A first-in-human phase 1 and pharmacological study of TAS-119, a novel selective Aurora A kinase inhibitor in patients with advanced solid tumours

Abstract

Background: This is a first-in-human study with TAS-119, an Aurora A kinase (AurA) inhibitor.

Methods: Patients with advanced, refractory, solid tumours were enrolled into 5 dose escalation cohorts (70-300 mg BID, 4 days on/3 days off, 3 out of 4 weeks or 4 out of 4 weeks). The expansion part consisted of patients with small-cell lung cancer, HER2-negative breast cancer, MYC-amplified/β-catenin-mutated (MT) tumours or other (basket cohort).

Results: In the escalation part (n = 34 patients), dose-limiting toxicities were one grade 3 nausea, two grade 2 and one grade 3 ocular toxicity and a combination of fatigue, ocular toxicity and nausea in one patient (all grade 2) at dose levels of 150, 200, 250 and 300 mg, respectively. Most frequent treatment-related adverse events were fatigue (32%), diarrhoea (24%) and ocular toxicity (24%). Toxicity grade ≥3 in ≥10% of patients were diarrhoea (15%) and increased lipase (12%). The maximum tolerated dose was 250 mg BID. Due to one additional grade 1 ocular toxicity, the RP2D was set at 200 mg BID (4 days on/3 days off, 3 out of 4 weeks), which was further explored in the expansion part (n = 40 patients). Target inhibition in paired skin biopsies was shown.

Conclusions: TAS-119 has a favourable and remarkably distinct safety profile from other AurA inhibitors.

Clinical trial registration: NCT02448589.

Conflict of interest statement

D.G.J.R.: travel expenses: Sanofi; consulting/advisory role: Bayer, Cantargia, Servier, Faron Pharmaceuticals, Merck Sharp & Dohme. J.L.: consulting/advisory role: Basilea, Genmab; research grant funding: Basilea, Genmab, Roche. E.C.: consulting/advisory role: Novartis, Nanobiotix, Janssen-Cilag, PsiOxus Therapeutics, Seattle Genetics, EUSA Pharma, Abbvie, Celgene, AstraZeneca, Guidepoint Global, Roche/Genentech, GLG, Pfizer, Servier, Amcure; leadership: START; Speakers’ Bureau: Novartis, travel/accommodation expenses: Roche/Genentech; relationship investigational therapeutics in oncological sciences, stock and other ownership interests: START, Oncoart Associated, International Cancer Consultants; honorario: HM Hospitales; research funding: AstraZeneca, Novartis, BeiGene, START. X.H.: employer: Taiho Oncology, Inc. H.H.: employer: Taiho Pharmaceutical Co.; stock holder; Otsuka Holdings Co., LTD; patents/royalties/other intellectual property: Taiho Pharmaceutical Co. N.S.: employer: Taiho Oncology, Inc. N.C.: consulting/advisory role: Tarveda Therapeutics, Epigene Therapeutics. A.D. declares no potential conflicts of interest. A.F.: travel/accommodation expenses: Amgen, Roche. V.M.: employer: START; consulting/advisory role: Merck; research funding: Abbvie, ACEA Biosciences, Adaptimmune, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, e-Therapeutics, GlaxoSmithKline, Menarini, Nanobiotix, Novartis, Pfizer, PharmaMar, PsiOxus Therapeutics, Puma Biotechnology, Regeneron, RigonTEC, Roche, Sanfoi, Sierra Oncolog, Synthon, Taiho Pharmaceutical, Takeda, Tesaro, Transgene, Bristol-Myers Squibb, Merck, BeiGene, Janssen; expert testimony: Medscape, Nanobiotix, Bayer; travel/accommodation expenses: Sanofi, Regeneron. F.A.L.M.E.: consulting/advisory role: Merck Serono, Roche, Eisai, Ipsen; travel expenses: Pfizer. J.S.d.B.: consulting/advisory role: AstraZeneca, Sanofi, Genentech/Roche, Astellas, Bayer Pharma, Merck Sharp & Dohme, Merck Serono, Boehringer Ingelheim, Sierra Oncology, Menarini Silicon Biosystems, Pfizer, Celgene, Taiho Pharmaceutical, Daiichi Sankyo, Janssen Oncology, Genmab, GlaxoSmithKline, Orion Pharma GmbH, Eisai, BioXCel Therapeutics; travel/accommodation expenses: AstraZeneca, Astellas Pharma, GlaxoSmithKline, Orion Pharma GmbH, Sanofi, Genmab, Taiho Pharmaceutical, Qiagen, Vertex; patents/royalties/other intellectual property on Abiraterone Rewards to Inventors, PARP inhibitors and DNA repair defects, targeting of IL23 in prostate cancer, CHK1 inhibitor; honoraria: AstraZeneca, Sanofi, Astellas Pharma, Pfizer, Genentech/Roche, Janssen, Menarini Silicon Biosystems, Daiichi Sankyo, Sierra Oncology, BioExcel; research funding: AstraZeneca, Genentech, Sanofi, Taiho Pharmaceutical, Daiichi Sankyo, Merck Serono, Astex Pharmaceuticals, Merck Sharp & Dohme, Orion Pharma GmbH, GlaxoSmithKline, CellCentric, Celgene, Sierra Oncology, Bayer, MedImmune, Medivation.

Figures

Fig. 1. Mean (±SD) plasma concentration versus time curves (linear scales) for TAS-119.

a Cycle 1 day 1. b Cycle 1 day 4. c Cycle 1 day 18. A total of 34 patients were evaluable for PK data. In 2 patients, parameters from one pre-dose sample and one day 4 sample, respectively, were unavailable. Parameters collected on a non-predefined day (2 patients) or collected from patients with dose omissions (2 patients) or dose reductions (1 patient) were excluded.

Fig. 2. Scatterplots of TAS-119 parameters (Cmax and AUC0 − last) versus dose on cycle 1 day 1.

aCmax versus dose in cycle 1 day 1. b AUC0-last versus dose in cycle 1 day 1. AUC0 − last = area under the plasma concentration–time curve from time 0 to the time point of last observable concentration, Cmax = maximum observed plasma concentration, PK pharmacokinetics. Note: Each symbol represents individual PK parameters. The regression curve was provided by the linear model. The shaded area indicates 90% confidence band.

Fig. 3. Mean pHH3-positive rates in paired skin samples.

Data based on 55 paired skin samples taken prior to TAS-119 administration and after receiving TAS-119 administered on day 4 of cycle 1. The p value is based on paired t test.