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.
Age 18-75 years, either sex.
Histologically confirmed newly-diagnosed WHO grade IV glioblastoma with at least one measurable lesion on MRI.
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).
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.
Single group
Maximal surgical resection
Procedure/SurgeryMaximal-safe resection of the contrast-enhancing tumour; if VE occurs, rapid closure and post-op MRI within 72 h to document extent of resection and any blood/ tumour spillage into the ventricles.
Concomitant Chemoradiotherapy (Stupp backbone)
RadiationIntensity-modulated radiotherapy (IMRT) 60 Gy in 30 fractions (2 Gy/fx, 5 fx/week). Oral temozolomide 75 mg/m² daily, starting on the first day of RT and continuing until the last fraction (≈ 42-49 days). Adjuvant Temozolomide begins 4 weeks after completion of RT: 150 mg/m² PO days 1-5 of a 28-day cycle; escalate to 200 mg/m² cycle 2 if ANC ≥ 1.5 and platelets ≥ 100 × 10⁹/L. Six cycles total.
Preventive Intrathecal Thiotepa
Drug10 mg thiotepa once weekly for 6 consecutive weeks, beginning within 7 days of the first RT fraction. Lumbar puncture or injection via intra-operatively placed Ommaya reservoir.
Leptomeningeal-metastasis-free survival (LMFS)
Kaplan-Meier estimate of the distribution of time without LM; primary efficacy endpoint.
Overall survival
Time from treatment initiation until death
Progression-free survival
Time from treatment initiation until disease progression( RECIST1.1 )
Safety assessment
Incidence and severity of treatment-related adverse events using CTCAE 5.0.
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