First-in-human phase I and pharmacological study of TAS-119, a selective Aurora A (AurA) kinase inhibitor, in patients (pts) with advanced solid tumors.

3063Background: AurA is a serine threonine kinase regulating cell division and cell cycle progression and has a role in carcinogenesis. This clinical trial investigated safety, pharmacokinetics and -dynamics and antitumor activity of the selective oral AurA kinase inhibitor TAS-119. Methods: Pts with advanced solid tumors were enrolled into 6 dose escalation cohorts (70-300 mg BID 4 days on/3 days off; every 3 out of 4 weeks; or the same schedule in a continuous weekly schedule). In the expansion phase (intermittent schedule), pts with small-cell lung cancer (SCLC), breast cancer, or MYC-amplified/B-catenin mutated (MT) tumors were enrolled, and pts with other solid tumors in a basket cohort. Results: Overall, 34 pts were enrolled to the escalation (median age 67 years; 45.3% > 2 prior therapies); DLT was observed in 5 (16.1%) of 31 DLT evaluable pts; 1/10 at 150 mg, 1/6 at 200 mg, 1/5 at 250 mg, and 2/2 at 300 mg BID (fatigue, nausea, dry eyes, corneal epithelial microcysts). The maximum tolerated dose (MTD) was 250 mg BID and recommended Phase 2 dose (RP2D) was 200 mg BID. The most frequent treatment-emergent adverse events were diarrhea (28.3%), eye disorders (27%), fatigue (22.9%), and decreased appetite (14.8%). Grade 3 ocular toxicity were corneal epithelial microcysts in 1 pt (300 mg cohort) and punctate keratitis (expansion breast cancer cohort) in 1 pt. Toxicity grade ≥ 3 in ≥ 10% of pts were diarrhea (escalation part only), and increased lipase. Plasma exposure was dose-proportional and accumulation ratio was low. Pharmacodynamic data demonstrated target inhibition. Overall, 40 pts were enrolled to multiple expansions (10 SCLC, 9 breast cancer, 13 MYC-amp/B-cat MT tumors, 8 other; median age 60 years; 72.5% > 2 prior therapies). Median delivered relative dose intensity was 89.1% (47.9% - 100%). Stable disease was reported in 37.8% of patients but no complete or partial responses. Conclusions: TAS-119 demonstrated favorable safety and tolerability. Low-grade eye toxicity was a dose-dependent toxicity. Preliminary anti-tumor activity of monotherapy TAS-119 is limited. A Phase 1 trial combining TAS-119 with paclitaxel was conducted in parallel. Clinical trial information: NCT02448589.