Deregulation of the cyclin-dependent kinases (CDK) 4 and 6 (cdk4/6)–cyclin D-INK4—retinoblastoma protein (Rb) signaling pathway is among the most common aberrations found in glioblastoma (GBM) with more than 80% of patients estimated to be affected. We conducted an open label, multi-center, phase II trial of abemaciclib in participants with recurrent glioblastoma (GBM) at their first relapse and with documented evidence of CDKN2A/B loss and intact RB from archival tissue. A total of 32 patients enrolled on the non-surgical arm of the study with 13 women (40.63%) and median KPS 90 [range 60-100]. The PFS6 rate was 9.37% [95% CI, 2.4%, 22.27%], median PFS 55 days [95% CI, 49, 56], and median OS 384 days [95% CI, 228, 488]. Out of 31 evaluable patients, best response was PR 1 (3.2%), SD 11 (35.5%), and PD 19 (61.3%). The most common grade 3 or higher toxicities at least possibly related to abemaciclib included leukopenia (21.9%), neutropenia (18.6%), lymphopenia (9.4%), and thrombocytopenia (6.3%). Abemaciclib has minimal activity in this preselected recurrent GBM population. Correlative studies from the surgical arm of this study are pending.