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

Study Overview
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Brief Summary
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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.

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

Conditions
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First Progression of Glioblastoma

Intervention / Treatment
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* Drug: Lomustine
* Radiation: Reirradiation


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | 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) | 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) | 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 | 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 | 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. | 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) |  | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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First progression, Glioblastoma, Phase III, Lomustine, Reirradiation