e23507 Background: Ewing sarcoma (EwS) is an aggressive sarcoma with few treatment options for patients with relapsed disease. CDK4 is a known genomic vulnerability in EwS, but an unappealing monotherapy target given propensity for innate resistance. In laboratory studies to identify targets synergistic with CDK4 inhibition, IGF-1R scored highly. We present the results of a phase 2 study combining palbociclib (CDK4/6 inhibitor) with ganitumab (IGF-1R monoclonal antibody) for patients with relapsed or refractory EwS. Methods: This was a prospective open-label, non-randomized, single-center, phase 2 study (NCT04129151) for patients with relapsed EwS and RECIST measurable disease. Patients with relapsed EwS ≥12 years and a documented fusion consistent with EwS were eligible. Patients initially received Palbociclib 125 mg on days 1-21 and ganitumab 18 mg/kg on days 1 and 15 of a 28-day cycle. The primary endpoints were objective response (complete or partial) per RECIST and toxicity by CTCAE. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A one-stage design required ≥4 responders out of 15 to evaluate an alternative hypothesis of 40% response rate against a null of 10%. Results: Ten evaluable patients enrolled between 5/2019-8/2021. The study closed 12/2021 due to lack of ganitumab drug supply. The median age at enrollment was 25.7 years (range 12.3-40.1; Table). The median duration of therapy was 2.5 months (range = 0.9-10.8). There were no complete or partial responders. Three of 10 patients had stable disease for > 4 cycles and 2 had stable disease at completion of planned therapy or study closure. 6-month PFS was 30±14.5%. Two patients had cycle 1 hematologic DLTs triggering the pre-defined toxicity rule; the palbociclib dose was subsequently reduced to 100 mg daily for 21 days. Among the remaining 8 patients, two had cycle 1 hematologic DLTs at the 100 mg dose. 80% of patients had grade 3/4 AEs; the most commons AEs were neutropenia (n = 8), white blood cell decreased (n = 7), and thrombocytopenia (n = 5). Total IGF-1 testing demonstrated intrapatient elevations in serum levels after a single cycle of therapy. Analysis of serial ctDNA samples is ongoing. Conclusions: Four responders out of 15 were required to reject the null hypothesis of a 10% response rate. With 0/10 responders, we concluded that this combination lacked adequate therapeutic activity for further study. The combination was tolerable at a palbociclib dose of 100 mg, with primarily hematologic toxicity in patients with relapsed EwS. Clinical trial information: NCT04129151. [Table: see text]