Abstract Background: Ewing sarcoma is a classic translocation-associated malignancy, with nearly all cases carrying an identifiable EWSR1 or FUS translocation. The translocation leads to an aberrant fusion oncoprotein that is thought to function as a pathogenic transcription factor. Despite our understanding of the fundamental biology of this disease, targeting this transcription factor has been elusive. The insulin-like growth factor receptor (IGF-1R) pathway has been long implicated in the pathogenesis of Ewing sarcoma based on early findings that IGF-1 and IGF-1R are overexpressed in Ewing sarcoma. A range of preclinical studies have demonstrated the activity of IGF-1R targeting antibodies in multiple Ewing sarcoma cell lines. Multiple early phase studies of IGF-1R inhibitors have demonstrated that approximately 10% of patients with relapsed disease respond to these agents as monotherapy. Recent work has identified CDK4 as a genomic vulnerability in Ewing sarcoma. Given that CDK4/6 inhibitor monotherapy is prone to resistance, a series of investigations were undertaken to identify potential combination approaches. In an open reading frame experiment designed to determine whether over expression of specific genes would confer resistance, IGF-1R scored highly. Subsequent in vitro and in vivo experiments demonstrated synergy between CDK4/6 inhibition and IGF-1R inhibition. We have translated these findings into an open phase 2 clinical trial of ganitumab, a monoclonal antibody inhibitor of IGF-1R, and palbociclib, a small molecule inhibitor of CDK4/6. Methods: This is a Phase 2, single-arm, single-stage, investigator-initiated clinical trial of palbociclib and ganitumab in patients 12-50 years of age with relapsed/refractory Ewing sarcoma (NCT04129151). The primary objectives are to estimate the objective radiographic response rate to the combination of palbociclib and ganitumab and to describe the toxicity of this drug combination in patients with relapsed/refractory Ewing sarcoma. Palbociclib is given at a dose of 100 mg PO on days 1-21 of a 28-day cycle. Ganitumab is given via IV at a dose of 18 mg/kg on days 1 and 15. The primary endpoint is objective response by RECIST, with disease evaluated after every 2 cycles. Up to 18 patients will be enrolled to yield 15 response evaluable patients. With 15 evaluable patients the study will have 91% power and a type-1 error rate of 0.056 to determine whether the response rate in this population is greater than 40% and significantly different from the 10% response rate seen with IGF-1R monotherapy. Pharmacodynamic testing for confirmation of IGF-1R inhibition (serum IGF-related proteins) is required for all patients. Circulating tumor DNA (ctDNA) is measured at study entry, on cycle 1 day 15, at start of cycle 2 and at each disease evaluation. ctDNA levels will be measured using next generation sequencing for quantification of ctDNA and association with response, and for identification of genomic and epigenetic markers of resistance. Enrollment began in December 2019. Citation Format: David S. Shulman, Katherine Thornton, Edwin Choy, Lillian M. Guenther, Kerri Cavanaugh, Megan Forsyth, Kylene DeSmith, Catherine Clinton, Kimberly Stegmaier, Brian Crompton, Wendy B. London, Steven G. DuBois. A phase 2 clinical trial of palbociclib and ganitumab for relapsed/refractory Ewing sarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT195.