Tesetaxel

Tesetaxel is a novel oral semi-synthetic taxane.  Taxanes, such as paclitaxel (Taxol®) and docetaxel (Taxotere®), are mainstays of modern anticancer therapy.  These drugs are believed to kill cancer cells by disrupting critical cellular proteins.  Taxanes have been formally approved by FDA for the treatment of breast, lung, ovarian, gastric, and prostate cancers.  However, all currently approved taxanes require intravenous (IV) infusion under close medical supervision.  Moreover, both paclitaxel and docetaxel can cause severe, occasionally fatal, infusion reactions, which require pre-medication with steroids and antihistamines.  Other serious reactions associated with taxanes include long-lasting damage to peripheral nerves (neuropathy).  An oral taxane with the anticancer activity of the IV drugs could provide substantially greater patient safety (by eliminating infusion reactions and precluding the need for pre-medication), a high level of patient convenience, and potentially greater flexibility to explore novel dosing schedules that might improve overall outcomes for patients.  

In preclinical testing, tesetaxel has shown clear anticancer activity, including activity against cancer cells that were resistant to paclitaxel and docetaxel.  Typically, cancer cells become resistant to taxanes by a mechanism known as “multidrug resistance” that is mediated by a factor called p-glycoprotein.  Resistance to tesetaxel did not appear to be mediated by this mechanism, suggesting that tesetaxel might be useful for diseases that are resistant to conventional taxanes.

CLINICAL PROGRAM

To date, oral tesetaxel has been studied in Phase 1 and Phase 2 studies involving more than 250 patients.  Objective clinical responses have been observed, no patients have developed hypersensitivity effects that have been associated with IV infusion reactions, and no patients have required pre-medication.  Unlike other IV taxanes (as well as other investigational oral taxanes), tesetaxel has not been associated with serious nerve damage, which can be quite disabling.  However, like all other taxanes, the most serious side-effects of tesetaxel have included lowering of the white blood cell count (neutropenia), and complications of this reaction have been fatal in some patients. Because of this reaction, the Food and Drug Administration (FDA) placed tesetaxel on “clinical hold” and requested further specific information in order to lift the clinical hold and allow patient testing to resume.  Genta is currently compiling that information for the FDA.

Representative publications:

Roche M, Kyriakou H, Seiden M. Drug evaluation: tesetaxel−an oral semisynthetic taxane derivative. Curr Opin Investig Drugs. 2006;7:1092-9.

Ono C, Takao A, Atsumi R. Absorption, distribution, and excretion of DJ-927, a novel orally effective taxane, in mice, dogs, and monkeys. Biol Pharm Bull. 2004;27:345-51.

Shionoya M, Jimbo T, Kitagawa M, Soga T, Tohgo A. DJ-927, a novel oral taxane, overcomes P-glycoprotein-mediated multidrug resistance in vitro and in vivo. Cancer Sci. 2003;94:459-66.

Beeram M, Saif WM, Sarantopoulos J, Schwartz G, Patnaik A, Tolcher AW. A Phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study of the combination of an oral antimicrotubular agent, DJ-927 (D), and capecitabine (C) in patients (pts) with advanced cancers. Proc Am Soc Clin Oncol. 2006;24:83s (Abstract 2016).

Syed SK, Beeram M, Takimoto CH, Jakubowitz J, Kimura M, Ducharme M, et al. Phase I and pharmacokinetics (PK) of DJ-927, an oral taxane, in patients (pts) with advanced cancers. Proc Am Soc Clin Oncol. 2004;22:134 (Abstract 2028).

Moore MR, Jones C, Harker G, Lee F, Ardalan B, Saif MW, et al. Phase II trial of DJ-927, an oral tubulin depolymerization inhibitor, in the treatment of metastatic colorectal cancer. Proc Am Soc Clin Oncol. 2006;24:168s (Abstract 3591).

Rhee JM, Lee F, Saif MW, Ardalan B, Wolff R, Eng C, et al. Phase II trial of DJ-927 as a second-line treatment for colorectal cancer demonstrates objective responses. Proc Am Soc Clin Oncol. 2005;23:284s (Abstract 3654).

Szczesna A, Milanowski E, Juhász E, Albert I, Von Pawel J, Sztancsik Z, et al. A Phase II study of DJ-927 administered orally once every three weeks as a second line therapy to subjects with locally advanced or metastatic non small cell lung cancer after failure of platinum-based non-taxane regimen. Proc Am Soc Clin Oncol. 2006;24:667s (Abstract 17006).

Evans T, Dobrila R, Berardi R, Sumpter KA, Wall LR, Oyama R, et al. A Phase II study of DJ-927 as second-line therapy in patients (pts) with advanced gastric cancer (GC) who have failed a 5-FU non taxane based regimen. Proc Am Soc Clin Oncol. 2006;24:198s (Abstract 4081).