The goal of this clinical trial is to test whether adding preventive intrathecal chemotherapy (thiotepa) to the standard Stupp regimen can lower the risk of leptomeningeal metastasis (LM) and extend survival in patients with newly diagnosed glioblastoma (GBM) whose tumors touch the sub-ventricular zone (SVZ+) or whose surgery accidentally opened the ventricle (VE). The main questions it aims to answer are:

Can six weekly intrathecal injections of thiotepa (10 mg) given during chemoradiotherapy increase the chance of remaining free of LM at one year? Does the approach also prolong overall survival and progression-free survival compared with historical controls? Is the combination safe and well-tolerated in this high-risk population?

Participants will:

Receive maximal safe tumor resection followed by standard radiotherapy (60 Gy/30 fractions) plus daily temozolomide (75 mg/m²).

Begin thiotepa injections (via lumbar puncture or Ommaya reservoir) within 1 week of starting radiotherapy, repeated every 7 days for 6 doses.

Continue standard adjuvant temozolomide (150-200 mg/m² days 1-5/28) for 6 cycles.

Understand that all procedures, toxicities and survival will be tracked for 2 years, with MRI and clinical visits every 4-8 weeks.

Provide CSF and blood samples for exploratory biomarkers that may predict response or resistance.

This is a single-arm, prospective, phase II exploratory study designed to estimate the efficacy and safety of preventive intrathecal thiotepa combined with the Stupp protocol in adults with newly diagnosed, WHO grade 4 IDH-wildtype glioblastoma who are at very high risk of leptomeningeal seeding. Risk is defined as:

1. pre-operative MRI showing tumor in direct contact with the sub-ventricular zone (SVZ+), or
2. intra-operative cerebrospinal-fluid leak (ventricular entry, VE) documented in the surgical note and/or early post-operative imaging.

SVZ+ and/or VE doubles the incidence of LM (≈25 % vs. 5-10 %) and shortens median overall survival to 12 months. Once LM occurs, median survival collapses to < 4 months and no standard therapy exists. Thiotepa is a lipophilic alkylating agent that achieves high CSF concentrations, penetrates the pia-glial barrier, and has documented activity against meningeal glioma deposits with lower neuro-toxicity than methotrexate. Delivering thiotepa while the circulating tumor cell burden is still minimal ("adjuvant to adjuvant therapy") is therefore mechanistically attractive.

Inclusion Criteria:

• Age 18-75 years, either sex.

• Histologically confirmed newly-diagnosed WHO grade IV glioblastoma with at least one measurable lesion on MRI.

• Must fulfil ONE of the following high-risk imaging/surgical conditions:

  1. Pre-operative MRI showing tumour in direct contact with the lateral ventricular sub-ventricular zone (SVZ+); OR
  2. Operative record and post-operative imaging documenting an intra-operative cerebro-spinal-fluid leak (ventricular entry, VE).

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 and estimated life expectancy ≥ 3 months.

• Neurological symptoms stable for ≥ 7 days before enrollment.

• Adequate bone-marrow reserve: neutrophils ≥ 1.5 × 10⁹/L, haemoglobin ≥ 90 g/L, platelets ≥ 75 × 10⁹/L.

• Coagulation acceptable: PT/INR and aPTT ≤ 1.5 × upper limit of normal (ULN). Hepatic: total bilirubin ≤ 1.5 × ULN, ALT & AST ≤ 1.5 × ULN, albumin ≥ 30 g/L. Renal: serum creatinine ≤ 2 × ULN and calculated or 24-h creatinine clearance ≥ 50 mL/min.

• Reliable contraception from first dose until 3 months after the last dose for both sexes.

Exclusion Criteria:

• Pregnant or lactating women.
• Active infection requiring intravenous antibiotics within 7 days before study entry, or therapeutic anticoagulation with warfarin.
• History of any other malignancy within the previous 5 years (except adequately treated basal-cell carcinoma of skin or cervical carcinoma in-situ).
• Known HIV infection, AIDS, immunodeficiency syndromes, or active autoimmune disease needing systemic therapy.
• Severe medical, neurological or psychiatric conditions that would preclude compliance with protocol procedures.
• Disrupted ventricular drainage catheter or anatomical contraindication preventing safe lumbar puncture or Ommaya reservoir placement.
• Uncontrolled chronic illnesses: diabetes, congestive heart failure (NYHA III/IV), hepatic cirrhosis, chronic kidney disease stage ≥ 3b, etc.
• Any condition judged by the investigator to increase the risks of intrathecal chemotherapy or to confound toxicity assessment.