tesetaxel and Neoplasms

Daiichi Sankyo Co Ltd (formerly Daiichi Seiyaku Co Ltd) was developing the oral semisynthetic taxane derivative tesetaxel for the potential treatment of cancer, including colorectal and gastric cancer. However, despite early signs of promise, in November 2006 tesetaxel was removed from Daiichi's development pipeline for failure to show clear benefit over existing, currently marketed agents for cancer chemotherapy.

Topics: Animals; Antineoplastic Agents, Phytogenic; Clinical Trials, Phase I as Topic; Contraindications; Drug Evaluation, Preclinical; Humans; Neoplasms; Structure-Activity Relationship; Taxoids

This phase I study was conducted primarily to determine the maximum tolerated dose (MTD) of tesetaxel, a novel, orally active, semisynthetic microtubule inhibitor of the taxane class, administered with oral capecitabine to patients with advanced solid tumors.. During each 21-day cycle, patients were to receive tesetaxel on Day 1 and capecitabine twice daily on Days 1 through 14. The starting dose was tesetaxel 18 mg/m(2) and capecitabine 1,250 mg/m(2)/day. These doses were increased based on tolerability during the first cycle according to the protocol-specified dose-escalation scheme. Response was evaluated every other treatment cycle according to RECIST. Serial blood samples were collected during the first and second cycles to explore possible pharmacokinetic drug interactions.. Twenty-seven patients were enrolled and treated. The most frequently reported dose-limiting toxicities were neutropenia and febrile neutropenia, with individual patients experiencing dose-limiting stomatitis and diarrhea. The MTD for the treatment regimen was defined as tesetaxel 27 mg/m(2) and capecitabine 2,500 mg/m(2)/day. The most common ≥ Grade 3 treatment-related adverse events included leukopenia (44% of patients) and neutropenia (41%). Of 22 evaluable patients, the best overall response was stable disease in 82% and progressive disease in 18%. No meaningful pharmacokinetic drug interactions were apparent.. The results of this study demonstrate that these two orally active agents can be combined at the individual MTD of each drug with acceptable toxicity. These data further support the continued clinical development of tesetaxel both as a single agent and in combination with other active cancer therapeutics.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Deoxycytidine; Female; Fluorouracil; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Taxoids