Pharmacokinetics (PK) and safety of tesetaxel, an orally administered taxane, in a study examining a range of doses including the active phase II dose

Abstract

e13535 Background: Tesetaxel is an orally active taxane with potent cytotoxic activity against various cancer cell lines in vitro, including cell lines and xenografts of human tumors that over-express P-glycoprotein. Tesetaxel displays markedly lower neurotoxicity than docetaxel in preclinical models. In Phase 2 studies, 2nd-line therapy with tesetaxel (27–35 mg/m2 every 3 weeks) was associated with overall response rates of 20% and 38% in patients (pts) with gastric and breast cancer, respectively. Neutropenia was the most common serious adverse event. We are conducting a dose-ranging study to examine the PK and safety of tesetaxel at doses including and just below the previously established MTD of 27 mg/m2. Methods: Eligibility criteria include advanced solid tumors, ECOG PS ≤ 2, and adequate organ function. The starting dose is 18 mg/m2, which is being escalated in increments of 3 mg/m2 to a maximum of 27 mg/m2. Tesetaxel is given for a minimum of 2 cycles; pts with response or stable disease may receive up to 2 more cycles. Plasma is assayed at various times to determine concentrations of parent drug and metabolites. A total of 12 patients will be entered into the dose-escalation phase, with sample expansion to 12 pts at the MTD. Results: Ongoing enrollment is expected to be completed in Q1 2009. Our group's prior study of tesetaxel 18 mg/m2 and 27 to 40 mg/m2 has shown that tesetaxel displays dose-proportional absorption and has a long terminal plasma half-life (mean approximately 180 hrs). We expect to confirm these data over a narrow dose range and to examine the data for correlations between PK and the duration and severity of neutropenia. Conclusions: Tesetaxel is an orally active taxane that eliminates infusion reactions and the associated need for premedication. It may overcome inherent or clinically acquired resistance to prototype taxanes and may prove to have reduced taxane-associated peripheral neuropathy in the clinical setting. Essential to future tesetaxel studies, this study will determine whether correlations between key PK parameters and dose-limiting reactions exist. [Table: see text]