Abstract CT140: A phase 1 study of the IAP inhibitor xevinapant (Debio 1143) to evaluate food effect and drug-drug interactions with a proton pump inhibitor in healthy volunteers
Authors: Nicolas-Métral Valérie , Rouits Elisabeth , Riff Camille , Spaggiari Dany , Wiedemann Norbert , Colin Pierre , Harrison-Moench Eleanor , Crabbé Rafael , Nauwelaerts Heidi , Schroeder Andreas , Haefliger Carolina , Vugmeyster Yulia 
Published: April 2024

Abstract
INTRODUCTION: Xevinapant is an oral IAP (inhibitor of apoptosis protein) inhibitor designed to restore cancer cell sensitivity to apoptosis, thereby enhancing the efficacy of chemoradiotherapy (CRT) and radiotherapy (RT). Xevinapant 200 mg/d (d1-14, Q3W) + CRT showed clinical benefit vs placebo + CRT in a phase 2 study of patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN; NCT02022098). Two phase 3 studies are currently ongoing evaluating xevinapant in combination with CRT (TrilynX; NCT04459715) or RT (XRay Vision; NCT05386550) in patients with LA SCCHN, with dosing under fasting conditions or without regard to food, respectively.
METHODS: A 2-stage study (Debio 1143-107) was conducted to assess the effect of food on 2 different formulations of xevinapant and the effect of co-administration with the proton pump inhibitor pantoprazole to evaluate the effect of high gastric pH on bioavailability of xevinapant. Stage 1 was an open-label, randomized, 4-arm, crossover study with 26 healthy volunteers (HV) treated with a single oral dose of xevinapant 200 mg in fasted or fed (high-fat diet) conditions with 2 different formulations. Stage 2 was a randomized, 2-way crossover study with 12 HV treated with a single oral dose of xevinapant 200 mg with or without pantoprazole. Pharmacokinetics (PK) and pharmacodynamics (PD) samples (Ciap1 levels in peripheral blood mononuclear cells [PBMCs]) were collected over 72 h post dose. The utilization of HV to address clinical pharmacology aspects of xevinapant was justified by holistic assessment of the toxicology, safety, and pharmacology profiles.
RESULTS: Following a single dose of xevinapant 200 mg, exposures in HV under fasted conditions were consistent with those observed previously in cancer patients. Xevinapant formulations were bioequivalent and were considered safe and well tolerated in both fasted and fed conditions. Food delayed Tmax and decreased xevinapant Cmax by 39% but did not meaningfully alter the extent of absorption of xevinapant, as evidenced by no change in AUC, which is the most relevant exposure metric for efficacy based on xevinapant’s mechanism of action. Stage 2 data indicated that the PK of xevinapant was not affected by treatment with pantoprazole. Ciap1 levels in PBMCs decreased at least 4-fold compared to the baseline for all treatments and were reduced up to 72 h post single dose. No relevant differences in PD were observed across treatments. PK simulations indicated no relevant change in AUC and no impact on target engagement at steady state with food.
CONCLUSION: These data indicate that xevinapant can be administered without regard to food or gastric acid reducing agents, which would be advantageous for patient convenience and compliance.
Citation Format: Valérie Nicolas-Métral, Elisabeth Rouits, Camille Riff, Dany Spaggiari, Norbert Wiedemann, Pierre Colin, Eleanor Harrison-Moench, Rafael Crabbé, Heidi Nauwelaerts, Andreas Schroeder, Carolina Haefliger, Yulia Vugmeyster. A phase 1 study of the IAP inhibitor xevinapant (Debio 1143) to evaluate food effect and drug-drug interactions with a proton pump inhibitor in healthy volunteers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT140.