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.

Debbie Robbrecht Erasmus MC, Rotterdam, Netherlands info_outline Debbie Robbrecht, Ferry Eskens, Emiliano Calvo, Xiaomin He, Hiroshi Hirai, Nital Soni, Natalie Cook, Afshin Dowlati, Angelica Fasolo, Victor Moreno, Johann S. De Bono

Authors Debbie Robbrecht Erasmus MC, Rotterdam, Netherlands info_outline Debbie Robbrecht, Ferry Eskens, Emiliano Calvo, Xiaomin He, Hiroshi Hirai, Nital Soni, Natalie Cook, Afshin Dowlati, Angelica Fasolo, Victor Moreno, Johann S. De Bono Organizations Erasmus MC, Rotterdam, Netherlands, Erasmus MC Cancer Institute, Rotterdam, Netherlands, START Madrid-Centro Integral Oncológico Clara Campal, Hospital Madrid Norte Sanchinarro, Madrid, Spain, Taiho Oncology, Princeton, NJ, Tsukuba Research Institute, Ibaraki, Japan, Christie Hospital, Manchester, United Kingdom, UH Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, San Raffaele Hospital, Milan, Italy, START Madrid-FJD, Madrid, Spain, Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, United Kingdom Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: 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