Ropidoxuridine as a Radiosensitizer in Newly Diagnosed IDH-Wildtype Glioblastoma With Unmethylated MGMT Promoter

Inclusion Criteria:

• Written informed consent form signed and dated by patient or legally authorizedrepresentative according to local guidelines, prior to the performance of anystudy-specific procedures, sampling, or analyses. Participants with impaireddecision-making capacity must have a close caregiver or legally authorizedrepresentative present.

• Histologically confirmed supratentorial glioblastoma isocitrate dehydrogenase (IDH)wild-type classification (2021 World Health Organization Classification of Tumours, 5th Edition, Volume 6) with unmethylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter (defined as MGMT methylation status ≤20% by pyrosequencing, and noprior radiation, electric field, or systemic therapy. Glucocorticoid therapy forsymptom control is allowed.

• Patients should, in the opinion of the investigator, be candidates for 60 Gyradiotherapy in 2 Gy fractions over 6 weeks, per standard of care. Hypofractionatedradiotherapy schedules (e.g., 36 Gy in 3 Gy fractions) are not allowed.

• Eastern Cooperative Oncology Group performance status of 0, 1 or 2.

• Adequate renal, liver and bone marrow function:

• Hemoglobin >9.0 g/dL

• Absolute neutrophil count >1.5 × 10^9/L

• Platelet count >100 × 10^9/L

• Total bilirubin ≤1.5 × upper limit of normal (ULN), unless due to documentedGilbert's disease (≤3 × ULN)

• Aspartate aminotransferase / alanine aminotransferase ≤4×ULN

• Creatinine clearance ≥60 mL/min calculated as per Cockcroft-Gault equation.

• Life expectancy ≥12 weeks.

• Have recovered from the immediate post-operative period and is maintained on astable corticosteroid regimen (no increase for 5 days) prior to initiation of studytreatment.

• Female patients, of childbearing potential, must have a negative serum pregnancytest within 7 days prior to taking study medication and agree to use at least onehighly effective form of contraception during study treatment and for at least 120days after the last dose of study treatment.

• Male patients must agree to use an adequate method of contraception from enrollmentthrough 120 days after the last dose of study treatment.

Exclusion Criteria:

• Any prior treatment for glioblastoma, including chemotherapy, immunotherapy,targeted therapy or therapy with biologic agent (including immunotoxins,immunoconjugates, antisense, peptide receptor antagonists, interferons,interleukins, lymphokine-activated killer cell therapy or gene therapy), orradiotherapy. Glucocorticoid therapy is permitted.

• Second primary malignancy expected to require active treatment within a 6-monthperiod (except basal cell or early-stage squamous cell carcinoma of the skin thatmay be excised). Patients who had another malignancy in the past but have been freeof active disease for more than 1 year, are eligible even if under activesurveillance, at the discretion of the Investigator. Adjuvant anti hormonaltreatment for prior breast or prostate cancer is allowed, but no other concomitantanticancer treatment.

• Any investigational therapy (for any concomitant condition) within 28 days or within 5 half-lives of study entry (whichever is shorter).

• Use of acid-reducing agents including proton pump inhibitors and histamine-2blockers.

• Inability to comply with protocol or study procedures.

• Women who are pregnant or breastfeeding.

• Inability to swallow oral medication or gastrointestinal disorder expected toseverely affect drug absorption (e.g., short bowel syndrome).

• Ongoing bacterial, viral, or fungal infection requiring systemic therapy.Prophylactic therapy is allowed. Patients with a history of Human ImmunodeficiencyVirus, Hepatitis B virus, Hepatitis C virus infection are allowed if treated witheffective anti-viral therapy that results in undetectable viral load.

• Any medical condition, which in the opinion of the Investigator, places the patientat an unacceptably high risk for toxicities, or makes the patient unsuitable forstudy participation.