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
Mené sur 34 patients atteints d’une tumeur solide de stade avancé, cet essai de phase I évalue la dose maximale tolérée de TAS-119, un inhibiteur de kinase Aurora A
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/?-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.