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

• Published in: British journal of cancer Vol. 124; no. 2; pp. 391 - 398
• Main Authors: Robbrecht, Debbie G J, Lopez, Juanita, Calvo, Emiliano, He, Xiaomin, Hiroshi, Hirai, Soni, Nital, Cook, Natalie, Dowlati, Afshin, Fasolo, Angelica, Moreno, Victor, Eskens, Ferry A L M, de Bono, Johann S
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 19.01.2021; Nature Publishing Group UK
• Subjects: Adult; Adverse events; Aged; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Aurora Kinase A - antagonists & inhibitors; Breast cancer; Diarrhea; Dose-Response Relationship, Drug; Enzyme inhibitors; ErbB-2 protein; Fatigue; Female; Humans; Lipase; Male; Maximum Tolerated Dose; Middle Aged; Myc protein; Nausea; Neoplasms - drug therapy; Patients; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Small cell lung carcinoma; Solid tumors; Toxicity; Tumors; β-Catenin
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-01100-3

This is a first-in-human study with TAS-119, an Aurora A kinase (AurA) inhibitor. 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). 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. TAS-119 has a favourable and remarkably distinct safety profile from other AurA inhibitors. NCT02448589.