AusPAR: Cabazitaxel - Therapeutic Goods Administration

Genotoxicity
AusPAR Jevtana Cabazitaxel Sanofi-Aventis Australia Pty Ltd PM-2010-02565-3-4
Final 9 February 2012
Therapeutic Goods Administration
Irregularity of growth plates was seen in the femur of rats treated with ≥5 mg/kg/3
weeks. There was no evidence of reversibility of the teeth or growth plate findings after an
8 week treatment free period. Taken together, the findings suggest an effect of cabazitaxel
on growth and development. This is not of particular concern for the intended patient
population.
Many of the toxic effects of cabazitaxel (most notably, haematopoietic toxicity and toxicity
to lymphoid organs, the gastrointestinal tract, male reproductive system, skin and
peripheral nervous system) were similar to those induced by other taxanes such as
paclitaxel and docetaxel, and are consistent with the pharmacological activity of this group
of drugs (Rowinsky et al., 1990; Bissery et al., 1995; Cavaletti et al., 1997). 12,13,14 The liver
and biliary system are exposed to drug/metabolites since it is the major organ of
metabolism and excretion. The lenticular changes are of unknown clinical relevance, while
effects on bone growth plates and growing teeth are not clinically relevant for the
intended patient population. Many of these effects occurred at or below clinical exposures,
indicating low or no safety margins. The central neurotoxicity observed in mice occurred
at sufficiently high exposures that it is unlikely to be of concern at the proposed clinical
dose. No toxicity studies were conducted with a cabazitaxel/prednisone combination.
An acceptable package of genotoxicity studies was submitted, including two bacterial
reverse mutation studies, a chromosomal aberration study in peripheral blood
lymphocytes and an in vivo rat micronucleus study. Metabolic activation in the in vitro
studies was achieved with rat liver S9 mix which metabolic studies revealed to be
adequate for metabolising cabazitaxel. Positive controls gave the expected findings in all
studies. The bacterial reverse mutation tests, which gave negative results, were
adequately conducted, with appropriate strains and cabazitaxel was tested up to
precipitating concentrations. The chromosomal aberration study involving two separate
assays gave negative results for structural aberrations but cabazitaxel increased the
number of polyploidy cells. Increases in mitotic index were observed, as might be expected
given the pharmacological activity of the drug but concentrations tested were adequate. In
the rat micronucleus test, all tested doses elicited significant increases in the incidence of
micronucleated polychromatic erythrocytes, as might be expected from the
pharmacological activity of the drug. Therefore, as with paclitaxel and docetaxel (Bissery
et al., 1995), cabazitaxel is clastogenic. 13
Carcinogenicity
Based on its positive findings in genotoxicity tests, and on its mode of action, cabazitaxel
may be a carcinogen. No carcinogenicity studies were submitted but this is considered
acceptable as the proposed indication is for the treatment of advanced cancer . 15
12 Rowinsky EK, Cazenave LA, Donehower RC. Taxol: A novel investigational antimicrotubule agent. JNCI
1990; 82: 1247-1258.
13 Bissery M-C, Nohynek G, Sanderlink G-J, Lavelle F. Docetaxel (Taxotere ® ): a review of preclinical and
clinical experience. Part I: preclinical experience. Anti Cancer Drugs 1997; 6: 339-368.
14 Cavaletti G, Cavaletti E, Montaguti P, Oggioni N, De Negri O, Tredici G. Effect on the peripheral nervous
system of the short-term intravenous administration of paclitaxel in the rat. NeuroToxic 1997; 18:
137-146.
15 EMEA, ICH Topic S9, Nonclinical Evaluation for Anticancer Pharmaceuticals, November 2009. Note for
Guidance on Nonclinical Evaluation for Anticancer Pharmaceuticals
(EMEA/CHMP/ICH/646107/2008).
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