of ibrutinib 150 .…”

Section: Managementmentioning

confidence: 99%

Chronic lymphocytic leukaemia

Kipps

Stevenson

et al. 2017

Nat Rev Dis Primers

403

408

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Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5+ B cells that is characterized by the accumulation of small, mature-appearing lymphocytes in the blood, marrow and lymphoid tissues. Signalling via surface immunoglobulin, which constitutes the major part of the B cell receptor, and several genetic alterations play a part in CLL pathogenesis, in addition to interactions between CLL cells and other cell types, such as stromal cells, T cells and nurse-like cells in the lymph nodes. The clinical progression of CLL is heterogeneous and ranges from patients who require treatment soon after diagnosis to others who do not require therapy for many years, if at all. Several factors, including the immunoglobulin heavy-chain variable region gene (IGHV) mutational status, genomic changes, patient age and the presence of comorbidities, should be considered when defining the optimal management strategies, which include chemotherapy, chemoimmunotherapy and/or drugs targeting B cell receptor signalling or inhibitors of apoptosis, such as BCL-2. Research on the biology of CLL has profoundly enhanced our ability to identify patients who are at higher risk for disease progression and our capacity to treat patients with drugs that selectively target distinctive phenotypic or physiological features of CLL. How these and other advances have shaped our current understanding and treatment of patients with CLL is the subject of this Primer.

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Section: Managementmentioning

confidence: 99%

Chronic lymphocytic leukaemia

Kipps

Stevenson

et al. 2017

Nat Rev Dis Primers

403

408

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“…In our study, 23 patients (82%) exhibited lymphocytosis; mean fold increase above baseline was 4.5-fold. 10 In all instances, lymphocytosis following ONO/GS-4059 resolved by cycle 6. As with other BTKis, 11,15 changes in serum levels of CCL3 and CCL4 showed a significant decrease at day 8, consistent with B-cell receptor signaling pathway blockade; tumor necrosis factor-a, interleukin-10 (IL-10), IL-6, and IL-8 also showed a significant decrease 8 days after treatment initiation (supplemental Figure 1A).…”

mentioning

confidence: 83%

“…Preliminary data indicate that these drugs have comparable activity to ibrutinib, but with reduced toxicities. [10][11][12] However, long-term follow-up and response data have not yet been reported. We provide an updated, 3-year follow-up of treatment efficacy, safety, and laboratory correlates, including baseline mutational profiling of CLL patients in the phase 1 ONO/GS-4059 extension study.…”

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confidence: 99%

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Long-term follow-up of patients with CLL treated with the selective Bruton’s tyrosine kinase inhibitor ONO/GS-4059

Walter

Jayne

Rule³

et al. 2017

Blood

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“…ONO-4059-This agent is a reversible BTK inhibitor that acts by blocking auto-phosphorylation at the tyrosine 223 position. Results from a phase I trial [141] (dose escalation study) showed an ORR of 96% in 25 patients with relapsed/refractory CLL. The drug was well tolerated with infrequent toxicities.…”

Section: Selinexor (Previously Kpt-330)mentioning

confidence: 99%

Chronic lymphocytic leukemia (CLL)—Then and now

Kanti

Jain²

2016

American J Hematol

127

100

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The field of chronic lymphocytic leukemia (CLL) has witnessed considerable change since the time clinical staging was introduced in clinical practice in 1975. Over the years, the prognostication in CLL has expanded with the addition in late 90s of mutational status of variable region of immunoglobulin heavy chain (IGHV), and chromosomal analyses using fluorescent in situ hybridization (FISH). More recently, stereotypy of BCR (B cell receptor) and whole exome sequencing (WES) based discovery of specific mutations such as NOTCH1, TP53, SF3B1, XPO-1, BIRC3, ATM, and RPS15 further refined the current prognostication system in CLL. In therapy, the field of CLL has seen major changes from oral chlorambucil and steroids prior to 1980s, to chemo-immunotherapy (CIT) with fludarabine, cyclophosphamide, rituximab (FCR) to the orally administered targeted therapeutic agents inhibiting kinases in the B cell receptor (BCR) signaling pathway such as Ibrutinib (BTK inhibitor) and Idelalisib (p110 PI3Kd inhibitor) and novel anti-CD20 mAb's (monoclonal antibodies) such as obinutuzumab. This progress is continuing and other targeted therapeutics such as Bcl2 antagonists (Venetoclax or ABT-199) and finally chimeric antigen receptor against T cells (CART) are in the process of being developed. This review is an attempt to summarize the major benchmarks in the prognostication and in the therapy of CLL. The topic allocated to us by Dr Ayalew Tefferi and Dr Carlo Brugnara is very appropriate to reminisce what our understanding of chronic lymphocytic leukemia (CLL) was in 1976 and how rapidly have the advances occurring in this field affected the patients with CLL. It is a disease of progressive accumulation of lymphocytes. CLL lymphocytes are morphologically indistinguishable from a normal mature lymphocyte CLL lymphocytes are functionally inert and perhaps as a direct consequence, their life-span is longer than of normal lymphocytes. It was also believed that CLL lymphocytes are not rapidly proliferating. CLL is a disease of elderly population In some cases, chronic lymphocytic leukemia (CLL) closely resembled leukemic Brill Symmers disease (leukemic form of follicular lymphoma). In an elegant study on 88 patients, the temporal profile of the clinical course of CLL was described by Galton et al.[1] Disease progression was assessed in relation to lymphadenopathy, splenomegaly and bone marrow infiltration. CLL was considered as an immunoproliferative disorder with low immunoglobulin levels, striking response to therapy with steroids and exaggerated skin reaction to arthropod bites. Management of CLL (then in 1976)Most clinicians recognized that at the time of initial diagnosis, patients with CLL, generally, were free of disease-related symptoms. Therefore, virtually all patients were followed on a wait-and-watch regimen, withholding any cytotoxic therapy. When, on clinical grounds, initiation of any therapy was considered appropriate, oral alkylating agents such as chlorambucil with/without steroids [3,4] or cyclophosphamide [5] with or...

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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

Cited by 231 publications

References 28 publications

Chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia

Long-term follow-up of patients with CLL treated with the selective Bruton’s tyrosine kinase inhibitor ONO/GS-4059

Chronic lymphocytic leukemia (CLL)—Then and now

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