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

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 ASO alone or with 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. Patients and Methods: Eligible patients had solid tumors and received prior standard-of-care treatment, including anti–PD-(L)1 therapy. Patient cohorts were treated with AZD8701 intravenously weekly at escalating doses, either alone (60–960 mg) or combined (240–720 mg) with durvalumab 1,500 mg intravenous every 4 weeks. The primary objective was safety and tolerability, with the aim of determining the MTD. Results: Forty-five patients received AZD8701 monotherapy, and 18 received AZD8701 with durvalumab. One dose-limiting toxicity (increased alanine aminotransferase) occurred with AZD8701 960 mg. The most common adverse events related to AZD8701 monotherapy were fatigue (22.2%), asthenia, pyrexia, and increased alanine aminotransferase (20% each); the safety profile was similar when combined with durvalumab. With AZD8701 monotherapy, 24.4% and 15.6% of the patients had stable disease for ≥16 and ≥24 weeks, respectively; one patient treated with AZD8701 720 mg and durvalumab had a partial response. FOXP3 mRNA changes were heterogeneous (8/13 patients showed a 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 adverse events, FOXP3 knockdown, and ASO delivery to the tumor.