Exploratory window‐of‐opportunity trial to investigate the tumor pharmacokinetics/pharmacodynamics of the IAP antagonist Debio 1143 in patients with head and neck cancer

Abstract

Inhibitor of apoptosis proteins (IAPs) regulate apoptosis and modulate NF-κB signalling thereby driving expression of genes involved in immune/inflammatory responses. The orally available IAP antagonist Debio 1143 has potential to enhance tumor response to chemoradiotherapy and/or immunotherapy. Patients with pre-operative squamous cell carcinomas of the head and neck (SCCHN) received: Debio 1143 monotherapy (200 mg/day D1-15 +/-2); Debio 1143 (200 mg/day D1-15 +/-2) plus cisplatin (40 mg/m 2 D-1 and 8); cisplatin alone (40 mg/m 2 D-1 and 8) (EudraCT: 2014-004655-31). Pharmacokinetic/pharmacodynamic effects were assessed in plasma and resected tumors. Primary endpoint; effect of Debio 1143 on cellular IAP-1 (cIAP-1). Levels of cIAP-1/-2, X-linked inhibitor of apoptosis protein (XIAP), tumor infiltrating lymphocytes (TILs) including CD8+ T cells, programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) and gene expression were also analyzed. Twenty-three of 26 patients completed treatment. In the Debio 1143 monotherapy cohort (n=13), mean tumor concentrations of Debio 1143 were 18-fold (maximum 55.2-fold) greater than in Accepted Article This article is protected by copyright. All rights reserved plasma, exceeding the IC 50 for cIAPs and XIAP by 100 to 1000-fold, with significant engagement/degradation of cIAP-1 (p <0.05). Overall, levels of CD8+ TILs, PD-1 and PD-L1 positive immune cells increased significantly (p <0.05) following Debio 1143 treatment. Changes were observed in the expression of genes related to NF-κB signalling. Treatments were well tolerated. Debio 1143 penetrated SCCHN tumors, engaged cIAP-1 and induced immune inflammatory changes in the tumor microenvironment. Based on the mode of action demonstrated here and in previous studies, these data support future combinations of Debio 1143 with immune-checkpoint agents.

Therapeutics Targeting the Core Apoptotic Machinery

“…Patients were stratified according to a predictive IAP gene expression signature, with each group randomized to receive neoadjuvant paclitaxel alone or in combination with LCL161. Pathological complete response was achieved in 30% of the positive gene expression signature group; however, significant toxicity, including severe neutropenia, was a concern in the combination arm [ 114 ]. A Phase II trial identified that high XIAP expression conferred resistance to LCL161 and that XIAP expression increased in patients that experienced disease progression [ 76 ].…”

Potential for reversing miR-634-mediated cytoprotective processes to improve efficacy of chemotherapy against oral squamous cell carcinoma

“…10,11 Furthermore, Debio 1143 (also known as AT-406), a small molecule antagonist of IAPs (XIAP, cIAP1, and cIAP2), was demonstrated to be safe and effective in preclinical models of several cancer types [12][13][14] and in combination with chemoradiotherapy for patients with locally advanced head and neck squamous cell carcinoma (HNSCC), including OSCC. [15][16][17] Thus, therapeutic targeting of IAPs is a promising approach to improve the efficacy of CDDP-based therapy.…”

Novel Systemic Treatment Modalities Including Immunotherapy and Molecular Targeted Therapy for Recurrent and Metastatic Head and Neck Squamous Cell Carcinoma

“…Cellular inhibitor of apoptosis (cIAPs) and X-linked IAP (XIAP) proteins are both negative regulators of caspase-mediated apoptosis, and additionally, XIAPs also regulates mitochondria-mediated apoptosis [ 124 ]. A potent, orally active, small-molecule IAP inhibitor, Debio 1143 (AT-406, SM-406, xevinapant), may promote apoptosis in tumor cells by blocking both XIAP and cIAPs via restoration of caspase activity [ 125 ].…”