479P - A phase I study of of mitomycin-C prodrug in pegylated liposomes

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Drug Development
Presenter Alberto Gabizon
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors A.A. Gabizon1, T. Golan2, T. Grenader1, R. Berger2, E. Tahover1, N.M. La-Beck3, Y. Amitay4, P. Ohana4
  • 1Oncology, Shaare Zedek Medical Center, 91031 - Jerusalem/IL
  • 2Oncology, Sheba Medical Center, Tel Hashomer/IL
  • 3Immunotherapeutics & Biotechnology, TTUHSC School of Pharmacy, Abilene/US
  • 4Lipomedix Pharmaceuticals, Lipomedix Pharmaceuticals, Jerusalem/IL

Abstract

Aim

Promitil® is a pegylated liposome formulation of a lipid-based prodrug of mitomycin C (MLP). MLP is activated to mitomycin C (MMC) by thiolytic cleavage. Pre-clinical studies of Promitil have shown long circulation time, reduced toxicity, and improved therapeutic index over MMC. The primary objectives of this study were to determine the maximal tolerated dose (MTD), identify dose-limiting toxicities (DLT), and characterize the pharmacokinetic (PK) profile of Promitil. Secondary objectives were to evaluate the safety profile of Promitil and anti-tumor responses. Plasma levels of sC5b-9 complex were measured to detect liposome infusion-related complement activation.

Methods

Enrolled patients were diagnosed with advanced solid tumors. Promitil was administered i.v. at 4-week intervals starting with an MLP dose of 0.5 mg/kg and escalating at 0.5 mg/kg stepwise increments. Each dose level cohort consisted of 3-6 patients. Dose escalation proceeded if no DLT observed after the 1st cycle. Each patient was scheduled to receive 3 cycles with PK analysis in 1st and 3rd cycles, and undergo re-evaluation in the 12th week, unless early discontinuation was clinically indicated. Treatment continuation beyond 3 cycles was at the discretion of the investigators.

Results

27 patients received 100 Promitil infusions (median = 3 cycles/patient; range = 1-12) between 18Nov2012 and 04May2014. The highest dose level tested was 3.5 mg/kg (=1.03 mg/kg MMC-equivalents) in a cohort of 6 patients. Although no DLT was observed for single dose Promitil, the occurrence of several cases of delayed thrombocytopenia grade 2-3 after 3 or more cycles of Promitil in patients treated at lower dose levels (2-3 mg/kg) led us to terminate dose escalation. The 1st cycle MTD of Promitil is 3 mg/kg and the recommended dose for additional cycles is 2 mg/kg at intervals of 28 days. PK analysis indicates MLP has a slow, nearly mono-exponential clearance, with a half-life of 20-24 hours and a small volume of distribution similar to blood volume.

Conclusions

The single dose MTD and the 12-week maximal cumulative dose of Promitil in MMC-equivalents are ∼3-fold greater than for MMC. Thrombocytopenia is cumulative dose limiting. The PK is characteristically Stealth-like as with other pegylated liposomes. Final results of safety, complement activation, PK, and tumor responses will be presented.

Disclosure

A.A. Gabizon: is founder, director, and chief scientist of Lipomedix Pharmaceuticals, the company developing the product Promitil; Y. Amitay: works as a Senior Scientist in Lipomedix Pharmaceuticals; P. Ohana: is Director of Medical Affairs for Lipomedix Pharmaceuticals. All other authors have declared no conflicts of interest.