Abstract 571: PK and antitumor activity of DEBIO 0507, a new platinum derivative, in preclinical tumor models

Abstract

Listen

Translate article

Abstract Background: Since the introduction of cisplatin, carboplatin and oxaliplatin, several new generations of platinum analogues have been developed as candidates for chemotherapy. DEBIO 0507/NC-4016 is a DACH-Platin Polymeric Micelle. The main objectives of this project were to assess pharmacokinetic (PK) profile of DEBIO 0507 and evaluate its efficacy in preclinical studies against a broad spectrum of experimental tumors including syngenic, xenogenic tumor models and a cisplatin-resistant cell line. Methods: PK and biodistribution studies were conducted in multiple matrices (blood, tumor, liver, spleen, kidneys and pancreas) collected in mice bearing C38 mouse colon carcinoma and treated with a single IV injection of DEBIO 0507 at 2 mg Pt/kg. Antitumor activity of DEBIO 0507 intravenously injected every 4, 7 or 14 days at different doses was investigated in C38 mouse colon carcinoma bearing C57BL/6 mice. Antitumor effect of DEBIO 0507 was also assessed in a panel of human tumor xenografted in nude mice, Calu-6 and A-549 human lung carcinoma, HT-29 human colon carcinoma, PC-3 human prostatic tumor, FaDu human pharynx carcinoma, NIH:OVCAR3 human ovarian tumor, BxPC-3 human pancreas tumor and HepG2 human hepatocarcinoma. Results: A concentration of 61 µg Pt/ml was detected in plasma from 5 minutes after injection and persisted during two hours. Platinum was very slowly cleared from plasma as it was still detected 14 days after injection (t1/2α : 40h). An accumulation was observed in tumor from 5 minutes to 8 days after injection and terminal elimination phase was very long since platinum was also detected 14 days after injection. The same PK and BD profiles were observed for other tissues. DEBIO 0507 was not active in the models of NIH: OVCAR3 human ovarian tumor, BxPC-3 human pancreas tumor and HepG2 human hepatocarcinoma. DEBIO 0507 exhibited a significant and dose-dependent antitumor activity against C38 mouse colon carcinoma when administered every 4, 7 or 14 days (optimal T/C of 0, 0 and 5%, respectively). We also demonstrated growth inhibitory effects of DEBIO 0507 in human PC-3 prostate, Calu-6 lung, FaDu head and neck and A-549 lung tumors xenografted in nude mice when injected with similar doses and schedules (optimal T/C of : 26, 29, 39 and 40%, for each model respectively). Conclusion: DEBIO 0507 displayed a marked antitumor activity against a large spectrum of tumor models associated with a long exposure of tumor to Pt. These preclinical results provide useful data to support the design of clinical trials for DEBIO 0507. DEBIO 0507/NC-4016 was produced by Nanocarrier Co.,Ltd. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 571.