486P - Pharmacokinetics (PK) and Safety of Tesetaxel, a Novel Oral Taxane, in Japanese Patients (PTS) with Advanced Solid Tumors

Abstract

ABSTRACT Background Tesetaxel is an orally administered taxane that, unlike IV analogs, is not a Pgp substrate (a primary mechanism of taxane resistance). This novel agent has a long plasma T½ (∼180 h), allowing administration once every 3 weeks (Q3W). Tesetaxel is particularly active in breast and gastric cancers, with response rates of 50% and 20%, respectively, in 1st-line metastatic breast and 2nd-line gastric cancer. Among > 500 pts treated to date, no hypersensitivity reactions have occurred, and neurotoxicity has been distinctly uncommon. In Western pts, the maximally tolerated dose (MTD) of tesetaxel is 27 mg/m2 Q3W, and neutropenia is dose limiting. We conducted a phase I intersubject dose-escalation study to evaluate safety and PK in Japanese pts. Methods Eligibility criteria included age ≥ 20 years, advanced or metastatic solid tumors, ECOG PS ≤ 1, and adequate organ function. Tesetaxel 24 mg/m2 was given on day 1 of a 21-day cycle to the first cohort. The dose was escalated to 27 mg/m2 and 31 mg/m2 in successive cohorts absent dose-limiting toxicity (DLT). Serial blood samples were obtained for PK analysis and assayed by HPLC. Results Twelve pts (9 men, 3 women; age 39-74 yr) were enrolled (3 each in the 24 and 31 mg/m2 cohorts and 6 in the 27 mg/m2 cohort). Most pts were heavily pretreated; the median number of prior chemotherapy regimens was 4. Neutropenia ≥ grade 3 occurred in 1 pt in the 24 mg/m2 and 27 mg/m2 cohorts and 2 pts in the 31 mg/m2 cohort. DLT (febrile neutropenia) was observed in 1 pt at the 31 mg/m2 dose. Mean PK data (see table) were similar in Western and Japanese pts, with an expected dose-dependent increase in exposure. Dose level Patients (n) Cmax Tmax AUC0-168 h 24 mg/m2 Western (11) 29.7 2.5 594 Japanese (3) 29.0 2.7 658 27 mg/m2 Western (7) 31.2 2.1 869 Japanese (3) † 46.6 4.7 818 * 31 mg/m2 Japanese (3) 57.0 2.0 1036 † Results of PK analyses for last 3 pts enrolled not yet available * Dose not studied in Western pts Conclusion This study indicates that tolerability and PK of tesetaxel is similar in Western and Japanese pts. Final data will be presented. Disclosure T. Cousin: I am an employee of Genta Incorporated, the company that is developing tesetaxel. All other authors have declared no conflicts of interest.