477P - Liposomal prodrug of mitomycin c with thiolytic activation: improved therapeutic index over mitomycin c in preclinical studies

Date 01 October 2012
Event ESMO Congress 2012
Session Poster presentation III
Topics Anticancer agents
Therapy
Biological therapy
Presenter Alberto A. Gabizon
Authors A.A. Gabizon1, Y. Amitay2, H. Shmeeda3, S. Zalipsky4
  • 1Oncology, Shaare Zedek Medical Center, 91031 - Jerusalem/IL
  • 2Experimental Oncology, Lipomedix Pharmaceuticals Inc., 91031 - Jerusalem/IL
  • 3Experimental Oncology, Shaare Zedek Medical Center, 91031 - Jerusalem/IL
  • 4Consultant, Lipomedix Pharmaceuticals Inc., 91031 - Jerusalem/IL

Abstract

We have developed a formulation of a mitomycin-C lipid-based prodrug (MLP) in pegylated liposomes (PL) in which MLP is activated by thiolytic cleavage to mitomycin C (MMC). PL-MLP (PROMITIL™) was previously reported to have reduced toxicity and an improved therapeutic index as compared to MMC in human and mouse tumor models. In the following studies, we examined the pharmacokinetics, toxicity, and therapeutic activity of scaled-up batches of PL-MLP (prepared under the same protocol design as for clinical batches) in rodent and miniswine species. PL-MLP is a liquid suspension of vesicles of ∼100 nm diameter with MLP entrapped in the lipid bilayer at 10% molar ratio. Pharmacokinetic studies revealed major (>100-fold) differences in Cmax, AUC, plasma clearance and volume of distribution between MMC (i.v. 3 mg/kg) and PL-MLP (i.v. 6 mg/kg in MMC-equivalents). While MMC is cleared from blood within minutes and extensively distributed to peripheral tissues, PL-MLP is cleared very slowly with a mono-exponential half-life of ∼15 hours in rats and has a limited volume distribution roughly equivalent to the blood volume. In rat toxicity studies in rats, the MTD of PL-MLP was two to three-fold higher than that of MMC in mg-equivalent doses. Therapeutic studies in BALB/c mice inoculated i.p. with C26 tumor cells show a clear survival advantage for treatment with PL-MLP over free MMC at all dose levels tested, whether treatment was administered by the i.v. or by the i.p. route. In the porcine model, no acute infusion reaction to i.v. administration of PL-MLP was observed. PL-MLP appears to be a stable formulation with minimal prodrug activation and release of MMC in circulation, yet significant antitumor activity, indicating in vivo prodrug activation in tumors. PL-MLP may represent an effective therapeutic tool in a broad spectrum of malignancies, including multi-drug resistant tumors, with improved safety over free MMC, and is due to be tested in a human phase I study in 2012.

Disclosure

A.A. Gabizon: I am the founder and Chief Scientist of Lipomedix Inc., a company with a vested interest in the product discussed in this presentation.

Y. Amitay: Paid employee of Lipomedix, a product of which is discussed here.

All other authors have declared no conflicts of interest.