BACKGROUND: Chemotherapy with lomustine is widely considered as standard treatment option for progressive glioblastoma. The value of adding radiotherapy to second-line chemotherapy is not known. METHODS: EORTC-2227-BTG (LEGATO, NCT05904119) is an investigator-initiated, pragmatic (PRECIS-2 score: 34 out of 45), randomized, multicenter phase III trial in patients with first progression of glioblastoma. A total of 411 patients will be randomized in a 1:1 ratio to lomustine (110 mg/m2 every 6 weeks) or lomustine (110 mg/m2 every 6weeks) plus radiotherapy (35 Gy in 10 fractions). Main eligibility criteria include histologic confirmation of glioblastoma, isocitrate dehydrogenase gene (IDH) wild-type per WHO 2021 classification, first progression at least 6 months after the end of prior radiotherapy, radiologically measurable disease according to RANO criteria with a maximum tumor diameter of 5 cm, and WHO performance status of 0-2. The primary efficacy endpoint is overall survival (OS) and secondary endpoints include progression-free survival, response rate, neurocognitive function, health-related quality of life, and health economic parameters. LEGATO is funded by the European Union's Horizon Europe Research program, was activated in March 2024 and will enroll patients in 43 sites in 11 countries across Europe with study completion projected in 2028. DISCUSSION: EORTC-2227-BTG (LEGATO) is a publicly funded pragmatic phase III trial designed to clarify the efficacy of adding reirradiation to chemotherapy with lomustine for the treatment of patients with first progression of glioblastoma. TRIAL REGISTRATION: ClinicalTrials.gov NCT05904119. Registered before start of inclusion, 23 May 2023.

Brainstrust the brain cancer people Isle of Wight Cowes UK

Department of Medical Oncology and Hematology University Hospital and University of Zurich Zurich Switzerland

Department of Medical Physics ASST GOM Niguarda Milano Italy

Department of Medicine 1 Division of Oncology Medical University of Vienna Waehringer Guertel 18 20 1090 Vienna Austria

Department of Neurology Leiden University Medical Centre Leiden The Netherlands

Department of Neurology University Hospital and University of Zurich Zurich Switzerland

Department of Neuropathology University Hospital Heidelberg and CCU Neuropathology DKFZ Heidelberg Germany

Department of Neurosurgery University Medical Centre Hamburg Eppendorf Hamburg Germany

Department of Radiation Oncology and Research Centre for Applied Molecular Oncology Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Radiological Sciences Oncology and Anatomical Pathology and IRCCS Neuromed Sapienza University Policlinico Umberto 1 Rome Italy

Department of Radiology and Nuclear Medicine Erasmus MC Rotterdam The Netherlands

EORTC Headquarters Team Brussels Belgium

Syreon Research Institute Budapest Hungary

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NCT05904119