Title: CRUK/19/004 - rEECur: International Randomised Controlled Trial of Chemotherapy for the Treatment of Recurrent and Primary Refractory Ewing Sarcoma
Funder: Cancer Research UK

Abstract: Background Ewing sarcoma peaks during adolescence. Approximately 50% of patients progress during or after first-line treatment. Five-year survival after progression is 10-15%. Several chemotherapy regimens are used at progression, based on weak and heterogeneous evidence. rEECur, the first randomised trial in this disease setting, opened in December 2014 to compare four chemotherapy regimens in widespread use: topotecan/cyclophosphamide, irinotecan/temozolomide, gemcitabine/docetaxel and high dose ifosfamide. It has recruited 270 patients in 14 countries. At the first interim assessment, the gemcitabine/docetaxel arm was dropped due to a worse response rate and event free survival. The trial is sponsored by the University of Birmingham and managed by Cancer Research UK Clinical Trials unit with delegated duties to six National Coordinating Centres (NCCs) across Europe and Australasia. Aims rEECur aims to compare treatments in relapsed and refractory Ewing sarcoma to identify the best with respect to efficacy, toxicity and acceptability to patients. Methods rEECur has a seamless, Multi-Arm, Multi-Stage (MAMS) randomised phase II/phase III adaptive design. Patients aged between 4 and 50 years with recurrent and refractory Ewing family tumours are eligible. Primary endpoints: objective response (OR) according to RECIST 1.1 after 4 cycles (phase II) and EFS (phase III). Secondary endpoints: EFS (phase II), OR (phase III), OS, toxicity, PET-CT response, quality of life. The adaptive design allows less active and/or more toxic arms to be sequentially dropped and new arms to be introduced in Phase II, with remaining arms moving to phase III evaluation. Patients recruited in phase II can contribute data to phase III, and phase II and phase III evaluation can take place simultaneously. We plan to introduce and evaluate a fifth chemotherapy arm in 2019 and a targeted therapy arm in 2020. How will the results be used 1. Define a standard, best chemotherapy regimen for relapsed disease. 2. Provision of robust EFS, OS, toxicity, and quality of life data for the evaluated regimens to inform clinicians and patients. 3. Define a chemotherapy backbone for the testing of novel therapies, to be either tested within future arms of rEECur, or inform future trials 4. Identify the most active agents for incorporation into first line treatment. As rEECur is open in almost every UK sarcoma centre and has representation from every cooperative sarcoma group in Europe, we expect its results to translate rapidly into clinical practice and first line trial design.

Lay abstract: Background Ewing sarcoma peaks during adolescence. Approximately 50% of patients progress during or after first-line treatment. Five-year survival after progression is 10-15%. Several chemotherapy regimens are used at progression, based on weak and heterogeneous evidence. rEECur, the first randomised trial in this disease setting, opened in December 2014 to compare four chemotherapy regimens in widespread use: topotecan/cyclophosphamide, irinotecan/temozolomide, gemcitabine/docetaxel and high dose ifosfamide. It has recruited 270 patients in 14 countries. At the first interim assessment, the gemcitabine/docetaxel arm was dropped due to a worse response rate and event free survival. The trial is sponsored by the University of Birmingham and managed by Cancer Research UK Clinical Trials unit with delegated duties to six National Coordinating Centres (NCCs) across Europe and Australasia. Aims rEECur aims to compare treatments in relapsed and refractory Ewing sarcoma to identify the best with respect to efficacy, toxicity and acceptability to patients. Methods rEECur has a seamless, Multi-Arm, Multi-Stage (MAMS) randomised phase II/phase III adaptive design. Patients aged between 4 and 50 years with recurrent and refractory Ewing family tumours are eligible. Primary endpoints: objective response (OR) according to RECIST 1.1 after 4 cycles (phase II) and EFS (phase III). Secondary endpoints: EFS (phase II), OR (phase III), OS, toxicity, PET-CT response, quality of life. The adaptive design allows less active and/or more toxic arms to be sequentially dropped and new arms to be introduced in Phase II, with remaining arms moving to phase III evaluation. Patients recruited in phase II can contribute data to phase III, and phase II and phase III evaluation can take place simultaneously. We plan to introduce and evaluate a fifth chemotherapy arm in 2019 and a targeted therapy arm in 2020. How will the results be used 1. Define a standard, best chemotherapy regimen for relapsed disease. 2. Provision of robust EFS, OS, toxicity, and quality of life data for the evaluated regimens to inform clinicians and patients. 3. Define a chemotherapy backbone for the testing of novel therapies, to be either tested within future arms of rEECur, or inform future trials 4. Identify the most active agents for incorporation into first line treatment. As rEECur is open in almost every UK sarcoma centre and has representation from every cooperative sarcoma group in Europe, we expect its results to translate rapidly into clinical practice and first line trial design.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS