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Active, not recruitingNCT02685605INTRAGO-IIUpdated Oct 14, 2025

Intraoperative Radiotherapy in Newly Diagnosed Glioblastoma Multiforme

A Phase 3 interventional study of Standard surgery and Intraoperative radiotherapy in Glioblastoma, sponsored by Universitätsmedizin Mannheim. Active, not recruiting at 19 sites in 8 countries. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2025-10-14.

Sponsored by Universitätsmedizin Mannheim · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
314
Allocation
Randomized
Ages
18 Years to 80 Years
Sex
All
01

Study 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.

02

Conditions studied

  • Glioblastoma

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Keywords

  • Glioblastoma
  • Intraoperative Radiotherapy
  • Radiotherapy Dose Escalation
03

Who can participate

Ages eligible
18 Years to 80 Years
Sexes eligible
All
Accepts healthy volunteers
No

Eligibility criteria

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
04

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
314 participants (actual)

Study arms

  • 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 · Radiation: Radiochemotherapy · Drug: Temozolomide

  • 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 · Drug: Temozolomide

Interventions

  • ProcedureStandard surgery
  • RadiationIntraoperative 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.

    Also known as: IORT

  • RadiationRadiochemotherapy

    EBRT to 60 Gy plus 75 mg/m2/d temozolomide

  • DrugTemozolomide

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

05

What researchers measure

Primary outcomes

  1. Median Progression-Free Survival

    Determined according to modified Response Assessment in Neuro-Oncology (RANO) criteria and serial perfusion imaging

    Time frame: 24 Months

Secondary outcomes

  1. Median Overall Survival

    Time frame: 24 Months

  2. 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

    Time frame: 24 Months

  3. OS with respect to Age

    Median overall survival of patients \<65 vs. ≥ 65 years

    Time frame: 24 Months

  4. PFS with respect to Age

    Progression-free survival of patients \<65 vs. ≥ 65 years; determined according to modified RANO criteria and serial perfusion imaging

    Time frame: 24 Months

  5. OS with respect to KPS

    Median overall survival of patients with KPS 80-100% vs. 60-70%

    Time frame: 24 Months

  6. 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

    Time frame: 24 Months

  7. 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)

    Time frame: 24 Months

  8. 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

    Time frame: 24 Months

  9. 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)

    Time frame: 24 Months

  10. 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)

    Time frame: 24 Months

  11. OS with respect to MGMT promoter methylation status

    OS in patients with promoter methylation vs. no promoter methylation

    Time frame: 24 Months

  12. 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

    Time frame: 24 Months

  13. Quality of Life (QoL) questionnaire

    Assessed by European Organization for Research and Treatment (EORTC)- Quality of Life Questionnaires (QLQ C30/BN20)

    Time frame: 24 Months

  14. 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.

    Time frame: 24 Months

  15. Radiation-related (acute / early delayed / late) neurotoxicity

    Assessed by regular neurological examinations and serial MRI scans

    Time frame: 24 Months

06

Study locations

19 sites
  • Barrow Neurological Institute (SJHMC)
    Phoenix, Arizona 85013, United States
  • Stritch School of Medicine Loyola University
    Maywood, Illinois 60153, United States
  • Long Island Jewish Medical Center, North Shore University Hospital
    Lake Success, New York 11042, United States
  • Lenox Hill Hospital, Hofstra Northwell School of Medicine
    New York, New York 10028, United States
  • West Virginia University
    Morgantown, West Virginia 26506-9260, United States
  • Hospital Alemão Oswaldo Cruz
    São Paulo, 01323-020, Brazil
  • Montreal Neurological Institute and Hospital
    Montreal, Quebec H3A 2B4, Canada
  • Beijing Tian Tan Hospital, Capital Medical University
    Beijing, 100050, China
  • University Hospital Augsburg
    Augsburg, 86156, Germany
  • Charité - Universitätsmedizin
    Berlin, 13353, Germany
  • St. Georg Hospital
    Leipzig, Germany
  • University Hospital Mannheim
    Mannheim, 68167, Germany
  • Technical University of Munich (TUM), Department of Radiation Oncology
    Munich, 81675, Germany
  • Klinikum Stuttgart
    Stuttgart, 70174, Germany
  • Helios University Hospital Wuppertal
    Wuppertal, 42283, Germany
  • Gangnam Severance Hospital, Yonsei University College of Medicine
    Seoul, 06273, South Korea
  • Catalan Institute of Oncology (ICO)
    Barcelona, 08908, Spain
  • Hospital Reina Sofia
    Córdoba, Spain
  • The London Clinic
    London, W1G 6BW, United Kingdom
07

References and documents

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. PubMed 25535398 ↗
  • 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. PubMed 31629553 ↗
  • 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. PubMed 37150259 ↗
  • 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. PubMed 34858846 ↗
  • 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. PubMed 34778080 ↗
  • Giordano FA, Ganslandt O, Munter MW, Combs SE, Diehl C, Meyer B, Herrlinger U, Schneider M, Kahl KH, Shiban E, Goenka A, Schulder M, Lucas A, Plans G, Brehmer S, Ruder AM, Garcia-Cabezas S, Solivera J, Cifarelli CP, Wenz F, Sarria GR, Pope WB, Layer JP, Tsien CI, Petrecca K; INTRAGO-II Study Group. Dose escalation with intraoperative radiotherapy in newly diagnosed glioblastoma (INTRAGO-II): an open-label, multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2026 Jul;27(7):864-878. doi: 10.1016/S1470-2045(26)00235-4. PubMed 42372746 ↗
  • 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. PubMed 29528443 ↗

Individual participant data

Plan to share: No

08

Registry details

Key details

Study ID
NCT02685605
Lead sponsor
Universitätsmedizin Mannheim
Collaborators
Carl Zeiss Meditec AG, University of California, Los Angeles
Responsible party
Frank A. Giordano (PI (Chair), Heidelberg University) — Principal investigator
First posted
Feb 19, 2016
Start date
Dec 9, 2016
Primary completion
Nov 2025 (estimated)
Completion
Jun 2026 (estimated)
Last update
Oct 14, 2025

Study contacts

Frank A. Giordano, MD
principal investigator · Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Germany
Kevin Petrecca, MD
principal investigator · Department of Neurosurgery, Montréal Neurological, Institute and Hospital, Montréal, Canada

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

Not currently enrolling

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