Abstract 5508: Antitumor activity of cabazitaxel in pediatric patient-derived tumor xenografts (PDX).
Authors: Vrignaud Patricia 
Published: August 2014

Background: Cabazitaxel (Jevtana®), a semi-synthetic taxane, was approved for patients with metastatic hormone-refractory prostate cancer previously treated with docetaxel-based therapy. Cabazitaxel, which stabilizes microtubules as efficiently as docetaxel, has a better antiproliferative activity than docetaxel against chemotherapy resistant tumor cell lines, a broad spectrum of in vivo antitumor activity in docetaxel-sensitive tumors and in tumor models in which docetaxel was either poorly active or inactive. Unlike docetaxel, cabazitaxel is able to cross the blood-brain barrier and is active in intracranial human glioblastomas (AACR 2000). The preclinical combination of cabazitaxel and cisplatin exhibits therapeutic synergism (AACR 2011). Finally, cabazitaxel demonstrates greater activity than docetaxel in 3 pediatric tumor xenografts, 1 rhabdomyosarcoma and 2 Ewing's sarcomas (AACR 2012).

Methods: The anti-tumor activity of cabazitaxel was further evaluated in comparison to docetaxel in 3 pediatric patient-derived tumor xenografts (PDX): 2 osteosarcomas derived from lung metastases of a 19 year old male (DM77) and a 3 year old female (DM113) patient; 1 Ewing's sarcoma taken from the bone of a 17 year old male patient (DM101). Cabazitaxel and docetaxel were dosed IV at 5.8, 9.3, 15 or 24.2 mg/kg, every 4 days for a total of 3 doses (initial tumor burden = 125 - 250 mm3).

Results: Both cabazitaxel and docetaxel demonstrated antitumor activity in these 3 PDX. In DM113, cabazitaxel is significantly more active than docetaxel at 9.3, 15 and 24.2 mg/kg. Additionally, when comparing the numbers of partial regressions (PR ≥ 50 % initial tumor size for at least 7days), cabazitaxel is more potent than docetaxel at 15 (4/10 PR versus 0/10 PR, respectively) and at 24.2 mg/kg (5/10 PR versus 1/10 PR, respectively). Using body weight loss as a gross indicator of toxicity, docetaxel appears to more toxic than cabazitaxel in the 2 other PDX studies. In DM101, cabazitaxel at 15 or 24.2 mg/kg doses was significantly more active than docetaxel at the same dose or at the equitoxic dose (9.3 or 15 mg/kg, respectively). In addition, cabazitaxel induces more complete regressions (CR = no palpable tumors for at least 7days) and tumor free animals on day 60 (TF) than docetaxel (9/9 CR and 7/9 TF for cabazitaxel versus 4/9 CR and 1/9 TF for docetaxel at 15 mg/kg; 9/9 CR and 8/9 TF for cabazitaxel versus 3/9 CR and 2/9 TFS for docetaxel at 24.2 mg/kg). Finally, in DM77, cabazitaxel at 15 and 9.3 mg/kg is also more active than docetaxel at an equivalent dose or a toxicity adjusted dose (9.3 or 5.8 mg/kg, respectively).

Conclusion: Both cabazitaxel and docetaxel are active in these 3 human pediatric PDX; however, cabazitaxel demonstrates greater activity than docetaxel. Taken together, preclinical data with cabazitaxel including activity in brain tumors and therapeutic synergism with cisplatin, support its development in pediatric indications.

Citation Format: Patricia Vrignaud. Antitumor activity of cabazitaxel in pediatric patient-derived tumor xenografts (PDX). [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 5508. doi:10.1158/1538-7445.AM2013-5508