Intraoperative Radiotherapy in Newly Diagnosed Glioblastoma Multiforme

Study Overview
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Brief Summary
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INTRAGO II resembles a multicentric, prospective, randomized, 2-arm, open-label clinical phase III trial which tests if the median progression-free survival (PFS) of patients with newly diagnosed glioblastoma multiforme (GBM) can be improved by the addition of intraoperative radiotherapy (IORT) to standard radiochemotherapy.

Official Title
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A Multicenter Randomized Phase III Trial on INTraoperative RAdiotherapy in Newly Diagnosed GliOblastoma Multiforme (INTRAGO II)

Conditions
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Glioblastoma

Intervention / Treatment
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* Procedure: Standard surgery
* Radiation: Intraoperative radiotherapy
* Radiation: Radiochemotherapy
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age ≥18 and ≤ 80 years Karnofsky Performance Score (KPS) ≥ 60% Supratentorial T1-Gd enhancing lesion(s) amenable to total resection Legal capacity and ability of subject to understand character and individual consequences of the clinical trial Patient's written IC obtained at least 24h prior to surgery For women with childbearing potential: adequate contraception Patients must have adequate organ functions Bone marrow function: Platelets ≥ 75.000/μL WBC ≥ 3.000/μL Hemoglobin ≥ 10.0 g/dL Liver Function: ASAT and ALAT ≤ 3.0 times ULN ALP ≤ 2.5 times ULN Total Serum Bilirubin < 1.5 times ULN Renal Function: Serum Creatinine ≤ 1.5 times ULN Inclusion Criteria Related to Surgery: IORT must be technically feasible Histology supports diagnosis of GBM Exclusion Criteria Multicentric disease (e.g. in both hemispheres) or non-resectable satellite lesions Previous cranial radiation therapy Cytostatic therapy / chemotherapy for cancer within the past 5 years History of cancers or other comorbidities that limit life expectancy to less than five years Previous therapy with anti-angiogenic substances (such as bevacizumab) Technical impossibility to use MRI or known allergies against MRI and/or CT contrast agents Participation in other clinical trials testing cancer-derived investigational agents/procedures. Pregnant or breast feeding patients Fertile patients refusing to use safe contraceptive methods during the study Exclusion Criteria Related to Surgery: Active egress of fluids from a ventricular defect In-field risk organs and/or IORT dose >8 Gy to any risk organ

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Arm (A)<br>Standard surgery plus intraoperative radiotherapy (20-30 Gy) followed by radiochemotherapy (EBRT: 60 Gy, 75 mg/m2/d temozolomide) and adjuvant chemotherapy with 150-200 mg/m2/d temozolomide per cycle (5/28 days). | Procedure: Standard surgery<br> <br> Radiation: Intraoperative radiotherapy<br>* Dose to applicator surface: 20-30 Gy; Carl Zeiss INTRABEAM System. IORT with a surface dose of 30 Gy is recommended.Should the proximity to any risk structure not allow to apply 30 Gy, a dose reduction by up to 10 Gy (resulting in a surface dose of 20 Gy) is allowed.<br>* Other names: IORT;Radiation: Radiochemotherapy<br>* EBRT to 60 Gy plus 75 mg/m2/d temozolomide<br>Drug: Temozolomide<br>* Adjuvant chemotherapy with 150-200 mg/m2/d temozolomide per cycle (5/28 days).<br>|
| Active Comparator: Control Arm (B)<br>Standard surgery followed by radiochemotherapy (EBRT: 60 Gy, 75 mg/m2/d temozolomide) and adjuvant chemotherapy with 150-200 mg/m2/d temozolomide per cycle (5/28 days). | Procedure: Standard surgery<br> <br> Radiation: Radiochemotherapy<br>* EBRT to 60 Gy plus 75 mg/m2/d temozolomide<br>Drug: Temozolomide<br>* Adjuvant chemotherapy with 150-200 mg/m2/d temozolomide per cycle (5/28 days).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-Free Survival | Determined according to modified Response Assessment in Neuro-Oncology (RANO) criteria and serial perfusion imaging | 24 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Overall Survival |  | 24 Months | 
| PFS within a 1-2 cm margin around the cavity | Determined by serial contrast-enhanced MRI scans using modified RANO criteria and serial perfusion imaging | 24 Months | 
| OS with respect to Age | Median overall survival of patients <65 vs. ≥ 65 years | 24 Months | 
| PFS with respect to Age | Progression-free survival of patients <65 vs. ≥ 65 years; determined according to modified RANO criteria and serial perfusion imaging | 24 Months | 
| OS with respect to KPS | Median overall survival of patients with KPS 80-100% vs. 60-70% | 24 Months | 
| PFS with respect to KPS | Progression-free survival of patients with KPS 80-100% vs. 60-70%; determined according to modified RANO criteria and serial perfusion imaging | 24 Months | 
| OS with respect to thickness of anticipated T1-Gd-enhancing (remaining) tumor margin | Thickness of anticipated T1-Gd-enhancing (remaining) tumor margin as per the discretion of the surgeon (margin ≥0.5 cm or multiple spots of residual tumor within the cavity vs. <0.5 cm) | 24 Months | 
| PFS with respect to thickness of anticipated T1-Gd-enhancing (remaining) tumor margin | Thickness of anticipated T1-Gd-enhancing (remaining) tumor margin as per the discretion of the surgeon (margin ≥0.5 cm or multiple spots of residual tumor within the cavity vs. <0.5 cm); determined according to modified RANO criteria and serial perfusion imaging | 24 Months | 
| OS with respect to extent of resection | Early postoperative MRI scans must be used to determine the extent of resection (EoR). The EoR is given as sum of all maximum diameters of residual lesions in cm. OS will be calculated for the following groups: Max Diameter group 0: 0 cm (no residual tumor) Max Diameter group 1: >0 to ≤1.5 cm (cumulative if multiple residual lesions) Max Diameter group 2: >1.5 cm (cumulative if multiple residual lesions) | 24 Months | 
| PFS with respect to extent of resection | Early postoperative MRI scans must be used to determine the extent of resection (EoR). The EoR is given as sum of all maximum diameters of residual lesions in cm. PFS will be determined according to modified RANO criteria and serial perfusion imaging for the following groups: Max Diameter group 0: 0 cm (no residual tumor) Max Diameter group 1: >0 to ≤1.5 cm (cumulative if multiple residual lesions) Max Diameter group 2: >1.5 cm (cumulative if multiple residual lesions) | 24 Months | 
| OS with respect to MGMT promoter methylation status | OS in patients with promoter methylation vs. no promoter methylation | 24 Months | 
| PFS with respect to MGMT promoter methylation status | PFS in patients with promoter methylation vs. no promoter methylation; determined according to modified RANO criteria and serial perfusion imaging | 24 Months | 
| Quality of Life (QoL) questionnaire | Assessed by European Organization for Research and Treatment (EORTC)- Quality of Life Questionnaires (QLQ C30/BN20) | 24 Months | 
| Activities of daily living (ADL), assessed using the Barthel Index (Mahoney & Barthel, 1965). | Change in functional outcomes as measured by BI from its baseline value. | 24 Months | 
| Radiation-related (acute / early delayed / late) neurotoxicity | Assessed by regular neurological examinations and serial MRI scans | 24 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glioblastoma, Intraoperative Radiotherapy, Radiotherapy Dose Escalation