title: Phase I study of OM-174, a lipid A analogue, with assessment of immunological response, in patients with refractory solid tumors.
abstract: BACKGROUND
  Lipids A, the lipophilic partial structure of lipopolysaccharides, induce regression of several tumor types in animal models. Rather than exerting direct cytotoxic effect, these compounds trigger the immune system which in turn stimulates secretion of cytokines, and activates the inducible nitric oxide synthase, as well as immune cell infiltration of tumors. OM-174 is an analogue of lipid A with dual action on Toll-like receptors 2 and 4. In an experimental model of peritoneal carcinomatosis induced in BDIX rats by intraperitoneal injection of syngeneic PROb colon cancer cells, it induced a complete regression of tumors. The present phase I trial was conducted to determine the maximum tolerated dose, the recommended phase II dose and biological response associated with OM-174 administered as intravenous infusion.
  
  
  METHODS
  Patients received OM-174 twice weekly for a total of 5, 10 or 15 injections of either 600, 800 or 1000 μg/m(2). Blood samples for pharmacokinetic analysis and cytokine dosages were collected. NK cells activity and Toll-like receptors 4 polymorphism analysis were also performed.
  
  
  RESULTS
  Seventeen patients were included. The highest dose administered was 1000 μg/m(2) repeated in 15 injections. The most common toxicities were a chills, fever, nausea/vomiting, diarrhea, fatigue and headache. No patient experienced haematological side effects. As no dose limiting toxicity was observed, despite a grade 3 respiratory complication, the maximal tolerated dose and recommended dose were not established. Three patients exhibited disease stabilization with a mean duration of 4 months. Pharmacokinetic profile of OM-174 was characterized by a low distribution volume and clearance. Analysis of TLR 4 polymorphysm showed that most (16/17) patients carried the wild type alleles. A progressive increase in NK cell number and activity was observed only in patients receiving 1000 μg/m(2) of OM-174. A peak of IL-8 and IL-10 concentrations were observed after each OM-174 injection. Peaks of TNF-alpha and IL-6 concentrations were detected after the first infusion and decreased progressively suggesting tolerance.
  
  
  CONCLUSIONS
  OM-174 therapy was well tolerated at biologically active concentrations. Whereas the recommended dose was not determined, further studies are planned in combination with chemotherapy as animal models suggest a strong synergistic antitumor effect.
  
  
  BACKGROUND
  NCT01800812 (ClinicalTrials.gov Identifier).
authors.affiliation: INSERM CIC-P803, CHU de Dijon, Batiment du Pr Marion, 14 rue Gaffarel, BP77908, 21079, Dijon Cedex, France. nisambert@cgfl.fr
authors.forename: Nicolas
authors.initials: N
authors.lastname: Isambert
authors.forename: Pierre
authors.initials: P
authors.lastname: Fumoleau
authors.forename: Catherine
authors.initials: C
authors.lastname: Paul
authors.forename: Christophe
authors.initials: C
authors.lastname: Ferrand
authors.forename: Sylvie
authors.initials: S
authors.lastname: Zanetta
authors.forename: Jacques
authors.initials: J
authors.lastname: Bauer
authors.forename: Kevin
authors.initials: K
authors.lastname: Ragot
authors.forename: Gérard
authors.initials: G
authors.lastname: Lizard
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Jeannin
authors.forename: Marc
authors.initials: M
authors.lastname: Bardou
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D011110:Polymorphism, Genetic; D051381:Rats; D051197:Toll-Like Receptor 4 / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; C400105:defoslimod
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