Phase I Trial of Debio 1143, an Antagonist of Inhibitor of Apoptosis Proteins, Combined with Cisplatin Chemoradiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Abstract

Purpose:Debio 1143 is an oral antagonist of inhibitor of apoptosis proteins, which enhances tumor response with concomitant chemoradiotherapy. Addition of Debio 1143 to cisplatin-based chemoradiotherapy in locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN) was evaluated in a phase I/II study to determine the MTD and recommended phase II dose (RP2D). Here, phase I results are reported.Patients and Methods:Treatment-naïve patients with LA-SCCHN (stages III/IVA/IVB) received Debio 1143 (100, 200, 300 mg/day), for 14 days every 3 weeks, with cisplatin (100 mg/m², every 3 weeks), for three cycles, and concomitant conventional fractionation radiotherapy (70 Gy/7 weeks). Dose-limiting toxicity (DLT) was evaluated over 9 weeks using continual reassessment.Results:Fourteen patients were treated/evaluable for DLT. Median age was 64.5 years, and all patients were current/former smokers. Primary tumors were hypopharynx, oropharynx (all human papillomavirus/p16 negative), larynx, and oral cavity. Two of six patients at 200 mg/day had DLT (grade 3 tubular necrosis, grade 3 aspartate aminotransferase/alanine aminotransferase increase, grade 4 febrile neutropenia, and grade 3 lipase increase), which was considered the MTD and RP2D. Common grade 3–4 adverse events were dysphagia (36%) and mucositis (29%). Laboratory abnormalities were frequent and generally mild, including anemia, white blood cell decrease, and increased creatinine. Addition of Debio 1143 did not compromise chemotherapy administration. Overall locoregional control rate at 18 months was 85%. Overall response rate was 85%, including 69% complete responses. Progression-free survival rate at 24 months was 74%.Conclusions:The RP2D of Debio 1143 is 200 mg/day for 14 days, every 3 weeks, when combined with concomitant high-dose cisplatin chemoradiotherapy in LA-SCCHN. Debio 1143 addition to chemoradiotherapy was safe and manageable. Preliminary efficacy is encouraging and supports further development.

Therapeutics Targeting the Core Apoptotic Machinery

“…IAP antagonists, initially developed to induce apoptosis, have more recently been shown to have broad immunomodulatory effects on both the innate and adaptive immune systems [ 115 , 116 , 117 ]. IAP antagonists modulate NF-κB activity which can enhance tumor cell killing and the immune status of a tumor by several mechanisms including the conversion of pro-tumoral M2 macrophages to pro-inflammatory M1-like macrophages, signals promoting B-cell survival and the activation of dendritic cells as well as delivering stimulatory signals to T-cells [ 118 ]. As such these agents may offer a powerful combination strategy for use with the emerging immunotherapeutic agents, potentially stimulating immune “cold” tumors to be responsive to this class of agents.…”

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.…”

A Review of the Current Impact of Inhibitors of Apoptosis Proteins and Their Repression in Cancer

“…Debio 1143 is capable of synergizing with taxanes, among other agents, against lung adenocarcinoma cells, even reducing the tumor volume in mice xenografts [ 139 ]. A phase I/II trial of Debio in combination with cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck provided encouraging results including high OS, CR and PFS rates [ 140 ]. Furthermore, it demonstrated efficacy in mice models of carboplatin-resistant ovarian cancer in combination with carboplatin, which is currently the first line of treatment, despite eventual relapse.…”