Phase II assessment of carboplatin with etoposide and high-dose ifosfamide in rEECur, an international randomised controlled trial of chemotherapy for the treatment of recurrent and primary refractory Ewing sarcoma (RR-ES).

10006 Background: rEECur, the first randomised controlled trial (RCT) in RR-ES, has previously defined high dose ifosfamide (IFOS) as the most effective regimen in this setting compared to gemcitabine-docetaxel, irinotecan-temozolomide and topotecan-cyclophosphamide. Platinum drugs show activity in RR-ES and are frequently given with etoposide in this setting. Methods: Patients aged at least 2 years with RR-ES were randomised to 3-week cycles of either IFOS 15 g/m 2 by continuous intravenous (IV) infusion over 5 days or IV carboplatin 400 mg/m 2 day 1 and etoposide 120 mg/m 2 days 1 to 3 (CE). Primary outcome was event-free survival time (EFS). Secondary outcomes included overall survival time (OS), toxicity and quality of life (QoL). A probability-based Bayesian approach was used. Results: 139 patients recruited between 22/03/21 and 28/05/24, were randomised 1:1 to IFOS (n = 69) or CE (70). Median age was 18 years (range 3-59). Patients had refractory disease (14%), 1 st recurrence (81%), > 1 st recurrence (6%). Sites of progression were primary site only (21%), pleuropulmonary metastases only (24%), and other or combined metastatic disease (55%). More CE patients had baseline GFR < 90 ml/min/1.73m 2 (41% versus 23%). Median follow-up (reverse Kaplan-Meier) was 18 months (mos). Median EFS was 5.1 mos (95% CI 3.1, 6.3) for IFOS and 3.5 mos (95% CI 2.5, 6.1) for CE. Median OS was 14.4 mos (95% CI 11.5, 20.7) for IFOS and 19.0 mos (95% CI 11.2, 24.6) for CE. Given the observed data the posterior probabilities that EFS and OS were better after IFOS than after CE (ie Pr[true hazard ratio > 1 | data]) were 87% and 55% respectively. Grade 3+ adverse events present in > 5% of patients randomised to IFOS (left hand values) compared with CE were febrile neutropenia (30% v 10%), anaemia (9% v 9%) and thrombocytopenia (3% v 7%). Acute kidney injury was present in 2% v 0% and encephalopathy in 5% v 0%. There were no measurable differences in QoL. Conclusions: There was insufficient evidence of efficacy with CE compared to IFOS to continue recruitment to phase III in this first RCT of a platinum-etoposide combination in RR-ES. IFOS remains the most effective regimen in this disease setting. The trial remains open, comparing IFOS with and without the tyrosine kinase inhibitor lenvatinib. Funded by Cancer Research UK (C22436/A28028, CTUQQR-Dec22/100006, A28474). Clinical trial information: ISRCTN36453794 .