Abstract Background: Activating mutations of the PI3K/mTOR pathway are highly prevalent in endometrial cancers (EC), but monotherapy targets of this pathway have shown modest activity and are associated with poor tolerance. LY3023414 is a selective inhibitor of class I PI3K isoforms, mTOR, and DNA-PK. Building on phase I experience of LY3023414, we sought to evaluate the efficacy and safety of LY3023414 in PI3K pathway activated advanced EC. Methods: Eligible patients (pts) had PI3K pathway activation defined as (1) loss of PTEN function including whole or partial gene deletion, frame shift mutations, or non-sense mutations (PTEN missense mutations excluded) or (2) activating mutation in PIK3CA, AKT1, PIK3R1, PIK3R2, or mTOR. Up to 4 prior lines of therapy were allowed. Each cycle was 21 days. Efficacy assessments were performed every 2 cycles and treatment-related adverse events (AEs) were assessed per CTCAE v. 4.03. The primary objective was best overall response rate by RECIST 1.1. Results: Of the 28 pts enrolled, 25 (89%) had 1-2 lines of therapy and 3 pts (11%) had 3-4 prior lines of therapy. LY3023414 was dosed at the RP2D of 200 mg orally twice daily. Three pts were excluded from efficacy assessment due to toxicity, noncompliance or early patient withdrawal. The clinical benefit rate (CBR), defined as the percentage of pts with complete response (CR) + partial response (PR) + stable disease (SD) ≥12 weeks, was 56% (14/25). Five patients achieved PR; 9 pts achieved SD at best response. Three of the 5 PRs were sustained from 44-52 weeks; 1 pt with PR is still on therapy > 84 weeks. The median PFS and median OS were 2.53 (CI 1.18-2.99) months and 9.24 (CI 5-NR) months, respectively. Twenty-one pts underwent further genomic sequencing; 16 pts (76%) had a PIK3CA mutation, 6 pts (29%) had a PIK3R1 and 10 pts (48%) had a PTEN mutation. There were no significant co-mutations identified and a correlation of molecular alterations with response was not identified. Across all cycles, the most common grade 3 LY3023414-related adverse events (AEs) were lymphopenia (n=10), hypokalemia (n=5), hypophosphatemia (n=4), hyponatremia (n=3), and anemia (n=3). There were 3 LY3023414-related grade 4 AEs: allergic reaction (n=1), CPK rise (n=1) and hyponatremia (n=1). There were no LY3023414-related G5 AEs. Conclusions: In PI3K pathway-altered, heavily pretreated advanced EC, LY3023414 demonstrated a manageable safety profile and promising single-agent efficacy. Enrollment is now complete and updated response data will be presented. Citation Format: Maria M. Rubinstein, David Hyman, Imogen Caird, Roisin O'Cearbhaill, Rachel Grisham, William Tew, Martee Hensley, Paul Sabbatini, Carol Aghajanian, Alexia Iasonos, Helen Won, Duygu Selcuklu, Catherine Zimel, Vicky Makker. Single-arm, open-label, phase II study of LY3023414 for the treatment of recurrent or persistent endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B18.