Prophylactic Regimen With Intrathecal Thiotepa in SVZ-positive or Meningeal-risk Glioblastoma

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:

• pre-operative MRI showing tumor in direct contact with the sub-ventricular zone (SVZ+), or
• 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:

• Pre-operative MRI showing tumour in direct contact with the lateral ventricular sub-ventricular zone (SVZ+); OR
• 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.