Development of OXY111A, a novel hypoxia-modifier as a potential antitumor agent in patients with hepato-pancreato-biliary neoplasms - Protocol of a first Ib/IIa clinical trial

English version České info

Background:
Solid tumors, such as hepato-pancreato-biliary cancer, develop tumor hypoxia with tumor growth. Despite advances in surgery, a majority of these patients are in an unresectable condition. At this stage standard cytotoxic chemotherapy regimens are applied with limited success. Novel biological treatment options based on an antiangiogenic mechanism of action neglect other hypoxia mediated mechanisms (e.g. epithelial-mesenchymal transition, Warburg effect, and immunological response) leading to an increased invasiveness with a poor outcome.

The novel antihypoxic molecule myo-inositoltrispyrophosphate (ITPP, OXY111A) acts as an allosteric effector of hemoglobin and promotes normoxia in hypoxic tumors. In preclinical studies, tumor growth was reduced and survival prolonged. Additionally, a beneficial side effect profile was observed.

Methods:
In this first Ib/IIa clinical trial we will assess safety and tolerability of OXY111A as well as a proof of concept regarding efficacy in patients with non-resectable primary and secondary tumors of the liver, pancreas, and biliary tract. The study design is exploratory, prospective, open-labelled and mono-centric. The study is divided in a dose escalation part with a maximum of 48 subjects and an extension part, in which 21 subjects will be included.

Discussion:
The novel antihypoxic compound OXY111A has been tested in several cancer animal models showing beneficial effects for both survival and low side effect profiles. This first in patient application of OXY111A will reveal potential beneficial outcomes if anti-hypoxic therapy is added to standard cytotoxic treatment in patients with primary and secondary hepatopancreatobiliary tumors.

Trial registration:
Institution Ethical Board Approval ID: KEK-ZH-Nr. 2014-0374; Swiss regulatory authority Swissmedic (2015DR1009); ClinicalTrials.gov Identifier: NCT02528526, prospectively registered on November 11^th, 2014.

Keywords:
Hypoxia, Hepatopancreatobiliary tumor, Colorectal cancer, Hepatocellular carcinoma, Cholangio carcinoma, Myo-inositol trispyrophosphate, ITPP

Autoři: Perparim Limani ^1,2; Michael Linecker ^1,2; Philipp Kron ^1,2; Panagiotis Samaras ^1,3; Bernhard Pestalozzi ^1,3; Roger Stupp ^1,3; Alexander Jetter ⁴; Philipp Dutkowski ^1,2; Beat Müllhaupt ⁵; Andrea Schlegel ^1,2; Claude Nicolau ⁶; Jean-Marie Lehn ⁷; Henrik Petrowsky ^1,2; Bostjan Humar ^1,2; Rolf Graf ^1,2; Pierre-Alain Clavien ^1,2*
Působiště autorů: Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Raemistrasse 100, Zurich CH- 091, Switzerland. ¹; Department of Surgery, University Hospital Zurich, Raemistrasse 100, CH- 091 Zurich, Switzerland. ²; Department of Oncology, University Hospital Zurich, Raemistrasse 100, Zurich CH- 091, Switzerland. ³; Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Raemistrasse 100, Zurich CH- 091, Switzerland. ⁴; Department of Gastroenterology and Hepatology, University Hospital Zurich, Raemistrasse 100, Zurich CH- 091, Switzerland. ⁵; Friedman School of Nutrition Science and Policy, 150 Harrison Ave, Boston, MA 02111, USA. ⁶; Institut de Science et d’Ingénierie Supramoléculaires (ISIS), Université de Strasbourg ⁷; allée Gaspard Monge, Strasbourg F-67000, France. ⁸
Vyšlo v časopise: BMC Cancer 2016, 16:812
Kategorie: Study protocol
prolekare.web.journal.doi_sk: https://doi.org/10.1186/s12885-016-2855-3

© 2016 The Author(s).

Open access
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
The electronic version of this article is the complete one and can be found online at: http://bmccancer.biomedcentral.com/articles/10.1186/s12885-016-2855-3

Souhrn

Keywords:
Hypoxia, Hepatopancreatobiliary tumor, Colorectal cancer, Hepatocellular carcinoma, Cholangio carcinoma, Myo-inositol trispyrophosphate, ITPP

Zdroje

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