Background: Hypoxia-inducible factor (HIF)-2α is a transcription factor that plays a central role in the hypoxic response pathway in tumors. HIF-2α heterodimerizes with HIF-1β and binds to hypoxic response elements in target genes. The first-in-class HIF-2α inhibitor, PT2385, demonstrated clinical activity in patients (pts) with clear cell renal cell carcinoma (ccRCC). PT2977 is a novel, orally administered selective small molecule HIF-2α inhibitor with improved potency compared to PT2385. PT2977 inhibited expression of HIF-2α target genes in tumor cells and induced regression in mouse xenograft models. Methods: Pts with advanced solid tumors who had received at least 1 prior therapy were treated with PT2977 once daily (QD) in a Phase 1 dose-escalation trial to determine the recommended Phase 2 dose (RP2D) and evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD). Plasma PK were measured on days 1 and 15 and PD weekly. Results: 29 pts were treated at doses of 20 - 160 mg QD in the dose-escalation. As of January 15, 2018, no treatment-related dose-limiting toxicities have been observed. The most common all-grade AEs have been anemia (35%), fatigue (24%), edema (17%), headache (17%), and nausea (17%). Anemia (11%) was the most common Grade 3 AE; there have been no Grade 4 events. Exposure increased with dose along with dose-dependent reductions in erythropoietin (PD marker) consistent with the pharmacology of PT2977. At the RP2D of 120 mg, PT2977 was rapidly absorbed (T_max = 3.1 h) with a C_max of 1.83 mg/mL, a C_min of 0.71 mg/mL, and a T_1/2 of 20 h. A pt with SDHB mutant paraganglioma has had stable disease (SD) > 25 weeks with sustained decrease in normetanephrine levels. Of 6 pts with ccRCC treated at 120 mg or 160 mg, there was one PR and 4 SD with tumor reductions from 8%-26%. Conclusions: PT2977 is well tolerated and has a favorable safety and PK/PD profile. Early evidence of clinical activity shows promise for HIF2a inhibition in the treatment of ccRCC. PT2977 is currently under evaluation in an expansion cohort of 50 pts with previously treated advanced ccRCC at a dose of 120 mg QD. Clinical trial information: NCT02974738.