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

Overview

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.