New Clinical Data for Tesetaxel, a Leading Oral Taxane, Show Anticancer Activity and Acceptable Safety in Ongoing Study
Responses Observed at Lower Doses -- “Flat Dosing” Feasible
The new clinical study has accrued 12 patients at doses ranging from 18 to 24 mg/m2 administered once every 3 weeks. To date, only one Grade 4 episode of neutropenia (the dose-limiting reaction for all taxanes) has been observed. Three objective and ongoing responses have been observed in the first 9 evaluable patients who received at least 2 doses, including one patient each with nasopharyngeal cancer (partial response), gastrointestinal stromal tumor (GIST) (minor response), and uterine cancer (minor response). Of note, all responses have occurred in older subjects (ages 83, 84 and 64, respectively) and at less than the previously established MTD of 27 mg/m2.
The presentation also examined the feasibility of converting the common practice of weight-based dosing (as in mg/m2 of body surface area) to “flat dosing”. For oral drugs like tesetaxel, flat dosing is far more accurate and convenient for patients and physicians. Pharmacokinetic analysis indicated that a fixed dose of 50 mg would be suitable for most Western patients.
“Prior Phase 2 studies have documented substantial antitumor activity in patients with advanced gastric cancer and breast cancer at the highest dose level of 27 mg/m2,” noted Dr. Raymond P. Warrell, Jr., Genta's Chief Executive Officer. “However, we were very pleased to observe major responses using lower doses, especially the response in nasopharyngeal cancer at 21 mg/m2. Importantly, the incidence of neutropenia has been acceptably low -- similar to other drugs in this class – and the tolerability in older subjects has also been impressive. We believe tesetaxel may offer patients major advantages compared with standard taxanes, and we look forward to accelerating our development programs with this new agent.”
Tesetaxel is a novel, orally absorbed, semi-synthetic taxane that is in the same class of drugs as paclitaxel and docetaxel. However, both prototype agents suffer from serious safety issues, particularly hypersensitivity reactions related to intravenous infusions that are occasionally fatal and that require careful premedication and observation. Other prominent side-effects of this drug class include myelosuppression (low blood counts) and peripheral neuropathy (disabling nerve damage).
With administration as an oral capsule, tesetaxel was developed to maintain the high antitumor activity of the taxane drug class while eliminating infusion reactions, reducing neuropathy, and increasing patient convenience. The oral route also enables development of novel schedules that may expand dosing options when tesetaxel is used alone or in combination with other anticancer drugs. Preclinically, tesetaxel has demonstrated substantially higher activity against cell lines that were resistant to paclitaxel and docetaxel, since acquired resistance is not mediated by the multidrug-resistant p-glycoprotein.
Tesetaxel has demonstrated anticancer activity in several Phase 2 clinical trials. The drug has not been associated with severe infusion reactions that are linked with other taxanes. Moreover, unlike other oral taxanes, nerve damage has not been a prominent side effect of tesetaxel. Thus, the drug offers substantial opportunities to improve patient convenience, safety, and anticancer activity. More than 260 patients worldwide have been treated with oral tesetaxel in Phase 1 and Phase 2 clinical trials.
Posted: June 2009