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

Sponsor

European Organisation for Research and Treatment of Cancer - EORTC (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05904119

Collaborator

(none)

411

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
First Progression of Glioblastoma	Drug: Lomustine Radiation: Reirradiation	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

411 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Mar 1, 2024

Anticipated Primary Completion Date :

Sep 1, 2027

Anticipated Study Completion Date :

Feb 1, 2028

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Overall Survival (OS) [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 Outcome Measures

Progression Free Survival (PFS) [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 .
Health-related Quality of Life (HRQoL) [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.
Toxicity profile of lomustine plus reirradiation [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.
Neurocognitive functioning of lomustine pus reirradiation [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)
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. [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.
Objective response (ORR) [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) [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

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)). [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.