AZD8701, an Antisense Oligonucleotide Targeting FOXP3 mRNA, as Monotherapy and in Combination with Durvalumab: A Phase I Trial in Patients with Advanced Solid Tumors
Mené sur 63 patients atteints de tumeurs solides avancées et ayant déjà reçu un traitement par anti-PD-(L)1, cet essai de phase I détermine la dose maximale tolérée de l'AZD8701 (un oligonucléotide antisens ciblant l'ARN messager de FOXP3) administré par voie intraveineuse, seul ou en combinaison avec le durvalumab
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.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.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.This study demonstrates the clinical feasibility of ASO therapy, with generally manageable adverse events, FOXP3 knockdown, and ASO delivery to the tumor.