title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Institution Ethical Board Approval ID: KEK-ZH-Nr. 2014-0374; Swiss regulatory authority Swissmedic (2015DR1009); ClinicalTrials.gov Identifier: NCT02528526 , prospectively registered on November 11th, 2014.
authors.affiliation: Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Raemistrasse 100, Zurich, CH-8091, Switzerland.|Department of Surgery, University Hospital Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland.
authors.forename: Perparim
authors.initials: P
authors.lastname: Limani
authors.affiliation: Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Raemistrasse 100, Zurich, CH-8091, Switzerland.|Department of Surgery, University Hospital Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Linecker
authors.affiliation: Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Raemistrasse 100, Zurich, CH-8091, Switzerland.|Department of Surgery, University Hospital Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kron
authors.affiliation: Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Raemistrasse 100, Zurich, CH-8091, Switzerland.|Department of Oncology, University Hospital Zurich, Raemistrasse 100, Zurich, CH-8091, Switzerland.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Samaras
authors.affiliation: Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Raemistrasse 100, Zurich, CH-8091, Switzerland.|Department of Oncology, University Hospital Zurich, Raemistrasse 100, Zurich, CH-8091, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Pestalozzi
authors.affiliation: Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Raemistrasse 100, Zurich, CH-8091, Switzerland.|Department of Oncology, University Hospital Zurich, Raemistrasse 100, Zurich, CH-8091, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Stupp
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Raemistrasse 100, Zurich, CH-8091, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Jetter
authors.affiliation: Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Raemistrasse 100, Zurich, CH-8091, Switzerland.|Department of Surgery, University Hospital Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Dutkowski
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital Zurich, Raemistrasse 100, Zurich, CH-8091, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Müllhaupt
authors.affiliation: Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Raemistrasse 100, Zurich, CH-8091, Switzerland.|Department of Surgery, University Hospital Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schlegel
authors.affiliation: Friedman School of Nutrition Science and Policy, 150 Harrison Ave, Boston, MA, 02111, USA.
authors.forename: Claude
authors.initials: C
authors.lastname: Nicolau
authors.affiliation: Institut de Science et d'Ingénierie Supramoléculaires (ISIS), Université de Strasbourg, 8 allée Gaspard Monge, Strasbourg, F-67000, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Lehn
authors.affiliation: Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Raemistrasse 100, Zurich, CH-8091, Switzerland.|Department of Surgery, University Hospital Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland.
authors.forename: Henrik
authors.initials: H
authors.lastname: Petrowsky
authors.affiliation: Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Raemistrasse 100, Zurich, CH-8091, Switzerland.|Department of Surgery, University Hospital Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland.
authors.forename: Bostjan
authors.initials: B
authors.lastname: Humar
authors.affiliation: Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Raemistrasse 100, Zurich, CH-8091, Switzerland.|Department of Surgery, University Hospital Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Graf
authors.affiliation: Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Raemistrasse 100, Zurich, CH-8091, Switzerland. clavien@access.uzh.ch.|Department of Surgery, University Hospital Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland. clavien@access.uzh.ch.
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Clavien
mesh_terms: D006801:Humans; D001661:Biliary Tract Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000860:Hypoxia / Q000378:metabolism; D007295:Inositol Phosphates / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012107:Research Design
chemical_list: D007295:Inositol Phosphates; C516441:inositol trispyrophosphate
keywords: Cholangio carcinoma; Colorectal cancer; Hepatocellular carcinoma; Hepatopancreatobiliary tumor; Hypoxia; ITPP; Myo-inositol trispyrophosphate