Results of the second interim assessment of rEECur, an international randomized controlled trial of chemotherapy for the treatment of recurrent and primary refractory Ewing sarcoma (RR-ES).

Abstract

11502 Background: Five-year survival of RR-ES is about 15%. Several chemotherapy regimens are used, but without robust evidence. rEECur, the first randomised controlled trial in this setting, is defining a standard of care, balancing efficacy and toxicity. Methods: Patients aged 4 to 50 with RR-ES and fit to receive chemotherapy were randomised between topotecan & cyclophosphamide (TC), irinotecan & temolozomide (IT), gemcitabine & docetaxel (GD) or high-dose ifosfamide (IFOS). Primary outcome measure was objective response (OR) after 4 cycles by RECIST 1.1. Secondary outcomes included PFS, OS and toxicity. A probability-based Bayesian approach was used with multiple pairwise comparisons. At the first interim analysis patients allocated to GD had worse OR and PFS than the other arms and accrual to the GD arm was halted. The second interim assessment was planned to determine which arm should be closed when at least 75 evaluable patients had been recruited to the remaining arms and evaluated for the primary outcome measure. Results: 366 patients (87% RECIST-evaluable), recruited between 18/12/14 and 17/12/19, were randomised to TC (n=124), IT (118), GD (72) and IFOS (53). Median age was 20 years (range 4-49). Patients had: refractory disease (19%), first recurrence (66%), > first recurrence (14%). Initial disease site was bone in (66%). Sites of progression were: primary site only (16%) pleuropulmonary only (32%), other metastatic (52%). At median follow up of 9.2 months, outcome in the IT arm was: response rate 20%, median PFS 4.7 months (95% CI: 3.4 to 5.7), median OS 13.9 months (95% CI: 10.6 to 18.1). The table shows, for each pairwise comparison of IT with the other open arms (randomly labelled A and B to maintain blinding), the probabilities that OR, PFS and OS were better for X than for each other arm (RR = risk ratio, HR = hazard ratio). For OR, PFS and OS, all comparisons favoured arms A and B. The main grade 3/4 adverse events (% patients with an event) for IT (left hand values) compared with A and B pooled were: vomiting (6% v 1%), nausea (6% v 0%), diarrhoea (17% v 0%), fatigue (3% v 1%) and febrile neutropenia (3% v 24%). Conclusions: The first randomised trial in RR-ES has shown that IT, used as a control arm in planned and ongoing randomised phase II studies in RR-ES, is less effective than A and B in achieving tumour shrinkage or prolonging PFS and OS. The remaining two arms are continuing to recruit patients. Clinical trial information: ISRCTN36453794 . [Table: see text]

Continuous 14 Day Infusional Ifosfamide for Management of Soft-Tissue and Bone Sarcoma: A Single Centre Retrospective Cohort Analysis

“…In these two cohorts, rates of haematological toxicity were higher than those presently reported, with rates of G4 neutropenia 97% in one study, and admission rates for febrile neutropenia of 77% in the other. Furthermore, whilst the final results of the rEEcur study are awaited, high-dose ifosfamide remains one of the open study arms [ 26 ].…”

Exploiting Gangliosides for the Therapy of Ewing’s Sarcoma and H3K27M-Mutant Diffuse Midline Glioma

“…A retrospective analysis of 51 relapsed ES patients calculated a PFS of 7.7 months for the pediatric subgroup [ 37 ]. However, interim analyses from an international randomized controlled trial of chemotherapy for the treatment of recurrent and primary refractory Ewing’s sarcoma (rEECur) revealed a median PFS of 4.7 months (95% CI: 3.4 to 5.7) for patients who had been treated in the IT arm [ 51 ]. Given this poor outcome, achieved treatment result in our patient by incorporating dinutuximab beta in an individualized treatment approach is quite remarkable, indicating a synergistic antineoplastic effect of IT and anti-GD2 antibodies in GD2 expressing ES.…”

Ewing Sarcoma—Diagnosis, Treatment, Clinical Challenges and Future Perspectives

“…For patients with earlier relapses, newer camptothecin-containing regimens are commonly used. An ongoing randomized European trial for patients with relapsed EwS, rEECur, is evaluating four chemotherapy regimens: high-dose ifosfamide; topotecan and cyclophosphamide; irinotecan and temozolomide; and gemcitabine and docetaxel [ 238 , 239 ] ( Table 2 ).…”

“…This combination has the added benefit of being available as an entirely oral regimen, which may be desirable for some patients with relapsed disease. The irinotecan and temozolomide regimen was reported to have an objective response rate of 20% in the rEECur trial and was determined to have a low likelihood of being superior to either topotecan and cyclophosphamide or high-dose ifosfamide which together had a pooled response rate of 23% [ 238 ] ( Table 2 ).…”