Phase Ib study of the combination of regorafenib with conventional chemotherapy in patients with newly diagnosed multi-metastatic Ewing sarcoma: The Rego-Inter-Ewing-1 study.

10008 Background: Regorafenib monotherapy has shown interesting but limited activity against relapsed Ewing sarcoma. We present the first results of the phase Ib study to identify the maximum tolerated dose (MTD) of regorafenib in combination with standard multimodal treatment in patients with newly diagnosed multi-metastatic Ewing sarcoma (NCT05830084). Methods: International multi-center phase Ib study of the combination of regorafenib with interval-compressed chemotherapy (VDC/IE) in patients aged 2-50 years with newly diagnosed metastatic (excluding lung/pleura only) Ewing sarcoma. VDC/IE chemotherapy was administered at the standard doses. Regorafenib was given orally for 21 days of a 28-day cycle (from day 5) at a starting dose level of 66 mg/m 2 /day (capped at 120 mg, DL0, 80% of the pediatric recommended phase 2 dose (RP2D)) and escalated to 82 mg/m 2 /day (100% RPD2, capped at 160 mg, DL1) or de-escalated to 50 mg/m 2 /day (60% RPD2, DL-1). The study implemented the Bayesian Optimal Interval (BOIN) design (Yuan et al, Clin Cancer Res 2016). Primary tumour local treatment was surgery and/or radiotherapy. Adjuvant therapy consisted of VC/IE cycles or high dose chemotherapy consolidation with Busulfan/Melphalan (BuMel) and autologous stem cell rescue (ASCR). Regorafenib was given concomitant to adjuvant VC/IE cycles and primary tumor radiotherapy to the extremities but permanently discontinued in those receiving BuMel/ASCR or primary tumour radiotherapy to sites other than extremities. Results: Thirteen patients (DL0: n=2, DL1: n= 11) with a median age of 15.2 years (range, 8.1-23.5), were enrolled between June 2023 and December 2024 in 7 centres and 3 countries. All were evaluable for toxicity. One dose-limiting toxicity (DLT) occurred in one patient at DL1 (pressure ulcer grade 2, requiring regorafenib dose interruption and reduction in a 17-year old patient). After the DLT period, one patient had regorafenib dose interruption/reduction. One patient presented with a grade 3 veno-occlusive disease after Bu-Mel/ASCR. Detailed toxicity data after the DLT period and pharmacokinetic data will be presented. At data cut-off of 21/01/2025, two patients had experienced disease progression before primary tumour local treatment, eight patients had finished all treatment cycles (three received Bu-Mel/ASCR consolidation) and three patients were on therapy. Conclusions: Regorafenib combined with VDC/IE chemotherapy is well tolerated with a MTD of 82 mg/m 2 /day (capped 160 mg). The efficacy of the addition of regorafenib to standard multimodal treatment in newly diagnosed patients with metastatic Ewing sarcoma will be tested in the Inter-Ewing-1 trial developed by the Euro Ewing Consortium (planned initiation in Q3 2025). Recruitment to the Rego-Inter-Ewing-1 continues at DL1 (maximum 24 patients), until Inter-Ewing-1 initiates. Clinical trial information: NCT05830084 .