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

Официальное название

A Pilot Study of Prophylactic Intrathecal Thiotepa Plus the Stupp Regimen for Glioblastoma With Subventricular Zone Contact or Intraoperative Ventricular Entry（PRISM-Trial）

Обзор

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.

Подробное описание

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.

Вмешательства

• Процедура Maximal 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.
• Лучевая терапия Concomitant 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.
• Препарат Preventive 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.

Первичные конечные точки

• Leptomeningeal-metastasis-free survival (LMFS) [Срок оценки: From first intrathecal thiotepa injection until documented leptomeningeal metastasis (radiologic or cytologic) or death from any cause, assessed up to 24 months.]

Вторичные конечные точки (3)

• Overall survival [Срок оценки: 3 months,6 months and 1 year after treatment]
• Progression-free survival [Срок оценки: 3 months,6 months and 1 year after treatment]
• Safety assessment [Срок оценки: From informed consent until 30 days after last protocol therapy (≈ 9 months)]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• 2nd Affiliated Hospital, School of Medicine — Ханчжоу

Идентификаторы

NCT: NCT07511725 · Y2025-1643

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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