Background: Inhibition of CDK4 is being studied in a variety of sarcomas, especially dedifferentiated liposarcoma (DDL) where prolonged progression free survival has been noted. Exposure to CDK4 inhibitors in Rb+ leiomyosarcoma (LMS) cell lines leads to decreased cell proliferation, and increased senescence, and G0/G1-phase arrest. When combined, ribociclib a CDK4 inhibitor and everolimus, an mTOR inhibitor show synergistic growth inhibition in multiple tumor models. Methods: Patients (pts) were enrolled to one of two cohorts: DDL or Rb+ LMS. LMS pts were required to have 1 prior line of therapy; DDL pts required no prior therapy. There were no limits to prior therapies in either group. Progression on prior therapy and measurable disease by RECIST 1.1 was also required. Ribociclib was given at 300 mg daily for 21/28 days and everolimus was given continuously at 2.5 mg daily in 28 day cycles. The primary endpoint was progression free rate at 16 weeks. A Simon two-stage design was utilized and if at least 8 out of 24 pts were progression free at 16 weeks, the treatment was declared promising for the cohort. Here in we present data on the LMS cohort. Results: Twenty-four LMS pts, 83% (n = 20) female, 58% (n = 14) uterine primary were treated. Median prior lines of therapy was 3.5 (range 1-9). Of 22 pts with complete data, 6 (27.2%) met the primary endpoint of non-progression at 16 weeks. Median PFS was 19.6 weeks (range 2.8-84), with progression as best response occurring in 13 pts. There were no objective responses. Five pts who had progressive disease on multiple lines of therapy experienced prolonged progression free survival (23-84 weeks). Grade 3-4, toxicities included neutropenia (29%), thrombocytopenia (12.5%) and leucopenia (12.5%) being most common. Tissue samples pre and on therapy as well as blood were collected in 21 and 18 pts respectively to evaluate pharmacodynamic changes. Conclusions: Final data on the primary endpoint for the LMS cohort is pending; it is notable that several heavily pre-treated LMS pts experienced prolonged progression free survival for > 9 months. Updated results and biology correlatives will be presented. Clinical trial information: NCT03114527.