Key Points• We report a first-in-human dose-escalation study in relapsed/refractory B-cell malignancies with the potent BTK inhibitor ONO/GS-4059.• ONO/GS-4059 induced clinically durable responses in relapsed/refractory B-cell malignancies without significant toxicities.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 doselimiting 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. (Blood. 2016;127(4):411-419)

Carbon dioxide laser vaporization of the turbinate has recently become accepted as a common treatment for allergic rhinitis. Usually, only a single procedure is applied to minimize trauma. However, repeated procedures on separate days are often required to achieve an adequate effect. Therefore, we attempted a new method of vaporization and evaluated the outcome, and also tried to determine which patients have good indications for laser treatment. To widely and deeply vaporize the inferior turbinate, we repeated the procedure 3 times in 1 session after removing the carbon coating from the previous vaporization under nasal endoscopic observation. After the procedure, most patients experienced complete nasal obstruction for 2 or 3 days, but there was no intraoperative or postoperative bleeding or severe pain. All patients obtained improvement of their chief complaints and were satisfied 2 months after the operation. In particular, 60% of the patients were completely relieved of refractory nasal obstruction. Most patients were more satisfied with the effects than are those treated by the usual methods. Completely successful cases (improvement in all symptoms and complete satisfaction obtained) were selected and were compared with other cases. Favorable prognostic factors are more severe complaints, longer symptomatic periods, stronger allergic reactions, and worse nasal resistance and its greater improvement with administration of decongestant nasal drops. This method may be especially accepted by patients with severe complaints, in particular nasal obstruction, who do not experience enough relief with conservative therapies or have enough time to make frequent visits to an outpatient clinic over a period of several weeks.

Purpose: Bruton’s tyrosine kinase (Btk) is a key regulator of the BCR signaling pathway and abberant BCR signaling has been implicated in the survival of malignant B-cells. The activated B-cell-like (ABC) sub-type of Diffuse Large B-Cell Lymphoma (DLBCL) correlates with poor prognosis. There is still a high unmet, medical need for new therapies, preferably chemo-sparing, to help treat patients with ABC-DLBCL and CLL as well as other B-cell malignancies. ONO-4059 is a highly selective, orally bioavailable inhibitor of Btk kinase activity with a potency (IC50) of 2.2 nM. ONO-4059 reversibly blocks BCR signaling and B-cell proliferation and activation. Data from the ongoing Phase 1 study (ONO-4059POE001), where ONO-4059 is administered as monotherapy (QD) demonstrated a best overall response rate of 47% (7/15) in non-GCB DLBCL patients (Walter et al, ASCO 2014; Rule et al, EHA 2014). We hypothesized that the efficacy of ONO-4059 could be further enhanced by increasing the drug trough concentration. To address this, we examined different dosing regimens of ONO-4059 in an ABC-DLBCL xenograft model. Methods: TMD-8 tumour cells (ABC-DLBCL cell line) were implanted sub-cutaneously into female SCID mice. Randomization of mice occurred when mean tumour volume was 100-200 or 400-450 mm3. ONO-4059 was administered orally or mixed in food at doses up to 20 mg/kg/day and animals were dosed QD or BD. Tumour volumes were measured twice a week after initiation of treatment, and tumour volumes were determined using the formula volume (= width2 x length)/2. Animals were euthanized when the tumours reached a maximum volume of 3,000 mm3. Results: For the100-200 mm3 tumour groups, tumour growth inhibition at the final treatment day was 23% in QD, 72.9% in BD and 100% in dose mixed in food, groups respectively. For the 400-450 mm3 tumour groups, no growth inhibition was observed in the QD group and, growth inhibitions of 27.5% in BD and 100% in dose mixed in food were observed. Interestingly, the treatment with ONO-4059-containing diets resulted in tumour remission in 10/10 animals, in both 100-200 and 400-450 mm3 treatment groups, whereas no tumour free animals were observed in the other treatment groups. The PK concentration and phosphorylated Btk (pBtk) inhibition levels of those animals whose dose was mixed in with food were higher than that of other treatment groups. Conclusion: Our previous study demonstrated that 100% tumour remission can be achieved partially with an ONO-4059 and GA101 or rituximab combination (Yoshizawa et al, ASH 2013). However, to date, no orally bioavailable targeted-agent administered as monotherapy has demonstrated 100% tumour remission in an advanced ABC-DLBCL xenograft model. Although the clinical data for ONO-4059 given as monotherapy (QD) is very encouraging in both relapsed and refractory CLL/NHL patients, this data indicates that a more frequent dosing regimen such as BD may be a more effective treatment, especially for non-GCB DLBCL and warrants further investigation in the clinical setting, along with food effect studies. Disclosures Yoshizawa: Ono Pharmaceutical Co., Ltd.: Employment. Yasuhiro:Ono Pharmaceutical Co., Ltd.: Employment. Honda:Ono Pharmaceutical Co., Ltd.: Employment. Kawabata:Ono Pharmaceutical Co., Ltd.: Employment.

Background The phase 3 VIALE-A trial (NCT02993523) reported that venetoclax-azacitidine significantly prolonged overall survival compared with placebo-azacitidine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy. Herein, efficacy and safety of venetoclax-azacitidine are analyzed in the Japanese subgroup of VIALE-A patients. Methods Eligible Japanese patients were randomized 2:1 to venetoclax-azacitidine (N = 24) or placebo-azacitidine (N = 13). Primary endpoints for Japan were overall survival and complete response (CR) + CR with incomplete hematologic recovery (CRi). Venetoclax (target dose 400 mg) was given orally once daily. Azacitidine (75 mg/m2) was administered subcutaneously or intravenously on Days 1–7 of each 28-day cycle. Results Median follow-up was 16.3 months (range, 1.0–20.3). Median overall survival was not reached with venetoclax-azacitidine (hazard ratio 0.409 and 95% confidence interval: 0.151, 1.109); overall survival estimate was higher with venetoclax-azacitidine than placebo-azacitidine at 12 (67 and 46%) and 18 months (57 and 31%), respectively. CR and CRi rates were 67% with venetoclax-azacitidine and 15% with placebo-azacitidine. Most common any-grade adverse events were febrile neutropenia (79 and 39%), thrombocytopenia (54 and 77%), constipation (54 and 54%) and decreased appetite (54 and 38%) in the venetoclax-azacitidine and placebo-azacitidine arms, respectively. Only 1 patient in the venetoclax-azacitidine arm, and no patients in the placebo-azacitidine arm, had grade 4 febrile neutropenia that led to treatment discontinuation. Conclusions This Japanese subgroup analysis of VIALE-A demonstrates comparable safety and efficacy outcomes compared with the global study and supports venetoclax-azacitidine as first-line standard-of-care for Japanese treatment-naive patients with acute myeloid leukemia who are ineligible for intensive chemotherapy.

Introduction The B-cell receptor (BCR) pathway plays a central role in signal transduction pathways that regulate survival, activation, proliferation and differentiation of B-lineage lymphoid cells. Bruton’s tyrosine kinase (Btk) is a critical kinase in BCR signal transduction and recent studies support that targeting Btk is effective in the treatment of B-cell malignancies. ONO-4059 is a highly potent and selective oral Btk inhibitor with an IC50 in the sub-nmol/L range that has demonstrated anti-tumour activity in several pre-clinical models (Yasuhiro T et al, AACR 2013). Methods This Phase I study was initiated to determine the safety, tolerability, dose-limiting toxicity (DLT), pharmacokinetics and pharmacodynamics of ONO-4059 given as monotherapy to patients with relapsed/refractory NHL for whom no therapy of higher priority was available. In this safety-driven, dose-escalating 3+3 design, ONO-4059 was administered as an oral, daily dose (flat dose) given continuously initially for up to 6 months, with the option of additional dosing up to 2 years. We present the safety and efficacy data on 14 evaluable patients (mantle cell lymphoma n=7, follicular lymphoma n=3, plasmablastic DLBCL n=1, ABC-DLBCL n=1, small lymphocytic lymphoma n=1 and Waldenstrom’s macroglobulinaemia n=1), with 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-containing regimen 93% (13/14) and 29% of patients (4/14) had prior ASCT. Patients received ONO-4059 at doses ranging from 20mg-160mg (cohorts 1-4) and the study is currently ongoing with additional dose escalation cohorts to be completed. Results ONO-4059 was found to be well tolerated, with no dose limiting toxicities (DLTs). A total of 18 ONO-4059-related adverse events were reported in 6 out of 14 patients; CTCAE-V4.0 G1 (n=10 [n=6 in 1 patient]) and G2 (n=5). Three ONO-4059-related G3 haematological toxicities were reported in 2 patients; thrombocytopenia (x2) and anemia. No ONO-4059-related G4 events, or related SAEs or infections were 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 inter- or intra-patient variability; with Btk occupancy in peripheral blood (as measured by phosphorylated Btk) being maintained for at least 24 hours across all dose levels. Responses have occurred at doses of 40, 80 and 160mg, with a best overall response rate of 42% [based on CT-scan and physical examination for 5/12 evaluable patients]; with 5 PR, 4 SD, 2 PD (both MCL) and one ABC-DLBCL patient was withdrawn due to non-related SAE during Cycle 1. Of the 6 evaluable MCL patients, 3 have achieved PR resulting in a best ORR of 50% (median reduction of lymph nodes was 73% [45%-84%]). Almost all patients experienced clinically meaningful rapid reductions in lymphadenopathy observed within the first cycle. Ten of the fourteen patients are currently still on study with a median progression-free survival of 93.5 days [Range 8-268]. In conclusion, ONO-4059 is a highly potent and selective oral Btk inhibitor that shows a favourable safety profile along with promising efficacy in this difficult-to-treat patient population. Disclosures: Salles: Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria. Karlin:Janssen: Honoraria; Celgene: Honoraria. Morschhauser:ONO Pharma: Honoraria; Roche: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria. Dyer:Ono Pharma: Honoraria, Research Funding. Hutchinson:Ono Pharma: Research Funding. Fegan:ONO Pharma: Honoraria. Cartron:ONO Pharma: Honoraria. Knurowski:ONO Pharma: Consultancy. Wright:ONO Pharma: Consultancy. Saunders:ONO Pharma: Consultancy; Pharmacyclics: Consultancy. Honda:ONO Pharma: Employment. Mazur:ONO Pharma: Consultancy. Yoshizawa:Ono Pharma: Employment. Kawabata:Ono Pharmaceutical Co., Ltd.: Employment. Birkett:Ono Pharma UK: Employment.