Intraoperative Radiotherapy in Newly Diagnosed Glioblastoma Multiforme (INTRAGO-II)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Glioblastoma
• Intervention / Treatment: Procedure: Standard surgery; Radiation: Intraoperative radiotherapy; Radiation: Radiochemotherapy; Drug: Temozolomide

• Study Type: Interventional
• Enrollment (Actual): 314
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • São Paulo, Brazil, 01323-020
    • Hospital Alemao Oswaldo Cruz
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3A 2B4
      • Montreal Neurological Institute and Hospital
• China
  • Beijing, China, 100050
    • Beijing Tian Tan Hospital, Capital Medical University
• Germany
  • Augsburg, Germany, 86156
    • University Hospital Augsburg
  • Berlin, Germany, 13353
    • Charité - Universitätsmedizin
  • Leipzig, Germany
    • St. Georg Hospital
  • Mannheim, Germany, 68167
    • University Hospital Mannheim
  • Munich, Germany, 81675
    • Technical University of Munich (TUM), Department of Radiation Oncology
  • Stuttgart, Germany, 70174
    • Klinikum Stuttgart
  • Wuppertal, Germany, 42283
    • Helios University Hospital Wuppertal
• South Korea
  • Seoul, South Korea, 06273
    • Gangnam Severance Hospital, Yonsei University College of Medicine
• Spain
  • Barcelona, Spain, 08908
    • Catalan Institute of Oncology (ICO)
  • Córdoba, Spain
    • Hospital Reina Sofia
• United Kingdom
  • London, United Kingdom, W1G 6BW
    • The London Clinic
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Barrow Neurological Institute (SJHMC)
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Stritch School of Medicine Loyola University
  • New York
    • Lake Success, New York, United States, 11042
      • Long Island Jewish Medical Center, North Shore University Hospital
    • New York, New York, United States, 10028
      • Lenox Hill Hospital, Hofstra Northwell School of Medicine
  • West Virginia
    • Morgantown, West Virginia, United States, 26506-9260
      • West Virginia University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental Arm (A); 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; 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.; Other Names: IORT; Radiation: 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).
Active Comparator: Control Arm (B); 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; Radiation: 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).

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Universitätsmedizin Mannheim
• Collaborators: University of California, Los Angeles; Carl Zeiss Meditec AG
• Investigators: Principal Investigator: Kevin Petrecca, MD, Department of Neurosurgery, Montréal Neurological, Institute and Hospital, Montréal, Canada; Principal Investigator: Frank A. Giordano, MD, Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Germany

Publications and helpful links

General Publications

• 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.
• 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.
• Giordano FA, Brehmer S, Murle B, Welzel G, Sperk E, Keller A, Abo-Madyan Y, Scherzinger E, Clausen S, Schneider F, Herskind C, Glas M, Seiz-Rosenhagen M, Groden C, Hanggi D, Schmiedek P, Emami B, Souhami L, Petrecca K, Wenz F. Intraoperative Radiotherapy in Newly Diagnosed Glioblastoma (INTRAGO): An Open-Label, Dose-Escalation Phase I/II Trial. Neurosurgery. 2019 Jan 1;84(1):41-49. doi: 10.1093/neuros/nyy018.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 9, 2016
• Primary Completion (Estimated): November 1, 2025
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: February 5, 2016
• First Submitted That Met QC Criteria: February 14, 2016
• First Posted (Estimated): February 19, 2016

Study Record Updates

• Last Update Posted (Estimated): October 14, 2025
• Last Update Submitted That Met QC Criteria: October 10, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: Glioblastoma; Intraoperative Radiotherapy; Radiotherapy Dose Escalation
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Therapeutics; Drug Therapy; Azoles; Dacarbazine; Triazenes; Imidazoles; Radiotherapy; Combined Modality Therapy; Temozolomide; Chemoradiotherapy
• Other Study ID Numbers: INTRAGO-II; ARO-2016-1 (Other Identifier: Working Party for Radiation Oncology (ARO) of the DKG); AG-NRO-03 (Other Identifier: German Society for Radiation Oncology (DEGRO))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• product manufactured in and exported from the U.S.: No