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NCT Number: NCT05904119

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

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.

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Key information

Conditions

First Progression of Glioblastoma Astrocytoma Glioblastoma Glioma Neoplasms Neoplasms by Histologic Type Neoplasms, Germ Cell and Embryonal Neoplasms, Glandular and Epithelial Neoplasms, Nerve Tissue Neoplasms, Neuroepithelial Neuroectodermal Tumors

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

A.O Landeskrankenhaus - Innsbruck Universitaetsklinik, Innsbruck, Austria

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

lomustine

Drug

Oral administration of Lomustine

Reirradiation

Radiation

Given at least 6 months after the end of prior radiotherapy

Primary outcomes

  1. 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

Secondary outcomes

  1. 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 .

  2. 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.

  3. 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.

  4. 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)

  5. 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.

  6. 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

  7. 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

Other outcomes

  1. 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.

Study contacts

Contact information is provided by the study sponsor or research team.

EORTC

CONTACT

[email protected]

+3227741611

Sponsors and collaborators

Lead sponsor

European Organisation for Research and Treatment of Cancer - EORTC

Network

Collaborators

  • Swiss Cancer Institute

Registry information

Acronym: LEGATO

Important dates

Study start
2024
Primary completion
2027
Study completion
2028
First posted
Jun 15, 2023
Registry last updated
Jun 8, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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