624. LYMPHOMA: THERAPY WITH BIOLOGIC AGENTS, EXCLUDING
`PRE-CLINICAL MODELS: POSTER III |
`NOVEMBER 15, 2013
`
`A Phase I Study Of The Oral Btk Inhibitor ONO-4059 In
`Patients With Relapsed/Refractory B-Cell Lymphoma
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`Simon Rule, MD,*,1 Nimish Shah, MD,*,1 Gilles Andre Salles, MD, PhD,2 Lionel Karlin, MD,*,3
`Franck Morschhauser, MD, PhD,*,4 Louis Terriou, MD,*,5 Martin JS Dyer, MA,
`DPhil, FRCP, FRCPath,6 Claire Hutchinson, BMedSci, MRCP, FRCPath,*,7
`Chris Fegan, MBBS,*,8 Guillaume Cartron, MD, PhD,*,9 Tomasz Knurowski, MD,*,10
`James
`G Wright, PhD,*,11 Andrew J Saunders, MD,*,12 Hideyuki Honda, Bsc,*,13 Andrew Mazur,*,13
`Toshio Yoshizawa, PhD,*,14 Kazuhito Kawabata, PhD,*,15
`Joseph TP Birkett, PhD*,16
`1Department of Haematology, Derriford Hospital, Plymouth, United Kingdom,
`2Hospices Civils de Lyon; Université Claude Bernard Lyon 1, Lyon, France,
`3Centre Hospitalier Lyon Sud/Hospices Civils de Lyon, Pierre-Bénite, France,
`4Service Maladies du Sang, CHRU - Hôpital Claude Huriez, Lille, France,
`5Hôpital Claude Huriez, Lille, France,
`6Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, United Kingdom,
`7Department Cancer Studies and Molecular Medicine, University of Leicester, Leicester, United Kingdom,
`8Department of Haematology, Cardiff University, Cardiff, United Kingdom,
`9Département d’Hématologie Clinique, CHU Montpellier, Monpellier, France,
`10Orion Clinical Services, Slough, United Kingdom,
`11Wright Dose Limited, Manchester, United Kingdom,
`12Linden Oncology, Edinburgh, United Kingdom,
`13ONO Pharma UK LTD, London, United Kingdom,
`14Ono Pharmaceutical CO., LTD, Osaka, Japan,
`15Ono Pharmaceutical Co., Ltd., Osaka, Japan,
`16Clinical Science Oncology, Ono Pharma UK Ltd., London, United Kingdom
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`Blood (2013) 122 (21) : 4397.
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`http://doi.org/10.1182/blood.V122.21.4397.4397
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`Abstract
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`Introduction
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`The B-cell receptor (BCR) pathway plays a central role in signal transduction pathways that regulate
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`survival, activation, proliferation and differentiation of B-lineage lymphoid cells. Bruton’s tyrosine kinase
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`(Btk) is a critical kinase in BCR signal transduction and recent studies support that targeting Btk is
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`effective in the treatment of B-cell malignancies. ONO-4059 is a highly potent and selective oral Btk
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`inhibitor with an IC50 in the sub-nmol/L range that has demonstrated anti-tumour activity in several pre-
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`clinical models (Yasuhiro T et al, AACR 2013).
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`Methods
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`This Phase I study was initiated to determine the safety, tolerability, dose-limiting toxicity (DLT),
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`pharmacokinetics and pharmacodynamics of ONO-4059 given as monotherapy to patients with relapsed/
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`refractory NHL for whom no therapy of higher priority was available. In this safety-driven, dose-escalating
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`3+3 design, ONO-4059 was administered as an oral, daily dose (flat dose) given continuously initially for
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`up to 6 months, with the option of additional dosing up to 2 years. We present the safety and efficacy data
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`on 14 evaluable patients (mantle cell lymphoma n=7, follicular lymphoma n=3, plasmablastic DLBCL n=1,
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`ABC-DLBCL n=1, small lymphocytic lymphoma n=1 and Waldenstrom’s macroglobulinaemia n=1), with
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`a median age 64 yrs (range 48-88), median baseline tumour burden 5,668 mm2 [1,582-19,509]. Patients
`received a median of 3 prior therapies [range 2-8], with all patients having prior exposure to a rituximab-
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`containing regimen 93% (13/14) and 29% of patients (4/14) had prior ASCT. Patients received ONO-4059
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`at doses ranging from 20mg-160mg (cohorts 1-4) and the study is currently ongoing with additional dose
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`escalation cohorts to be completed.
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`Results
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`ONO-4059 was found to be well tolerated, with no dose limiting toxicities (DLTs). A total of 18 ONO-4059-
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`related adverse events were reported in 6 out of 14 patients; CTCAE-V4.0 G1 (n=10 [n=6 in 1 patient])
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`and G2 (n=5). Three ONO-4059-related G3 haematological toxicities were reported in 2 patients;
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`thrombocytopenia (x2) and anemia. No ONO-4059-related G4 events, or related SAEs or infections were
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`reported. The pharmacokinetics of ONO-4059 reflects rapid absorption and elimination, a half-life of ∼6
`hours, a dose dependent increase in exposure with no accumulation of ONO-4059 exposure and low
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`inter- or intra-patient variability; with Btk occupancy in peripheral blood (as measured by phosphorylated
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`Btk) being maintained for at least 24 hours across all dose levels. Responses have occurred at doses of
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`40, 80 and 160mg, with a best overall response rate of 42% [based on CT-scan and physical examination
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`for 5/12 evaluable patients]; with 5 PR, 4 SD, 2 PD (both MCL) and one ABC-DLBCL patient was
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`withdrawn due to non-related SAE during Cycle 1. Of the 6 evaluable MCL patients, 3 have achieved
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`PR resulting in a best ORR of 50% (median reduction of lymph nodes was 73% [45%-84%]). Almost all
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`patients experienced clinically meaningful rapid reductions in lymphadenopathy observed within the first
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`cycle. Ten of the fourteen patients are currently still on study with a median progression-free survival of
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`93.5 days [Range 8-268]. In conclusion, ONO-4059 is a highly potent and selective oral Btk inhibitor that
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`shows a favourable safety profile along with promising efficacy in this difficult-to-treat patient population.
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`Disclosures:
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`Salles: Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria. Karlin: Janssen: Honoraria;
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`Celgene: Honoraria. Morschhauser: ONO Pharma: Honoraria; Roche: Honoraria; Celgene: Honoraria;
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`Mundipharma: Honoraria. Dyer: Ono Pharma: Honoraria, Research Funding. Hutchinson: Ono Pharma:
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`Research Funding. Fegan: ONO Pharma: Honoraria. Cartron: ONO Pharma: Honoraria. Knurowski:
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`ONO Pharma: Consultancy. Wright: ONO Pharma: Consultancy. Saunders: ONO Pharma: Consultancy;
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`Pharmacyclics: Consultancy. Honda: ONO Pharma: Employment. Mazur: ONO Pharma: Consultancy.
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`Yoshizawa: Ono Pharma: Employment. Kawabata: Ono Pharmaceutical Co., Ltd.: Employment. Birkett:
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`Ono Pharma UK: Employment.
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`Author notes
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`* Asterisk with author names denotes non-ASH members.
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`© 2013 by the American Society of Hematology
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