The Bruton’s Tyrosine Kinase (BTK) Inhibitor ONO-4059: Promising Single Agent Activity and Well Tolerated in Patients with High Risk Chronic Lymphocytic Leukaemia (CLL)
Authors: Fegan Christopher , Bagshawe Joanne , Salles Gilles , Karlin Lionel , Rule Simon , Shah Nimish , Morschhauser Franck , Terriou Louis , Dyer Martin JS , Walter Harriet , Hutchinson Claire , Cartron Guillaume , Sharpe John , Duffy Kevin , Nishimura Akhisa , Abe Shin-ichiro , Honda Hideyuki , Yasuhiro Tomoko , Yoshizawa Toshio , Birkett Joseph , Courtenay-Luck Nigel 
Published: November 2019

Abstract
Introduction
Bruton’s tyrosine kinase (BTK) is a critical kinase involved in B-cell receptor signal transduction. ONO-4059, a highly potent and selective oral BTK inhibitor has demonstrated anti-tumour activity in pre-clinical models (Yasuhiro et al, AACR2013) and in the clinic in both CLL and NHL patients (Morschhauser et al, EHA 2014; Rule et al, EHA 2014). Here, we present data from 25 CLL patients enrolled in the ongoing Phase I study ONO-4059POE001.
Methods
Twenty five CLL patients were administered ONO-4059 as monotherapy, given once daily (QD) to determine safety, pharmacokinetics and pharmacodynamics, and preliminary efficacy. Patients can receive ONO-4059 for up to a maximum of 3 years and upon completion of the first 6 months of treatment, intra-patient dose escalation is permitted. Here, we present data for 25 evaluable patients treated with ONO-4059 at doses ranging from 20-600mg (8 cohorts).
Patients had a median age 67 yrs [range 40-79], median baseline tumour burden 3,943 mm2 [461-19,750 mm2], median of 4 prior therapies [2-8], including fludarabine (23/25) and rituximab-containing therapy (23/25). Baseline median haematology parameters included lymphocytes 34.6 x 109/L [0.1-391], haemoglobins 11.1 g/dL [8.5-15.2], platelets 97 x 109/L [23-185], neutrophils 2.39 x 109/L [0.5-11.1]. 9/24 patients were 17p deleted [38%] and 6/24 had the 11q deletion [25%], 20/24 were IgVH unmutated status [83%], with 13/24 [54%] displaying TP53 mutation).
Results
To date, 19 of 25 patients remain on treatment with a median duration of treatment of 363 days [27-659]. ONO-4059 was found to be well tolerated with few adverse reactions over a long duration. A total of sixty two ONO-4059-related Grade 1- 2 adverse events were reported in 19 out of 25 patients. Eight dose independent ONO-4059-related G3 or G4 haematological toxicities were reported in 5 patients; with neutropenia in 3 patients, [G3 x 1, G4 x 2]), febrile neutropenia in 1 patient [G3] and leucopenia in 2 patients [G3 x 4]. Six Grade 3 ONO-4059-related non-haematological events were reported (pyrexia x 1, Hepatitis E reactivation x 1, Lymphocytic infiltration, Purpura, Urinary tract infection and Haematoma in just one patient). Nine ONO-4059-related SAEs were reported in 6 patients (febrile neutropenia [G3] and pyrexia [G3] at 20 mg, rash [G2] at 80 mg, hepatitis E reactivation [G3] at 320mg, neutropenia [G4] at 320 mg, purpura x 2 [G2, G3] and lymphocytic infiltration [G3] at 400 mg, haematoma [G2] at 500mg).
All patients experienced rapid reductions in lymphadenopathy observed early in treatment between Cycle1 and Cycle3, accompanied by an increase in absolute lymphocyte count in 72% of patients. Almost all patients have durable response over a long duration. Best overall response rate according to IWCLL criteria (including modified PR with lymphocytosis) was 84% [based on CT-scan and P/E for 21/25 evaluable patients with 17 PR, 4 PR with lymphocytosis (for 21 responding patients, median reduction of lymph nodes was 83% [51-100]), 1 SD and 2 PD], with 89% response rate on 17p deleted. The early tumour shrinkage was associated with a rise in haemoglobin and platelet count. An increase in exposure (as assessed by Cmax and AUC) that was proportional to an increase in dose was seen for all doses of ONO-4059 ranging from 20-600mg.
Conclusion
ONO-4059 is a highly potent and selective oral Btk inhibitor with a favourable safety profile along with promising efficacy over a long duration in this heavily pre-treated population, with responses observed in relapsed, refractory and currently poor prognostic 17p deleted patients.

Disclosures
Fegan: ONO PHARMA: Honoraria. Salles:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; genetech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Karlin:Janssen: Honoraria; celgene: Consultancy, Honoraria; Sandoz: Consultancy. Rule:Pharmacyclics, J&J: Consultancy, Membership on an entity's Board of Directors or advisory committees. Morschhauser:ONO PHARMA: Honoraria; Roche: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria. Dyer:ONO PHARMA: Research Funding. Cartron:ONO PHARMA: Honoraria. Honda:Ono Pharmaceutical Co., Ltd.: Employment. Yasuhiro:Ono Pharmaceutical Co., Ltd.: Employment. Yoshizawa:Ono Pharmaceutical Co., Ltd.: Employment.