Lomustine With and Without Reirradiation for First Progression of Glioblastoma: a Randomized Phase III Study (LEGATO)

February 12, 2026 updated by: European Organisation for Research and Treatment of Cancer - EORTC
Despite comprehensive multimodal treatment of newly diagnosed glioblastoma, almost all patients suffer from tumour relapse. Currently, no standard of care exists to treat these tumour relapses. Treatment options include repeated surgery (if feasible), systemic therapy (bevacizumab, lomustine, temozolomide re-challenge), reirradiation and best supportive care. Currently, the superiority of combined chemoradiation versus chemotherapy alone remains unproven. Given that lomustine is the standard chemotherapeutic agent for the treatment of recurrent glioblastoma in Europe and the unclear efficacy of reirradiation, we want to explore whether combining lomustine and reirradiation may be a better treatment than lomustine alone. The results of the prospective randomized trial proposed here should demonstrate a significant improvement in overall survival when lomustine is combined with reirradiation in patients with recurrent glioblastoma compared to lomustine alone without adversely affecting quality of survival. The trial will be stopped based on overall survival in a preplanned futility and efficacy interim analysis.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

411

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Austria
      • Innsbruck, Austria, 6020
        • Recruiting
        • A.O Landeskrankenhaus - Innsbruck Universitaetsklinik
        • Contact:
          • Meinhard Nevinny-Stickel, Univ. Prof. Dr. med.
        • Principal Investigator:
          • Meinhard Nevinny-Stickel, Univ. Prof. Dr. med.
      • Linz, Austria, 4020
        • Recruiting
        • Kepler University Hospital - Neuromed campus
        • Contact:
          • Josef Pichler, MD
        • Principal Investigator:
          • Josef Pichler, MD
      • Vienna, Austria
        • Recruiting
        • Universitaetsklinikum Wien - AKH unikliniken
        • Contact:
          • Matthias Preusser, Univ. Prof. Dr.
        • Principal Investigator:
          • Matthias Preusser, Univ. Prof. Dr.
  • Belgium
      • Aalst, Belgium, 9300
        • Recruiting
        • AZORG
      • Brussels, Belgium, 1200
        • Recruiting
        • Cliniques Universitaires Saint-luc
      • Ghent, Belgium, 9000
        • Recruiting
        • Universitair Ziekenhuis Gent
      • Gilly, Belgium, 6060
        • Recruiting
        • Grand Hôpital de Charleroi - Site Les Viviers
      • Leuven, Belgium, 3000
        • Recruiting
        • U.Z. Leuven - Campus Gasthuisberg
  • Czechia
      • Brno, Czechia
        • Recruiting
        • Masaryk Memorial Cancer Institute
        • Principal Investigator:
          • Tomas Kazda
  • Denmark
      • Aarhus, Denmark, 8200
        • Recruiting
        • Aarhus University Hospitals - Region Midtjylland - Aarhus University Hospital-Skejby
  • France
      • Amiens, France, 80054
        • Recruiting
        • CHU d'Amiens - CHU Amiens Picardie - Site Sud
      • Clermont-Ferrand, France, 63000
        • Recruiting
        • CLCC - Jean Perrin
      • Lille, France, 59037
        • Recruiting
        • CHRU de Lille
      • Lyon, France
        • Recruiting
        • CHU de Lyon - CHU Lyon - Hopital neurologique Pierre Wertheimer
        • Principal Investigator:
          • François DUCRAY
      • Montpellier, France
        • Recruiting
        • Institut du Cancer de Montpellier
        • Principal Investigator:
          • Marie Charissoux, Dr.
      • Nice, France, 06000
        • Recruiting
        • CHU de Nice - Hopital Pasteur
      • Paris, France
        • Recruiting
        • Assistance Publique Hopitaux Paris- APHP - APHP Nord - Univ De Paris Cite - Hop. Saint Louis
        • Principal Investigator:
          • Stefania Cuzzubbo
      • Paris, France, 75013
        • Recruiting
        • Assistance Publique Hopitaux Paris- APHP - APHP Sorbonne Univ - Hopital la Pitie-Salpetriere (233)
      • Saint-Herblain, France, 44805
        • Recruiting
        • Institut de Cancerologie de l´Ouest (ICO) - Saint Herblain
  • Germany
      • Bochum, Germany, 44892
        • Recruiting
        • Univ. Knappschaft Krankenhaus Bochum
        • Principal Investigator:
          • Corinna Seliger-Behme, Dr
      • Cologne, Germany, 50937
        • Recruiting
        • Universitaetsklinikum Koeln
      • Erlangen, Germany
        • Recruiting
        • Universitaetsklinikum Erlangen-Schwabachanlage
        • Principal Investigator:
          • Martin Uhl
      • Heidelberg, Germany, 69120
        • Recruiting
        • Universitaetsklinikum Heidelberg - UniversitaetsKlinikum Heidelberg - Head Hospital
      • Leipzig, Germany, 04103
        • Recruiting
        • Universitätsklinikum Leipzig-Klinik für Strahlentherapie und Radioonkologie
        • Contact:
          • Clemens Seidel, PD Dr. Med.
        • Principal Investigator:
          • Seidel Clemens, PD Dr. Med.
      • Munich, Germany, 81377
        • Recruiting
        • Ludwig-Maximilians-Universitaet Muenchen - Campus Grosshadern
      • Regensburg, Germany
        • Recruiting
        • Universitaetsklinikum Regensburg
        • Principal Investigator:
          • Peter Hau
      • Tübingen, Germany, 72076
        • Recruiting
        • Universitaetsklinikum Tuebingen- Crona Kliniken
  • Italy
      • Bologna, Italy, 40139
        • Recruiting
        • IRCCS-Ospedale Bellaria-Bologna
      • Legnago, Italy, 37045
        • Recruiting
        • ULSS 9 Scaligera Veneto - Azienda Unita Locale Socio-Sanitaria N. 9-Mater Salutis Hospital
      • Milan, Italy, 20089
        • Recruiting
        • Istituto Clinico Humanitas
      • Padua, Italy, 35128
        • Recruiting
        • IRCCS - Istituto Oncologico Veneto
      • Roma, Italy, 00161
        • Recruiting
        • Azienda ospedaliero Univ Policlinico Umberto I
  • Netherlands
      • Enschede, Netherlands, 7512 KZ
        • Recruiting
        • Medisch Spectrum Twente
        • Principal Investigator:
          • Matthijs Van der Meulen
      • Leiden, Netherlands
        • Recruiting
        • Leiden University Medical Centre
        • Principal Investigator:
          • Josefine Schopman
      • Rotterdam, Netherlands
        • Recruiting
        • Erasmus MC
        • Contact:
          • Marjolein Geurts, Prof.
        • Principal Investigator:
          • Marjolein Geurts, Prof.
      • Tilburg, Netherlands, 5022
        • Recruiting
        • ETZ Tilburg - ETZ - St. Elisabethziekenhuis
  • Norway
      • Oslo, Norway, NO 0379
        • Recruiting
        • Oslo University Hospital - Radiumhospitalet
      • Trondheim, Norway, NO 7030
        • Recruiting
        • St Olavs University Hospital - St. Olavs Hospital, Trondheim University Hospital
  • Spain
      • Badalona, Spain, 08916
        • Recruiting
        • Institut Catala d'Oncologia - ICO Badalona - Hospital Germans Trias i Pujol (Institut Catala D'Oncologia) (381)
      • L'Hospitalet de Llobregat, Spain, 08908
        • Recruiting
        • ICO L'Hospitalet - Hospital Duran i Reynals (Institut Catala D'Oncologia)
      • Madrid, Spain, 28041
        • Recruiting
        • Hospital Universitario 12 de Octubre
    • Barcelona
      • Badalona, Barcelona, Spain
        • Recruiting
        • Hospital Germans Trias i Pujol (Institut Catala D'Oncologia)
  • Switzerland
      • Bellinzona, Switzerland, 6500
        • Recruiting
        • Oncology Institute of Southern Switzerland (IOSI) - Ospedale San Giovanni

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Before patient's enrolment, written informed consent must be given according to ICH/GCP, and national/local regulations.
  • Patients with first progression or recurrent glioblastoma after standard chemoradiotherapy (any treatment other than use of nitroureas) having occurred at least 6 months after the end of prior radiotherapy
  • Measurable disease according to RANO criteria with a maximum tumour diameter of 5 cm (local investigator assessment)
  • In case of surgery for recurrence: fully recovered from surgery, confirmation of recurrence by histology, and patient fit for treatment as per local investigator assessment.
  • Histologically proven diagnosis of glioblastoma, IDH wildtype per WHO 2021 classification and local assessment of tissue from diagnosis or recurrence
  • Initial treatment of newly diagnosed glioblastoma by maximal safe resection and postsurgical concurrent conventionally fractionated or abbreviated (minimum 15 fractions) chemoradiotherapy with or without maintenance chemotherapy with temozolomide (patient must have received at least one dose)
  • Stable or decreasing dose of steroids for 7 days prior to enrolment
  • Age ≥ 18 years
  • WHO Performance status of 0-2
  • Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment.
  • Patients of childbearing / reproductive potential must agree to use adequate birth control measures during the study treatment period and for at least 6 months after the last dose of study treatment. A highly effective method of birth control is defined as a method which results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly.
  • Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 6 months after the last study treatment.
  • Non-sterile males must use contraception during treatment and for 6 months after the last dose.
  • Non-sterile males must avoid sperm donation for the duration of the study and for at least 6 months after the last dose of study treatment.

Exclusion Criteria:

  • Any prior anticancer treatment for recurrent glioblastoma (except surgery)
  • Significant reduction in thrombocyte and/or leukocyte counts as well as severe renal impairment according to investigator's opinion
  • History or present acute leukaemia or any myeloid disease
  • Known hypersensitivity to the active components or excipients of lomustine
  • Known coeliac disease or wheat allergy
  • Live attenuated vaccine in the 3 months prior to lomustine initiation
  • Any serious or uncontrolled medical condition (e.g., infections, chronic alcoholism, drug addiction) or abnormality, in the judgment of the investigator that prohibits obtaining informed consent, safe participation and study completion
  • Known contraindication to imaging tracer or any product of contrast media and Magnetic Resonance Imaging (MRI) contraindications
  • Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be assessed and discussed with the patient before the enrolment in the trial.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Control group
Lomustine alone
Drug: Lomustine
Oral administration of Lomustine
Experimental: Experimental group
Lomustine plus reirradiation
Drug: Lomustine
Oral administration of Lomustine
Radiation: Reirradiation
Given at least 6 months after the end of prior radiotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival (OS)
Time Frame: From the date of enrolment up to the date of death, assessed up to 40 months after first patient is enrolled
Defined as the number of days from date of enrolment to the date of death due to any cause
From the date of enrolment up to the date of death, assessed up to 40 months after first patient is enrolled

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression Free Survival (PFS)
Time Frame: From the date of enrolment up to the date of first objective progression or the date of death whichever occur first, assessed up to 40 months after first patient is enrolled
Events are progressions based on Response Assessment in Neuro Oncology (RANO) criteria as determined by the local investigator .
From the date of enrolment up to the date of first objective progression or the date of death whichever occur first, assessed up to 40 months after first patient is enrolled
Health-related Quality of Life (HRQoL)
Time Frame: From the date of enrolment until disease progression, assessed up to 40 months after first patient is enrolled
HRQoL will be assessed with the EORTC Quality of Life Questionnaire (QLQ-C30) version 3.
From the date of enrolment until disease progression, assessed up to 40 months after first patient is enrolled
Toxicity profile of lomustine plus reirradiation
Time Frame: From the date of enrolment until end of study treatment 30 (± 7 days) after last dose, assessed up to 40 months after first patient is enrolled
Safety according to the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0 for toxicity and Serious Adverse Event reporting.
From the date of enrolment until end of study treatment 30 (± 7 days) after last dose, assessed up to 40 months after first patient is enrolled
Neurocognitive functioning of lomustine pus reirradiation
Time Frame: From the date of enrolment until end of study treatment 30 (± 7 days) after last dose, assessed up to 40 months after first patient is enrolled
Neurocognitive functioning assessed by Mini Mental State Examination (MMSE)
From the date of enrolment until end of study treatment 30 (± 7 days) after last dose, assessed up to 40 months after first patient is enrolled
To transform self-reported quality of life data from the QLQ-C30 into health utility values, ready to be used in subsequent health economic analyses.
Time Frame: From the date of enrolment until disease progression, assessed up to 40 months after first patient is enrolled
A deterioration event is defined as ≥>10-point worsening from baseline in the GHQ without further improvement (i.e., no subsequent ≥>10 point improvement) or death due to any cause.
From the date of enrolment until disease progression, assessed up to 40 months after first patient is enrolled
Objective response (ORR)
Time Frame: From the date of enrolment up to the date of first objective progression or the date of death whichever occur first, assessed up to 40 months after first patient is enrolled
From the date of enrolment up to the date of first objective progression or the date of death whichever occur first, assessed up to 40 months after first patient is enrolled
Complete response (CRR)
Time Frame: From the date of enrolment up to the date of first objective progression or the date of death whichever occur first, assessed up to 40 months after first patient is enrolled
From the date of enrolment up to the date of first objective progression or the date of death whichever occur first, assessed up to 40 months after first patient is enrolled

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
To assess health-related quality of life over time based on the results of 3 different scales (QLQ-C30, QLQ-BN20 and the item list (IL46)).
Time Frame: From the date of enrolment until disease progression, assessed up to 40 months after first patient is enrolled

Changes in HRQoL from baseline in the GHQ/QoL, fatigue, nausea/vomiting, physical, role and social functioning scale scores assessed over time will be evaluated descriptively. Descriptive summaries such as median, range (minimum, maximum), IQR, mean and standard deviation will be provided for all the other scales from the QLQ-C30, QLQ-BN20 and the item list (IL46).

For functional and global HRQoL scales, higher scores represent a better level of functioning and are converted to a 0 to 100 scale. For symptom-oriented scales, a higher score represents more severe symptoms.
From the date of enrolment until disease progression, assessed up to 40 months after first patient is enrolled

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

European Organisation for Research and Treatment of Cancer - EORTC

Collaborators

Swiss Cancer Institute

Investigators

  • Principal Investigator: Matthias Preusser, Prof., EORTC Study Coordinator
  • Principal Investigator: Giuseppe Minniti, Dr., EORTC Study Coordinator

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 15, 2024

Primary Completion (Estimated)

September 1, 2027

Study Completion (Estimated)

February 1, 2028

Study Registration Dates

First Submitted

May 23, 2023

First Submitted That Met QC Criteria

June 6, 2023

First Posted (Actual)

June 15, 2023

Study Record Updates

Last Update Posted (Actual)

February 17, 2026

Last Update Submitted That Met QC Criteria

February 12, 2026

Last Verified

February 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EORTC-2227-BTG

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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