Phase III Randomized Study of Lomustine With or Without Reirradiation in First Progression of Glioblastoma

The primary objective of this study is to demonstrate that **overall survival** (OS) is superior with the combination of **lomustine** and reirradiation compared to lomustine monotherapy in patients experiencing the first progression of **glioblastoma**. This is clinically relevant as improving overall survival is a critical endpoint in the management of glioblastoma, a highly aggressive brain tumor with limited treatment options.

Secondary objectives include:

• To show that progression-free survival (PFS) is improved with lomustine plus reirradiation compared to lomustine monotherapy.
• To assess the toxicity profile of lomustine plus reirradiation.
• To evaluate neurocognitive functioning with lomustine plus reirradiation.
• To assess whether lomustine plus reirradiation improves quality of life deterioration-free survival (QDFS), with a focus on global health quality of life (GHQ), compared to lomustine monotherapy.
• To transform self-reported quality of life data from the QLQ-C30 into health utility values for subsequent health economic analyses.
• To demonstrate that response is improved with lomustine plus reirradiation.
• To assess health-related quality of life across all other scales from the QLQ-C30, QLQ-BN20, and the item list (IL46) over time.

The clinical trial involves a total of **12 participants** diagnosed with **glioblastoma**, a type of brain cancer. The study population includes both male and female subjects, aged **18 years and older**, with a **WHO Performance status** of 0-2, indicating they are ambulatory and capable of all self-care or up and about more than 50% of waking hours. Participants were selected based on their first progression or recurrence of glioblastoma after initial treatment, with measurable disease according to RANO criteria. The trial does not include a vulnerable population. Key lifestyle considerations include the requirement for a stable or decreasing dose of steroids for 7 days prior to enrollment. Participants must have a histologically proven diagnosis of glioblastoma, IDH wildtype, and must be candidates for treatment with lomustine as per physician's assessment. The trial ensures that women of childbearing potential have a negative serum pregnancy test before the first dose and agree to use effective birth control measures during and after the study treatment period.

The clinical trial is designed to evaluate the efficacy of **lomustine** with or without reirradiation in patients experiencing the first progression of **glioblastoma**. This is a randomized, phase III study with a double-blind, controlled design. The primary objective is to determine if the combination of lomustine and reirradiation improves overall survival compared to lomustine monotherapy. The trial is expected to commence recruitment on March 19, 2024, and conclude by February 29, 2028. Participants will be involved in the study for a maximum treatment period of 12 months, with the possibility of early termination if adverse events occur or if the disease progresses beyond the criteria set by the Response Assessment in Neuro Oncology (RANO) guidelines.

The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, performance status, and histological confirmation of glioblastoma. Follow-up visits will be scheduled to monitor treatment response, assess safety, and evaluate secondary endpoints such as progression-free survival, neurocognitive functioning, and health-related quality of life. The end-of-study visit will occur after the completion of the treatment period or upon early termination. Participants will be required to adhere to specific conditions, including the use of effective birth control methods and maintaining a stable or decreasing dose of steroids prior to enrollment. The primary endpoint is overall survival, while secondary endpoints include progression-free survival, objective response rates, and safety assessments according to the CTCAE Version 5.0.

The clinical trial involves the use of **lomustine**, an alkylating agent, as the experimental medication. Lomustine is administered in an **oral** pharmaceutical form, identified by the code PHF00006MIG. The dosage is calculated based on body surface area, with a maximum daily dose of 2.62 mg/m² and a total maximum dose of 200 mg. The treatment period is limited to a maximum of 12 months. The administration of lomustine is intended for the first progression of **glioblastoma**. The chemical origin of lomustine is confirmed, and it is not formulated for pediatric use.

In this randomized phase III study, lomustine is evaluated both as a monotherapy and in combination with reirradiation. The primary objective is to determine if the combination therapy improves overall survival compared to lomustine alone. The trial does not include a placebo or other comparator treatments beyond the standard-of-care reirradiation. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

Efficacy in this clinical trial will be assessed primarily through the measurement of **overall survival (OS)**. OS is defined as the number of days from the date of enrolment to the date of death due to any cause. This endpoint will provide a direct measure of the treatment's impact on survival in patients with glioblastoma experiencing first progression.

Secondary efficacy endpoints include progression-free survival (PFS), which will be evaluated based on the Response Assessment in Neuro Oncology (RANO) criteria as determined by the local investigator. Additionally, objective and complete response rates will be assessed using the same RANO criteria. Safety will be monitored according to the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0, focusing on toxicity and serious adverse event reporting.

Other secondary endpoints involve the assessment of neurocognitive functioning using the Mini Mental State Examination (MMSE) and health utility derived from patient-reported health-related quality of life (HRQoL) data collected via the QLQ-C30 questionnaire. Changes in HRQoL from baseline will be evaluated descriptively, with summaries including median, range, interquartile range, mean, and standard deviation provided for various scales from the QLQ-C30, QLQ-BN20, and the item list (IL46).