Preclinical profile of cabazitaxel

Abstract

First-generation taxanes have changed the treatment paradigm for a wide variety of cancers, but innate or acquired resistance frequently limits their use. Cabazitaxel is a novel second-generation taxane developed to overcome such resistance. In vitro, cabazitaxel showed similar antiproliferative activity to docetaxel in taxane-sensitive cell lines and markedly greater activity in cell lines resistant to taxanes. In vivo, cabazitaxel demonstrated excellent antitumor activity in a broad spectrum of docetaxel-sensitive tumor xenografts, including a castration-resistant prostate tumor xenograft, HID28, where cabazitaxel exhibited greater efficacy than docetaxel. Importantly, cabazitaxel was also active against tumors with innate or acquired resistance to docetaxel, suggesting therapeutic potential for patients progressing following taxane treatment and those with docetaxel-refractory tumors. In patients with tumors of the central nervous system (CNS), and in patients with pediatric tumors, therapeutic success with first-generation taxanes has been limited. Cabazitaxel demonstrated greater antitumor activity than docetaxel in xenograft models of CNS disease and pediatric tumors, suggesting potential clinical utility in these special patient populations. Based on therapeutic synergism observed in an in vivo tumor model, cabazitaxel is also being investigated clinically in combination with cisplatin. Nonclinical evaluation of the safety of cabazitaxel in a range of animal species showed largely reversible changes in the bone marrow, lymphoid system, gastrointestinal tract, and male reproductive system. Preclinical safety signals of cabazitaxel were consistent with the previously reported safety profiles of paclitaxel and docetaxel. Clinical observations with cabazitaxel were consistent with preclinical results, and cabazitaxel is indicated, in combination with prednisone, for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with docetaxel. In conclusion, the demonstrated activity of cabazitaxel in tumors with innate or acquired resistance to docetaxel, CNS tumors, and pediatric tumors made this agent a candidate for further clinical evaluation in a broader range of patient populations compared with first-generation taxanes.

Initial testing (stage 1) of the anti‐microtubule agents cabazitaxel and docetaxel, by the Pediatric Preclinical Testing Program

“…Cabazitaxel is a semisynthetic taxane that was identified through a large‐scale screening process designed to select agents that show consistent activity in both docetaxel‐sensitive and docetaxel‐resistant cell lines and in vivo models . Cabazitaxel, which is the 7,10 dimethyloxy derivative of docetaxel, demonstrates greater activity than docetaxel in multiple adult solid tumor models with inate or acquired taxane resistance .…”

A phase 1/2 dose‐finding, safety, and activity study of cabazitaxel in pediatric patients with refractory solid tumors including tumors of the central nervous system

“…Thus, cabazitaxel showed high permeability in cells expressing high levels of P‐gp, and higher intracellular accumulation than first‐generation taxanes in multidrug‐resistant ABCB1 (+) cell lines . Cabazitaxel penetrates BBB both in non‐tumor bearing and orthotopic glioma models, with similar exposure patterns observed in mice, rats and dogs …”

“…Preclinical evaluation suggested that cabazitaxel may be able to penetrate the BBB, providing rationale for the evaluation of cabazitaxel in pediatric patients with CNS tumors . In the phase 1 study, cabazitaxel was assessed in pediatric patients with recurrent/refractory solid tumors, including CNS tumors.…”

Surfactant‐Stripped Cabazitaxel Micelles Stabilized by Clotrimazole or Mifepristone

“…As Figure 1A shows, CTX had higher solubility in F127, up to 6 mg mL −1 , compared to DTX and PTX (1 mg mL −1 and 2 mg mL −1 , respectively). This may stem from the somewhat higher lipophilicity of CTX compared to other taxanes (CTX has a log P partition coefficient of 3.7, whereas DTX has a log P of 2.6, and PTX has a log P of 3.2) …”

“…The main mechanism of the action of CTX is to stabilize the tubulin polymerization, leading to cellular apoptosis . Microtubule polymerization was evaluated using a porcine tubulin assay.…”