Debbie G J Robbrecht1, Juanita Lopez2, Emiliano Calvo3, Xiaomin He4, Hirai Hiroshi5, Nital Soni4, Natalie Cook6, Afshin Dowlati7, Angelica Fasolo8, Victor Moreno9, Ferry A L M Eskens10, Johann S de Bono2. 1. Erasmus MC Cancer Institute, Rotterdam, the Netherlands. d.robbrecht@erasmusmc.nl. 2. The Royal Marsden and The Institute of Cancer Research, London, UK. 3. START Madrid-Centro Integral Oncológico Clara Campal, Hospital Madrid Norte Sanchinarro, Madrid, Spain. 4. Taiho Oncology Inc, Princeton, NJ, USA. 5. Taiho Pharmaceutical Co., Ltd., Tokyo, Japan. 6. Christie NHS Foundation Trust and the University of Manchester, Manchester, UK. 7. UH Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA. 8. Unit of New Drugs and Innovative Therapies Dept. Medical Oncology San Raffaele Hospital - Scientific Institute Via Olgettina, Milan, Italy. 9. START-Madrid-FJD, Hospital Fundacion Jimenez Diaz, Madrid, Spain. 10. Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
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.
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.
Authors: Mark G Manfredi; Jeffrey A Ecsedy; Arijit Chakravarty; Lee Silverman; Mengkun Zhang; Kara M Hoar; Stephen G Stroud; Wei Chen; Vaishali Shinde; Jessica J Huck; Deborah R Wysong; David A Janowick; Marc L Hyer; Patrick J Leroy; Rachel E Gershman; Matthew D Silva; Melissa S Germanos; Joseph B Bolen; Christopher F Claiborne; Todd B Sells Journal: Clin Cancer Res Date: 2011-10-20 Impact factor: 12.531
Authors: Dale O Cowley; Jaime A Rivera-Pérez; Mark Schliekelman; Yizhou Joseph He; Trudy G Oliver; Lucy Lu; Ryan O'Quinn; E D Salmon; Terry Magnuson; Terry Van Dyke Journal: Mol Cell Biol Date: 2008-12-15 Impact factor: 4.272
Authors: E A Eisenhauer; P Therasse; J Bogaerts; L H Schwartz; D Sargent; R Ford; J Dancey; S Arbuck; S Gwyther; M Mooney; L Rubinstein; L Shankar; L Dodd; R Kaplan; D Lacombe; J Verweij Journal: Eur J Cancer Date: 2009-01 Impact factor: 9.162