Background: Dedifferentiated liposarcoma (DDLPS) is characterized by near universal amplification of the cyclin-dependent kinase 4 (CDK4) gene. Palbociclib (P) is a selective CDK4/6 inhibitor that has demonstrated promise in phase II studies of DDLPS. Anti-PD-1 therapy has also shown signals of efficacy, with an approximate overall response rate of 10% in DDLPS patients. CDK4/6 inhibitors upregulate antigen processing and presentation, suppress regulatory T cells, and increase inflammation within the tumor microenvironment. Combined with anti-PD-1 blockade, they can induce an inflamed T cell phenotype and tumor regression in pre-clinical models. We hypothesize that P combined with the anti-PD-1 inhibitor retifanlimab (R) will be safe and tolerable and have synergistic activity leading to activation of T cells and resultant clinical responses. Methods: NCT04438824 is a phase II study of P plus R with a safety lead-in phase. Patients with unresectable or metastatic DDLPS who have received any number of prior therapies are eligible to enroll. On the safety lead-in phase, 6 patients received P (125 mg once daily orally for 21 days followed by 7 days off) plus R (500 mg IV flat dose), repeated in 28-day cycles. P was initiated as monotherapy two weeks prior to initiation of R. The primary endpoint of the safety lead-in was to confirm the recommended phase two dose of the combination. Accrual to the safety lead-in has been completed and a pre-planned phase II expansion portion was opened to accrual. A study amendment was passed that revised the treatment schedule on the expansion cohort to start both P and R concomitantly on day 1 of each cycle. This revised schedule was based on recent data demonstrating the superior safety of a concurrent, rather than staggered, dosing schedule. The primary endpoint of the expansion phase is to estimate the best overall response rate (ORR) by RECIST 1.1. Secondary endpoints include describing the safety and estimating clinical benefit rate, duration of response, progression-free, and overall survival. A total of 30 patients treated with the revised dosing scheme will be enrolled onto the expansion phase. Twelve patients have been enrolled to date. An ORR of 5% will be considered not promising, while an ORR of 25% will be considered promising. The null hypothesis will be rejected if 4 or more patients have a confirmed objective response to treatment. This design has a type I error rate of 0.06 and a type II error rate of 0.04. Mandatory pre- and on-treatment biopsies will be performed for correlative analyses. Clinical trial information: NCT04438824.