Background: Renal cell carcinoma (RCC) is one of the 10 most common neoplasms in the United States. Patients with clear cell RCC (ccRCC) commonly have inactivation of the von Hippel-Lindau tumor suppressor protein, resulting in accumulation of hypoxia-inducible factor alpha (HIFα) subunits (especially HIF-2α) and leading to tumor growth. AB521, an orally bioavailable small molecule inhibitor of HIF-2α, potently inhibits transcription of HIF-2α-dependent genes in cell lines and preclinical species. Single doses of AB521 (3 mg, 10 mg, 30 mg, and 100 mg) and multiple ascending doses of AB521 (15 mg, 30 mg, and 50 mg) have been previously studied in healthy volunteers. ARC-20 is a first-in-patient study to investigate the safety, tolerability, and pharmacology of AB521 monotherapy in patients with solid tumors and evaluate the clinical activity of AB521 in previously treated patients with ccRCC. Methods: ARC-20 (NCT05536141) is a phase 1, multicenter, open-label study. Eligible patients are adults with solid tumors with ≥1 measurable lesion(s) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and an Eastern Cooperative Oncology Group performance status of 0 or 1. ARC-20 has 2 stages, dose escalation and dose expansion. The dose escalation stage uses a standard 3+3 design and includes patients with pathologically confirmed solid tumors and no other available treatment options. Patients will be sequentially assigned to 1 of 4 cohorts evaluating doses of AB521 ranging from 20 to 200 mg/day. Intermediate dose cohorts may be evaluated based on emergent safety or pharmacologic data. The dose expansion stage will evaluate approximately 30 patients with histologically confirmed ccRCC who have received previous treatment for metastasis with an anti-programmed cell death protein 1 (anti-PD-1) therapy and a vascular endothelial growth factor (VEGF)-targeting tyrosine kinase inhibitor (TKI). Patients previously treated with a HIF-2α-targeting therapy are not eligible for dose expansion. Results from the dose-escalation stage will inform the dose and schedule used during dose expansion. Primary endpoints are the incidence of dose-limiting toxicity and adverse events. Secondary endpoints include objective response rate, AB521 plasma concentration, and AB521 pharmacokinetics. Exploratory endpoints include changes in expression of erythropoietin and other HIF-2α driven biomarkers in blood and tumor tissues, along with progression-free survival for ccRCC patients during dose expansion. Clinical trial information: NCT05536141.