Phase I study of OM-174, a lipid A analogue, with assessment of immunological response, in patients with refractory solid tumors

Nicolas Isambert, Pierre Fumoleau, Catherine Paul, Christophe Ferrand, Sylvie Zanetta, Jacques Bauer, Kevin Ragot, Gérard Lizard, Jean-François Jeannin, Marc Bardou, Nicolas Isambert, Pierre Fumoleau, Catherine Paul, Christophe Ferrand, Sylvie Zanetta, Jacques Bauer, Kevin Ragot, Gérard Lizard, Jean-François Jeannin, Marc Bardou

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.

Conclusion: 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.

Trial registration: NCT01800812 (ClinicalTrials.gov Identifier).

Figures

Figure 1
Figure 1
a Increase of IL-8 concentration after each injection of OM-174 with a peak at second hour, independently of dose of OM-174 and number of injections. Black, doted and white boxes represent the value of the cytokine of interest 1, 2 and 4 hours after the injection of interest. Analyses were conducted on all 17 patients according to their number of OM-174 injections. 1b and 1c Both concentration of TNF-α and IL-6 decreased after each injection of OM-174 suggesting a tolerance. The peak of secretion is observed respectively 1 and 2 hours after the first injection of OM-174 for TNF-α and IL-6. Black, doted and white boxes represent the value of the cytokine of interest 1, 2 and 4 hours after the injection of interest. Analyses were conducted on all 17 patients according to their number of OM-174 injections.
Figure 2
Figure 2
Increase of NK activity after each injection of 1000 μg/m2 OM-174 and in association with IL-2.

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