AZD8701, an Antisense Oligonucleotide Targeting FOXP3 mRNA, as Monotherapy and in Combination with Durvalumab: Phase I trial in Patients with Advanced Solid Tumors.

Abstract

Purpose: AZD8701 uses next-generation antisense oligonucleotide (ASO) technology to selectively reduce human forkhead box P3 (FOXP3) expression in regulatory T cells, reversing their immunosuppressive function. FOXP3 ASOs alone or with programmed cell death protein (ligand) 1 (PD-[L]1) inhibition attenuated tumor growth in mice. We report a phase I study of AZD8701 alone or combined with durvalumab in patients with advanced solid tumors.

Methods: Eligible patients had solid tumors and had received prior standard-of-care treatment including anti-PD-(L)1 therapy. Patient cohorts were treated with AZD8701 intravenously (IV) weekly at escalating doses, either alone (60-960 mg) or combined (240-720 mg) with durvalumab 1,500 mg IV every 4 weeks. The primary objective was safety and tolerability, with the aim of determining the maximum tolerated dose.

Results: Forty-five patients received AZD8701 monotherapy and 18 received AZD8701 with durvalumab. One dose-limiting toxicity (increased alanine aminotransferase [ALT]) occurred with AZD8701 960 mg. The most common adverse events (AEs) related to AZD8701 monotherapy were fatigue (22.2%), asthenia, pyrexia, and increased ALT (20%, each); the safety profile was similar when combined with durvalumab. With AZD8701 monotherapy, 24.4% and 15.6% of patients had stable disease for ≥16 and ≥24 weeks, respectively; one patient treated with AZD8701 720 mg and durvalumab had a partial response. FOXP3mRNA changes were heterogeneous (8/13 patients showed reduction), with no clear dose relationship. ASO accumulated in the tumor epithelium and stroma.

Conclusions: This study demonstrates the clinical feasibility of ASO therapy, with generally manageable AEs, FOXP3 knockdown, and ASO delivery to the tumor.