Background: Ewing’s sarcoma (ES) is the second most common malignant bone tumor affecting children and young adults. Patients with relapsed disease have a poor prognosis and need effective therapies. EWS-FLI1, the most common ES fusion gene (90-95% of cases), is an oncogenic transcription factor that downregulates intrinsic cyclin-dependent kinase (CDK) inhibitors, CDKN1A and CDKN1C, which promote cell cycle arrest and upregulates CDK4, which drives entry into the cell cycle. This provides a biological rationale for the clinical evaluation of CDK4/6 inhibitors in ES. Abemaciclib is a selective CDK4/6 inhibitor approved for the treatment of breast cancer. It is approximately 14 times more potent against CDK4/cyclin D1 than CDK6/cyclin D3 in enzymatic assays and has the advantage of continuous dosing schedule without breaks for neutrophil recovery. Abemaciclib is currently also in clinical development for paediatric patients with relapse/refractory solid tumors in combination with irinotecan and temozolomide (JPCS study, NCT04238819). This study, NCT05440786, will evaluate the potential benefit of adding abemaciclib to irinotecan plus temozolomide for the treatment of relapsed/refractory ES. Methods: This randomized, open-label, Phase 2 study is part of the CAMPFIRE master protocol. It is enrolling paediatric and young adult patients (1–39 years) with relapsed/refractory ES or ES-like tumors. Approximately 45 patients will be randomized 2:1 between 2 arms: irinotecan and temozolomide with or without abemaciclib. Stratification factors include age, pulmonary/non-pulmonary site of metastases, and time to recurrence from initial diagnosis. Patients will receive irinotecan (50 mg/m²/day intravenously) and temozolomide (100 mg/m²/day orally) on days 1-5. Abemaciclib will be administered orally twice-daily on a continuous 21-day cycle. The abemaciclib dose will be 55mg/m² BID for patients < 18 years and 100mg BID for those ≥18 years. Besides 25 and 50mg tablets, abemaciclib will be available as 2.5mg granules allowing administration of doses as low as 10mg to patients with a body surface area lower than 0.2m². Treatment continues until disease progression or other discontinuation criteria are met. The primary endpoint is progression-free survival (PFS) determined by a blinded independent review committee using Response Evaluation Criteria in Solid Tumors, Version 1.1. Key secondary endpoints include overall survival, objective response rate, duration of response, disease control rate, PFS determined by investigator assessment, safety, and pharmacokinetics. Additional analysis includes exploratory biomarker testing. This study is open and actively enrolling in Australia, Europe, Japan, and United States. Clinical trial information: NCT05440786.