Background: Treatment options for patients with recurrent or persistent endometrial cancer (EC) are limited. The PI3K/AKT/mTOR pathway has been implicated in the pathogenesis of EC. This single arm, open-label trial was designed to evaluate the activity of GDC-0980, a dual PI3K/mTOR inhibitor, in patients with advanced EC. NCT01455493. Methods: Patients with recurrent or persistent EC treated with 1 or 2 prior lines of chemotherapy but no prior PI3K/mTOR inhibitor received oral GDC-0980 40 mg daily on a 28-day cycle until progression or intolerable toxicity. Type I/II diabetics requiring insulin were excluded. The primary endpoints were progression-free survival (PFS) at 6 months and objective response rate (ORR). Archival tissue samples were collected for PI3K pathway biomarker analysis. Results: A total of 56 women were enrolled including 13 (23%) with well-controlled diabetes at study entry. Discontinuation reasons were disease progression, 24 (43%); adverse events, 13 (23%); withdrawal by subject, 12 (21%). Frequency of Grade 3/4 related adverse events in all patients were hyperglycemia (46%), rash (30%), colitis (5%), and pneumonitis (4%). At 6 months, 20% of patients were progression free (K-M estimate 95% CI: 7%-33%). ORR was 9% (unconfirmed). Median PFS was 3.5 months (95% CI: 2.7-3.7 months). Median time on study was 69 (12-226) days for non-diabetic and 27(4-84) days for diabetic patients. Discontinuation prior to first tumor assessment occurred in 19 patients, with 8/13 diabetics discontinued prior to Cycle 2, due to hyperglycemia. Dose reductions were required for 4 (31%) diabetics and 18 (42%) non-diabetics. Evaluable archival tumor samples were obtained from 44 (85%) patients, and 52% of patients had at least one alteration in PIK3CA, PTEN or AKT1. All 3 patients with a confirmed response had at least one alteration in a PI3K pathway gene. Conclusions: Evaluation of the anti-tumor activity of 40mg GDC-0980 daily was limited by tolerability, especially in diabetic patients. The trial provides data about the PI3K pathway mutation frequency in patients with recurrent EC and suggests that patients with a PI3K pathway mutation may have derived enhanced benefit from GDC-0980. Clinical trial information: NCT01455493.