Preclinical Data

In preclinical trials, tesetaxel was tested against various types of cancer cells including p-glycoprotein positive cells and cells that were resistant to paclitaxel and docetaxel.

The safety and efficacy of tesetaxel have not been established for any use.

• Pgp+ Lung Cancer Cells
• Breast Cancer Cells
• Taxane Resistant Cells
• Neuropathy

• Pgp Positive Lung Cancer Cells

  Typically, cancer cells become resistant to taxanes by a mechanism known as “multidrug resistance” that is mediated by a factor called p-glycoprotein (pgp). In preclinial studies, 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. The table below displays intracellular levels of tesetaxel in pgp-positive lung cancer cells.

  

• Orally administered tesetaxel showed potent anti-tumor activity against various types of human solid tumor xenografts in nude mice.  The anti-tumor effects of tesetaxel were superior to those of intravenously administered paclitaxel and docetaxel in pgp over-expressing tumors.  Tesetaxel-resistant sub-lines produced few single clones, and the rate of clonal growth was considerably slower.

  

   

• Both paclitaxel and docetaxel were less effective against the paclitaxel-resistant clone NCI-H460 (human non-small cell lung cancer cells)/PTX13 (resistance ratios: >20).  In contrast, tesetaxel exhibited potent cytotoxic activity against both the parent cell line and the NCI-H460/PTX13 cells (resistance ratio: 1.85).  As shown in the figure below, in mice inoculated with NCI-H460/PTX13 clone tumors, tesetaxel showed significant anti-tumor activity (inhibition rate [IR] = 74.9%) at the maximum tolerated dose (MTD), while neither docetaxel nor paclitaxel at their MTD exhibited anti-tumor effects.

  

   

   

   

• One of the key preclinical observations of tesetaxel is its relative lack of injury to nerve cells.  This side-effect of standard taxanes (known as peripheral neuropathy) causes pain and numbness in fingers and toes, and it can permanently impair position sense and walking as the effect progresses.  Peripheral neuropathy is a common reason why patients discontinue treatment with standard taxanes even if they have achieved a significant anticancer benefit.

  Genta is hopeful that the reduced nerve damage seen in preclinical studies transfers to the clinical setting and becomes an important distinguishing feature between tesetaxel and other taxanes.  The potential ability to substitute tesetaxel for other taxanes in patients who have developed clinically significant neuropathy may represent an important option for patients.

  The safety and efficacy of tesetaxel have not been established for any use.