Background: The forkhead box family transcription factor FOXP3 is essential for T regulatory cells (Tregs) development and immune suppressive function. Tregs are an integral component of the adaptive immune system and contribute to maintaining tolerance to self-antigens and preventing autoimmune diseases. In the context of cancer, however, Tregs contribute to tumor progression by suppressing antitumor immunity. To date inhibition of Treg-mediated immunosuppression tested in the clinic has lacked specificity. Targeting FOXP3 provides a selective approach to impair the immunosuppressive function of Tregs but targeting transcription factors has been a challenge using conventional drug modalities. AZD8701 employs next-generation antisense oligonucleotide (ASO) technology (Ionis Pharmaceuticals) to bind mRNA with high affinity and selectively reduce human Foxp3 mRNA expression levels. Foxp3-specific ASOs promote potent dose-dependent reductions in Foxp3 mRNA and protein in vitro. In preclinical models, AZD8701 induced Foxp3 knockdown results in Tregs with a reduced immunosuppressive capacity, loss of immunosuppressive markers, and increased markers of activation on CD8⁺ T-cells. AZD8701 reduces tumor growth as monotherapy in preclinical models and increased tumor inhibition is obtained by combining AZD8701 with a PD-L1 inhibitor. Methods: This is a Phase I multicenter study of AZD8701 alone or in combination with durvalumab in participants with selected advanced solid tumors. Eligible patients must have ECOG performance status 0 or 1, measurable target lesion per RECIST v1.1 and be diagnosed with selected tumor types as described below. Monotherapy and combination dose escalation phase is open for participants with head and neck squamous cell carcinoma (HNSCC), triple-negative breast cancer (TNBC), non-small-cell lung cancer (NSCLC), clear cell renal cell carcinoma (ccRCC), gastroesophageal cancer, melanoma, cervical cancer, small-cell lung cancer (SCLC), and/or solid tumors that have demonstrated a response to prior programmed death-ligand-1 (PD-[L]1) treatment (as defined by duration of response > 18 weeks). Participants with NSCLC, HNSCC, TNBC, and ccRCC will be included in the pharmacodynamic cohort at the selected monotherapy dose and/or disease expansion cohorts. The primary objectives are to assess safety and tolerability and to determine the preliminary antitumor activity of AZD8701 (objective response rate) when administered as monotherapy or in combination with durvalumab. Secondary endpoints include, disease control rate, duration of response, progression free survival and overall survival, pharmacokinetics and pharmacodynamics (including changes in Foxp3 mRNA in paired tumor samples). The trial is currently recruiting. Clinical trial information: NCT04504669.