Abstract 5001: Open-label, non-randomized, exploratory pre-operative window-of-opportunity trial to investigate the pharmacokinetics and pharmacodynamics of the smac mimetic Debio 1143 in patients with resectable squamous cell carcinoma of the head and neck
Authors: Gomez-Roca Carlos , Even Caroline , Tourneau Christophe Le , Rotllan Neus Basté , Delord Jean-Pierre , Sarini Jerome , Vergez Sebastien , Teman Stephane , Hoffmann Caroline , Rochaix Philippe , Gavillet Bruno , Rouits Elisabeth , Brichory Franck , Rechavi-Robinson Dalit , Bize Vincent , Rizzo Sebastien Del , Purcea Daniela , Brienza Silvano , Zanna Claudio , Vuagniaux Gregoire , Szyldergemajn Sergio 
Published: August 2019

Abstract
Background: Inhibitor of Apoptosis Proteins (IAPs) regulate apoptosis and modulate NFκB signaling, which in turn drives the expression of genes involved in immune and inflammatory responses. Debio 1143 is an orally available antagonist of IAPs with the potential to enhance tumor response, when combined with chemo/radiotherapy and/or immunotherapy, that is currently being tested in phase II clinical trials.
Methods: We investigated the pharmacokinetics and pharmacodynamic effects of Debio 1143 monotherapy (200 mg/day D1-15 +/-2 p.o.) in paired tumor samples collected at diagnosis and at time of surgical resection in a window of opportunity trial in patients with potentially resectable squamous cell carcinoma of the head and neck (SCCHN) (EudraCT Number: 2014-004655-31). Pharmacokinetic disposition of Debio 1143 was evaluated in tumor samples by quantitative mass spectrometry imaging (QMSI), and in plasma by LC-MS/MS. Immunohistochemistry for cellular IAP1 (cIAP1), cleaved caspase-3 apoptosis marker, Ki-67 proliferation marker, CD3+, CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs), PD-1 and PD-L1 were performed in pre- and post-treatment specimens. Exploratory transcriptomic analyses were conducted to assess the effects of Debio 1143 on gene expression.
Results: Twelve patients were evaluated. Debio 1143 monotherapy was well tolerated. Tumor penetration was high, with Debio 1143 concentrations up to 55-fold those found in plasma at the time of the resection. Pharmacodynamic analysis of resected tumors showed a significant target engagement with degradation of cIAP1 (p &lt; 0.05). There was no significant change in cleaved caspase-3 or proliferation measured by Ki67. Overall, the levels of CD8+ TILs, PD-1 and PD-L1 positive immune cells increased significantly (p &lt; 0.05) compared to pre-treatment levels. Changes were observed in the expression of genes related to NFκB signaling.
Conclusions: This study demonstrates that Debio 1143 distributes widely into SCCHN tumors, engages its target cIAP1, and induces downstream effects that may modulate immunity in the tumor microenvironment supporting future combination therapy with immune-checkpoint agents in cancer patients.
Citation Format: Carlos Gomez-Roca, Caroline Even, Christophe Le Tourneau, Neus Basté Rotllan, Jean-Pierre Delord, Jerome Sarini, Sebastien Vergez, Stephane Teman, Caroline Hoffmann, Philippe Rochaix, Bruno Gavillet, Elisabeth Rouits, Franck Brichory, Dalit Rechavi-Robinson, Vincent Bize, Sebastien Del Rizzo, Daniela Purcea, Silvano Brienza, Claudio Zanna, Gregoire Vuagniaux, Sergio Szyldergemajn. Open-label, non-randomized, exploratory pre-operative window-of-opportunity trial to investigate the pharmacokinetics and pharmacodynamics of the smac mimetic Debio 1143 in patients with resectable squamous cell carcinoma of the head and neck [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5001.