Intraoperative Radiotherapy in Newly Diagnosed Glioblastoma Multiforme

Glioblastoma Clinical Trial

— INTRAGO-II  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02685605
• Other study ID #: INTRAGO-II
• Secondary ID: ARO-2016-1AG-NRO
• Status: Recruiting
• Phase: Phase 3
• Start date: December 9, 2016
• Est. completion date: June 2026

Study information

• Verified date: June 2024
• Source: Universitätsmedizin Mannheim
• Contact: Daniel Buergy, MD
• Phone: +49-621-383
• Email: daniel.buergy[@]umm.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 314
• Est. completion date: June 2026
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria

1. Age =18 and = 80 years

2. Karnofsky Performance Score (KPS) = 60%

3. Supratentorial T1-Gd enhancing lesion(s) amenable to total resection

4. Legal capacity and ability of subject to understand character and individual consequences of the clinical trial

5. Patient's written IC obtained at least 24h prior to surgery

6. For women with childbearing potential: adequate contraception

7. 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:

8. IORT must be technically feasible

9. Histology supports diagnosis of GBM

Exclusion Criteria

1. Multicentric disease (e.g. in both hemispheres) or non-resectable satellite lesions

2. Previous cranial radiation therapy

3. Cytostatic therapy / chemotherapy for cancer within the past 5 years

4. History of cancers or other comorbidities that limit life expectancy to less than five years

5. Previous therapy with anti-angiogenic substances (such as bevacizumab)

6. Technical impossibility to use MRI or known allergies against MRI and/or CT contrast agents

7. Participation in other clinical trials testing cancer-derived investigational agents/procedures.

8. Pregnant or breast feeding patients

9. Fertile patients refusing to use safe contraceptive methods during the study

Exclusion Criteria Related to Surgery:

10. Active egress of fluids from a ventricular defect

11. In-field risk organs and/or IORT dose >8 Gy to any risk organ

Related Conditions & MeSH terms

• Glioblastoma

Intervention

Procedure:
• Standard surgery

Radiation:
• Intraoperative radiotherapy
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.
• Radiochemotherapy
EBRT to 60 Gy plus 75 mg/m2/d temozolomide

Drug:
• Temozolomide
Adjuvant chemotherapy with 150-200 mg/m2/d temozolomide per cycle (5/28 days).

Locations

Country	Name	City	State
Brazil	Hospital Alemão Oswaldo Cruz	São Paulo
Canada	Montreal Neurological Institute and Hospital	Montréal	Quebec
China	Beijing Tian Tan Hospital, Capital Medical University	Beijing
Germany	University Hospital Augsburg	Augsburg
Germany	Charité - Universitätsmedizin	Berlin
Germany	St. Georg Hospital	Leipzig
Germany	University Hospital Mannheim	Mannheim
Germany	Technical University of Munich (TUM), Department of Radiation Oncology	Munich
Germany	Klinikum Stuttgart	Stuttgart
Germany	Helios University Hospital Wuppertal	Wuppertal
Korea, Republic of	Gangnam Severance Hospital, Yonsei University College of Medicine	Seoul
Spain	Catalan Institute of Oncology (ICO)	Barcelona
Spain	Hospital Reina Sofia	Córdoba
United Kingdom	The London Clinic	London
United States	Long Island Jewish Medical Center, North Shore University Hospital	Lake Success	New York
United States	Stritch School of Medicine Loyola University	Maywood	Illinois
United States	West Virginia University	Morgantown	West Virginia
United States	Lenox Hill Hospital, Hofstra Northwell School of Medicine	New York	New York
United States	Barrow Neurological Institute (SJHMC)	Phoenix	Arizona

Sponsors (3)

Lead Sponsor	Collaborator
Universitätsmedizin Mannheim	Carl Zeiss Meditec AG, University of California, Los Angeles

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  China,  Germany,  Korea, Republic of,  Spain,  United Kingdom, 

References & Publications (5)

Ayala Alvarez DS, Watson PGF, Popovic M, Heng VJ, Evans MDC, Panet-Raymond V, Seuntjens J. Evaluation of Dosimetry Formalisms in Intraoperative Radiation Therapy of Glioblastoma. Int J Radiat Oncol Biol Phys. 2023 Nov 1;117(3):763-773. doi: 10.1016/j.ijrobp.2023.04.031. Epub 2023 May 5. — View Citation

Cifarelli CP, Jacobson GM. Intraoperative Radiotherapy in Brain Malignancies: Indications and Outcomes in Primary and Metastatic Brain Tumors. Front Oncol. 2021 Nov 11;11:768168. doi: 10.3389/fonc.2021.768168. eCollection 2021. — View Citation

Giordano FA, Brehmer S, Abo-Madyan Y, Welzel G, Sperk E, Keller A, Schneider F, Clausen S, Herskind C, Schmiedek P, Wenz F. INTRAGO: intraoperative radiotherapy in glioblastoma multiforme-a phase I/II dose escalation study. BMC Cancer. 2014 Dec 22;14:992. doi: 10.1186/1471-2407-14-992. — View Citation

Sarria GR, Smalec Z, Muedder T, Holz JA, Scafa D, Koch D, Garbe S, Schneider M, Hamed M, Vatter H, Herrlinger U, Giordano FA, Schmeel LC. Dosimetric Comparison of Upfront Boosting With Stereotactic Radiosurgery Versus Intraoperative Radiotherapy for Glioblastoma. Front Oncol. 2021 Oct 28;11:759873. doi: 10.3389/fonc.2021.759873. eCollection 2021. — View Citation

Sarria GR, Sperk E, Han X, Sarria GJ, Wenz F, Brehmer S, Fu B, Min S, Zhang H, Qin S, Qiu X, Hanggi D, Abo-Madyan Y, Martinez D, Cabrera C, Giordano FA. Intraoperative radiotherapy for glioblastoma: an international pooled analysis. Radiother Oncol. 2020 Jan;142:162-167. doi: 10.1016/j.radonc.2019.09.023. Epub 2019 Oct 16. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Median Progression-Free Survival	Determined according to modified Response Assessment in Neuro-Oncology (RANO) criteria and serial perfusion imaging	24 Months
Secondary	Median Overall Survival		24 Months
Secondary	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
Secondary	OS with respect to Age	Median overall survival of patients <65 vs. = 65 years	24 Months
Secondary	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
Secondary	OS with respect to KPS	Median overall survival of patients with KPS 80-100% vs. 60-70%	24 Months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	OS with respect to MGMT promoter methylation status	OS in patients with promoter methylation vs. no promoter methylation	24 Months
Secondary	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
Secondary	Quality of Life (QoL) questionnaire	Assessed by European Organization for Research and Treatment (EORTC)- Quality of Life Questionnaires (QLQ C30/BN20)	24 Months
Secondary	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
Secondary	Radiation-related (acute / early delayed / late) neurotoxicity	Assessed by regular neurological examinations and serial MRI scans	24 Months