Abstract 2754: Pediatric Preclinical Testing Program (PPTP) stage 1 evaluation of the antimicrotubule agents cabazitaxel and docetaxel.
Authors: Houghton Peter J. , Kang Min , Reynolds C Patrick , Lock Richard B. , Carol Hernan , Gorlick Richard , Kolb E Anders , Maris John M. , Keir Stephen T. , Billups Catherine A. , Kurmasheva Raushan T. , Smith Malcolm Anders 
Published: August 2014

Introduction: Cabazitaxel (C) is a novel taxane active in preclinical models of both chemotherapy-sensitive and -resistant human tumors. Cabazitaxel is active in patients with advanced prostate cancer who have progressed following docetaxel (D) treatment. We compared the antitumor activity of cabazitaxel with that of docetaxel (both provided by Sanofi) against in vitro and in vivo models of pediatric cancers.

Methods: Both agents were evaluated against the 23 cell lines of the PPTP in vitro panel using 96 hour exposure at concentrations from 0.01 nM to 0.1 μM. They were tested against the PPTP solid tumor xenografts (SCID mice) using a dose of 7.5 or 10.0 mg/kg administered by the IV route every 4 days X 3.

Results: In vitro the median relative IC50 (rIC50) for cabazitaxel was 0.47 nM and for docetaxel was 0.88 nM. Cabazitaxel and docetaxel rIC50 and Ymin% values were significantly correlated with each other. Cabazitaxel rIC50 values were significantly correlated with cell line ABCB1 expression, but showed a weaker relationship compared to that for docetaxel. In vivo, there was a trend for greater weight loss and greater toxicity for cabazitaxel-treated versus docetaxel-treated animals. A direct comparison of the EFS distributions for cabazitaxel and docetaxel showed that 5 xenografts had significantly longer EFS for cabazitaxel compared to docetaxel, while docetaxel was more effective for no models for this measure. 5 of 10 xenografts showed maintained complete responses (MCRs) to cabazitaxel, with MCRs observed across multiple histologies. Only 1 of 10 docetaxel-treated models showed an MCR. In vivo results are summarized in the Table using standard PPTP objective response criteria.

Tumor Histology C Response D Response P-value for EFS (C vs D) KT-10 Wilms MCR PD2 &lt;0.001 SK-NEP-1 Ewing sarcoma MCR MCR 0.211 CHLA258 Ewing sarcoma MCR PR 0.033 Rh30R Rhabdomyosarcoma SD PD2 &lt;0.001 Rh18 Rhabdomyosarcoma PD2 PD1 0.147 Rh36 Rhabdomyosarcoma MCR PD2 0.033 NB-1691 Neuroblastoma PD2 PD1 &lt;0.001 OS-1 Osteosarcoma SD PD2 1.000 OS-17 Osteosarcoma SD CR 0.195 OS-33 Osteosarcoma MCR CR 0.552

Conclusions: Cabazitaxel was more potent in vitro than docetaxel against the PPTP cell lines and showed greater in vivo activity than docetaxel, although with somewhat greater toxicity. (Supported by award NO1-CM-42216 from the NCI).

Citation Format: Peter J. Houghton, Min Kang, C Patrick Reynolds, Richard B. Lock, Hernan Carol, Richard Gorlick, E Anders Kolb, John M. Maris, Stephen T. Keir, Catherine A. Billups, Raushan T. Kurmasheva, Malcolm Anders Smith. Pediatric Preclinical Testing Program (PPTP) stage 1 evaluation of the antimicrotubule agents cabazitaxel and docetaxel. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2754. doi:10.1158/1538-7445.AM2013-2754