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 Cytotoxic agents
Colon and Rectal Cancer
Therapy
Biological therapy
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.