INTRAGO-Intraoperative Radiotherapy for Glioblastoma - a Phase I/II Study

Study Overview
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Brief Summary
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Glioblastoma multiforme (GBM) is a disease with an extremely poor prognosis. Despite surgery and radiochemotherapy, the tumors are likely to grow back very quickly. Intraoperative radiotherapy (IORT) may improve local control rates while sparing healthy tissue (Giordano et al. 2014). IORT takes place before cranioplasty directly after gross (or subtotal) tumor resection. Several past studies on IORT for GBM conducted in Japan and Spain have yielded encouraging results (Sakai et al. 1989; Matsutani et al. 1994; Fujiwara et al. 1995; Ortiz de Urbina et al. 1995). However, the full potential of the procedure is to date largely unexplored as most previous studies used forward-scattering (electron-based) irradiation techniques, which frequently led to inadequately covered target volumes. With the advent of the spherically irradiation devices such as the Intrabeam® system (Carl Zeiss Meditec AG, Oberkochen, Germany), even complex cavities can be adequately covered with irradiation during IORT. However, there is no data on the maximum tolerated dose of IORT with low-energy X-rays as generated by this system. The INTRAGO I/II study aims to find out which dose of a single shot of radiation, delivered intraoperatively direct after surgery, is tolerable for patients with GBM. A secondary goal of the study is to find out whether the procedure may improve survival rates.

Official Title
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INTRAGO-Intraoperative Radiotherapy for Glioblastoma - a Phase I/II Study

Conditions
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Glioblastoma Multiforme

Intervention / Treatment
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* Radiation: Intraoperative Radiotherapy (Applicator Surface Dose: 20-40 Gy)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed glioblastoma multiforme in frozen sections Age ≥50 years Karnofsky Performance Index ≥ 50% Informed consent Adequate birth control (e.g., oral contraceptives) Exclusion Criteria: Astrocytoma ≤ WHO grade III Gliomatosis cerebri Multifocal lesions Infratentorial localization Previous cranial radiation therapy (any location) Uncontrolled intercurrent illnesses including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements. Contraindications for general anaesthesia Bleeding or clotting disorders Contraindications for MRI or CT scans Pregnant or breastfeeding women

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intraoperative Radiotherapy<br>Following conventional frameless neuronavigation-guided microsurgical tumor resection, patients will receive IORT with 20-40 Gy (prescribed to the applicator surface). Not later than 4 weeks, radiochemotherapy (RCT) will be initiated, consisting of a total EBRT dose of 60 Gy (delivered in fractions of 2 Gy) and concomitant chemotherapy with temozolomide (50 mg/m2/d). Four weeks after RCT, cycling chemotherapy with temozolomide (150-200mg/m2/d/cycle) will be applied. | Radiation: Intraoperative Radiotherapy (Applicator Surface Dose: 20-40 Gy)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | The maximum tolerated (single) dose of IORT with 50 kV X-rays will be assessed using a classical 3+3 design: The first cohort of 3 patients will receive IORT with 20 Gy (prescribed to the applicator surface). If none of these patients experiences a DLT, another three patients will be treated at the next higher dose level (30 Gy). However, should a patient experience a DLT, 3 more patients will be treated at the same dose level. The dose escalation stops if two ore more patients in a cohort of 3-6 patients experience DLT. The MTD is then defined as the dose level just below the toxic dose level. Two types of DLT are defined: Early DLT (≤ 3 weeks after IORT): wound infections / wound healing difficulties requiring surgical intervention IORT-related cerebral bleeding or ischemia Delayed DLT (≤ 3 months after IORT): Symptomatic brain necrosis requiring surgical intervention Early termination of EBRT (before the envisaged dose of 60 Gy) due to radiotoxicity | 3 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival |  | 3 Years | 
| Overall Survival |  | 3 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glioblastoma Multiforme, High-Grade Glioma, Malignant Glioma, IORT