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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02685605
Recruitment Status : Recruiting
First Posted : February 19, 2016
Last Update Posted : May 11, 2023
Sponsor:
Collaborators:
Carl Zeiss Meditec AG
University of California, Los Angeles
Information provided by (Responsible Party):
Frank A. Giordano, University Hospital, Bonn

Study Description
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Brief 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.

Condition or disease Intervention/treatment Phase
Glioblastoma Procedure: Standard surgery Radiation: Intraoperative radiotherapy Radiation: Radiochemotherapy Drug: Temozolomide Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 314 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter Randomized Phase III Trial on INTraoperative RAdiotherapy in Newly Diagnosed GliOblastoma Multiforme (INTRAGO II)
Actual Study Start Date : December 9, 2016
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : March 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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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 Name: 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).


Outcome Measures
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Primary Outcome Measures :
  1. Median Progression-Free Survival [ Time Frame: 24 Months ]
    Determined according to modified Response Assessment in Neuro-Oncology (RANO) criteria and serial perfusion imaging


Secondary Outcome Measures :
  1. Median Overall Survival [ Time Frame: 24 Months ]
  2. PFS within a 1-2 cm margin around the cavity [ Time Frame: 24 Months ]
    Determined by serial contrast-enhanced MRI scans using modified RANO criteria and serial perfusion imaging

  3. OS with respect to Age [ Time Frame: 24 Months ]
    Median overall survival of patients <65 vs. ≥ 65 years

  4. PFS with respect to Age [ Time Frame: 24 Months ]
    Progression-free survival of patients <65 vs. ≥ 65 years; determined according to modified RANO criteria and serial perfusion imaging

  5. OS with respect to KPS [ Time Frame: 24 Months ]
    Median overall survival of patients with KPS 80-100% vs. 60-70%

  6. PFS with respect to KPS [ Time Frame: 24 Months ]
    Progression-free survival of patients with KPS 80-100% vs. 60-70%; determined according to modified RANO criteria and serial perfusion imaging

  7. OS with respect to thickness of anticipated T1-Gd-enhancing (remaining) tumor margin [ Time Frame: 24 Months ]
    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)

  8. PFS with respect to thickness of anticipated T1-Gd-enhancing (remaining) tumor margin [ Time Frame: 24 Months ]
    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

  9. OS with respect to extent of resection [ Time Frame: 24 Months ]

    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)

  10. PFS with respect to extent of resection [ Time Frame: 24 Months ]

    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)

  11. OS with respect to MGMT promoter methylation status [ Time Frame: 24 Months ]
    OS in patients with promoter methylation vs. no promoter methylation

  12. PFS with respect to MGMT promoter methylation status [ Time Frame: 24 Months ]
    PFS in patients with promoter methylation vs. no promoter methylation; determined according to modified RANO criteria and serial perfusion imaging

  13. Quality of Life (QoL) questionnaire [ Time Frame: 24 Months ]
    Assessed by European Organization for Research and Treatment (EORTC)- Quality of Life Questionnaires (QLQ C30/BN20)

  14. Activities of daily living (ADL), assessed using the Barthel Index (Mahoney & Barthel, 1965). [ Time Frame: 24 Months ]
    Change in functional outcomes as measured by BI from its baseline value.

  15. Radiation-related (acute / early delayed / late) neurotoxicity [ Time Frame: 24 Months ]
    Assessed by regular neurological examinations and serial MRI scans


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02685605


Contacts
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Contact: Martina Nesper-Brock, PhD +49-621-383 ext 3530 martina.nesper-brock@umm.de
Contact: Clinical Trial Office UMM +49-621-383 ext 3498 strahlentherapie.studien@umm.de

Locations
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Sponsors and Collaborators
Universitätsmedizin Mannheim
Carl Zeiss Meditec AG
University of California, Los Angeles
Investigators
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Principal Investigator: Frank A. Giordano, MD Department of Radiation Oncology, University Hospital Bonn, Univeristy of Bonn, Bonn, Germany
Principal Investigator: Kevin Petrecca, MD Department of Neurosurgery, Montréal Neurological, Institute and Hospital, Montréal, Canada
More Information
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Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Frank A. Giordano, PI (Chair), University Hospital, Bonn
ClinicalTrials.gov Identifier: NCT02685605    
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) )
First Posted: February 19, 2016    Key Record Dates
Last Update Posted: May 11, 2023
Last Verified: May 2023
Keywords provided by Frank A. Giordano, University Hospital, Bonn:
Glioblastoma
Intraoperative Radiotherapy
Radiotherapy Dose Escalation
Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
 Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents