Glioblastoma (GBM)
Conditions
Keywords
Prophylactic Intrathecal chemotherapy, thiotepa, ventricular invasion, ventricular entry
Brief summary
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.
Detailed description
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.
Interventions
PROCEDUREMaximal surgical resection
Maximal-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.
RADIATIONConcomitant Chemoradiotherapy (Stupp backbone)
Intensity-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.
DRUGPreventive Intrathecal Thiotepa
10 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.
Sponsors
Second Affiliated Hospital, School of Medicine, Zhejiang University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Leptomeningeal-metastasis-free survival (LMFS) | From first intrathecal thiotepa injection until documented leptomeningeal metastasis (radiologic or cytologic) or death from any cause, assessed up to 24 months. | Kaplan-Meier estimate of the distribution of time without LM; primary efficacy endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival | 3 months,6 months and 1 year after treatment | Time from treatment initiation until death |
| Progression-free survival | 3 months,6 months and 1 year after treatment | Time from treatment initiation until disease progression( RECIST1.1 ) |
| Safety assessment | From informed consent until 30 days after last protocol therapy (≈ 9 months) | Incidence and severity of treatment-related adverse events using CTCAE 5.0. |
Countries
China
Contacts
CONTACTTing Zhang, phD.
Outcome results
None listed