600TiP - A phase 1B study of pegylated liposomal mitomycin-C prodrug with or without capecitabine and bevacizumab in third line chemotherapy of colorectal c...

Date 08 October 2016
Event ESMO 2016 Congress
Session Poster Display
Topics Anti-Cancer Agents & Biologic Therapy
Colon Cancer
Rectal Cancer
Presenter Alberto Gabizon
Citation Annals of Oncology (2016) 27 (6): 149-206. 10.1093/annonc/mdw370
Authors A.A. Gabizon1, T. Grenader1, E. Tahover1, H. Shmeeda1, T. Golan2, R. Berger2, R. Geva3, I. Wolf3, R. Perets4, Y. Amitay5, P. Ohana5
  • 1Oncology, Shaare Zedek Medical Centre Oncology Institute, 91031 - Jerusalem/IL
  • 2Oncology, Chaim Sheba Medical Center, Ramat Gan/IL
  • 3Dept. Of Oncology, Tel Aviv Sourasky Medical Center-(Ichilov), 64239 - Tel Aviv/IL
  • 4Oncology, Rambam Health Care Center, Haifa/IL
  • 5Lipomedix Pharmaceuticals, Lipomedix Pharmaceuticals Ltd., Jerusalem/IL

Abstract

Background

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. A Phase 1, dose-escalating study, in 27 patients with advanced cancer showed that the maximal tolerated dose of Promitil® (in mitomycin C-equivalents) is ∼3-fold greater than the maximal recommended dose of MMC. The cumulative dose-limiting toxicity of Promitil® is thrombocytopenia. Pharmacokinetic (PK) analysis indicates that Promitil® has a slow blood clearance, with a half-life of ∼24 hours (in contrast to ∼15 minutes for MMC). This Phase 1 study has been expanded to a Phase 1B study that includes 3 cohorts of patients with advanced colorectal cancer (CRC), after failure to 2 or more lines of chemotherapy. The study includes 3 successive cohorts of Promitil® either as single agent (Cohort A), in combination with Capecitabine (Cap) (Cohort B), or in combination with Cap and Bevacizumab (Bev) (Cohort C). Cohorts A and B have been completed. Cohort C is ongoing. The primary objectives of this Phase 1B study are to clear a safe dose-schedule, and characterize the PK profile of Promitil® with or without Cap and Bev in advanced CRC patients. Secondary objectives are evaluation of safety profile and anti-tumor responses to Promitil® with or without Cap and Bev.

Trial design

Fifty to 60 patients are scheduled to receive three 28-day treatment cycles with PK analysis in 1st cycle, and undergo re-evaluation at the 12th week, unless early discontinuation is clinically indicated. Treatment continuation beyond 3 cycles is at the discretion of the investigators. 42 patients diagnosed with advanced CRC, 3rd line chemotherapy (i.e., post-Oxaliplatin-5FU and post-Irinotecan-5FU, with or w/o Bev, and, if indicated, post-Cetuximab/Panitumumab) have been enrolled. A regimen of 2.0 mg/kg Promitil®, i.v., on day 1, Cap at a flat dose of 1,000 mg bid, p.o., on days 1-14, given every 28 days, has been cleared and established as safe for 3 consecutive cycles. In Cohort C, Bev 5.0 mg/kg, i.v., on days 1 and 15 is added to the Promitil-Cap regimen. Safety, efficacy and comparative PK data of the 3 cohorts will be presented.

Clinical trial identification

NCT01705002

Legal entity responsible for the study

Lipomedix Pharmaceuticals Ltd.

Funding

Lipomedix Pharmaceuticals Ltd.

Disclosure

A.A. Gabizon: Shareholder and President of Lipomedix Pharmaceuticals, the company financing the clinical trial. All other authors have declared no conflicts of interest.