Background: Oligodendroglioma is a malignant glial neoplasm arising primarily in young adults. Although radiotherapy (RT) and chemotherapy result in durable disease control, tumor recurrence is inevitable and life-limiting. The cyclin D1-CDK4 axis is frequently dysregulated in recurrent oligodendroglioma. Abemaciclib is a selective CDK4/6 inhibitor that has been shown to achieve pharmacologically-relevant concentrations in brain tumor tissue. Methods: We conducted a single-center, single-arm, phase 2 trial evaluating the efficacy of abemaciclib in patients with recurrent oligodendroglioma, IDH-mutant and 1p/19q-codeleted, WHO Grade 3, following prior RT and ≥ 1 line of alkylating chemotherapy. Patients received abemaciclib 200mg twice daily. Primary endpoint was progression-free survival status at 6 months (PFS-6). Ten patients were needed for 80% power to detect the difference between the null (PFS-6 = 50%) and alternative (PFS-6 = 85%) hypotheses; one-sided α = 0.05. Modified RANO criteria were used for patients with enhancing tumors and RANO low-grade glioma criteria for patients with nonenhancing tumors. Results: Between November 2019 - August 2022, 10 patients were enrolled (Baseline Characteristics). Most common treatment-related adverse event (trAE) was grade 1-2 diarrhea, occurring in all 10 patients. Grade 3-4 trAEs included grade 4 thrombocytopenia (n=2), grade 3 neutropenia (n=1), grade 3 fatigue (n=2), and grade 3 ALT increase (n=1). In patients with enhancing tumor (n=9), best response was partial response in 2 patients (ORR=22.2%; DOR 13.1 and 7.7 months, respectively), stable disease (SD) in 3 patients (33.3%; duration of SD 17.0, 6.7, and 2.5 months, respectively), progressive disease in 3 patients (33.3%), and not evaluable in 1 patient (11.1%). In the patient with nonenhancing tumor, best response was SD (duration 10.2 months). Median PFS was 7.7 months (95% CI, 1.7 – 13.1 months); median overall survival was not reached (median follow-up 17 months). The study’s primary endpoint was not met; 5/10 patients (50%) were alive and progression-free at 6 months, below the minimum required (8/10) to consider abemaciclib worthy of further investigation. Conclusions: Despite objective responses and durable disease control in a small subset of patients, the efficacy of abemaciclib in recurrent grade 3 oligodendroglioma was not adequate to warrant further clinical evaluation of abemaciclib monotherapy in unselected patients. Correlative studies are ongoing to identify which patients with oligodendroglioma may benefit from abemaciclib. Clinical trial information: NCT03969706.