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

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ClinicalTrials.gov Identifier: NCT02685605
Recruitment Status : Recruiting
First Posted : February 19, 2016
Last Update Posted : January 23, 2019
Sponsor:
Collaborators:
Carl Zeiss Meditec AG, Oberkochen, Germany
Brain Tumor Imaging, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Information provided by (Responsible Party):
Frank A. Giordano, Universitätsmedizin Mannheim

Tracking Information
First Submitted Date  ICMJE February 5, 2016
First Posted Date  ICMJE February 19, 2016
Last Update Posted Date January 23, 2019
Study Start Date  ICMJE June 2016
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 12, 2016)
Median Progression-Free Survival [ Time Frame: 24 Months ]
Determined according to modified Response Assessment in Neuro-Oncology (RANO) criteria and serial perfusion imaging
Original Primary Outcome Measures  ICMJE
 (submitted: February 14, 2016)
Median Progression-Free Survival [ Time Frame: 24 Months ]
Determined according to updated Response Assessment in Neuro-Oncology (RANO) criteria
Change History Complete list of historical versions of study NCT02685605 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 12, 2016)
  • Median Overall Survival [ Time Frame: 24 Months ]
  • 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
  • OS with respect to Age [ Time Frame: 24 Months ]
    Median overall survival of patients <65 vs. ≥ 65 years
  • 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
  • OS with respect to KPS [ Time Frame: 24 Months ]
    Median overall survival of patients with KPS 80-100% vs. 60-70%
  • 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
  • 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)
  • 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
  • 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)
  • 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)
  • OS with respect to MGMT promoter methylation status [ Time Frame: 24 Months ]
    OS in patients with promoter methylation vs. no promoter methylation
  • 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
  • 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)
  • 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.
  • Radiation-related (acute / early delayed / late) neurotoxicity [ Time Frame: 24 Months ]
    Assessed by regular neurological examinations and serial MRI scans
Original Secondary Outcome Measures  ICMJE
 (submitted: February 14, 2016)
  • Median Overall Survival [ Time Frame: 24 Months ]
  • PFS within a 1-2 cm margin around the cavity [ Time Frame: 24 Months ]
    Determined by serial contrast-enhanced MRI scans using RANO criteria
  • OS with respect to Age [ Time Frame: 24 Months ]
    Median overall survival of patients <65 vs. ≥ 65 years
  • PFS with respect to Age [ Time Frame: 24 Months ]
    Progression-free survival of patients <65 vs. ≥ 65 years; determined according to updated Response Assessment in Neuro-Oncology (RANO) criteria
  • OS with respect to KPS [ Time Frame: 24 Months ]
    Median overall survival of patients with KPS 80-100% vs. 60-70%
  • PFS with respect to KPS [ Time Frame: 24 Months ]
    Progression-free survival of patients with KPS 80-100% vs. 60-70%; determined according to updated Response Assessment in Neuro-Oncology (RANO) criteria
  • 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)
  • 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 updated Response Assessment in Neuro-Oncology (RANO) criteria
  • 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)
  • 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 updated Response Assessment in Neuro-Oncology (RANO) criteria 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)
  • OS with respect to MGMT promoter methylation status [ Time Frame: 24 Months ]
    OS in patients with promoter methylation vs. no promoter methylation
  • 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 updated Response Assessment in Neuro-Oncology (RANO) criteria
  • 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)
  • 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.
  • IORT related (acute / early delayed / late) toxicity [ Time Frame: 24 Months ]
    Assessed by regular neurological examinations and serial MRI scans
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Intraoperative Radiotherapy in Newly Diagnosed Glioblastoma Multiforme
Official Title  ICMJE A Multicenter Randomized Phase III Trial on INTraoperative RAdiotherapy in Newly Diagnosed GliOblastoma Multiforme (INTRAGO II)
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Glioblastoma
Intervention  ICMJE
  • Procedure: Standard surgery (neuronavigation-guided)
  • 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).
Study Arms  ICMJE
  • 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).
    Interventions:
    • Procedure: Standard surgery (neuronavigation-guided)
    • 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).
    Interventions:
    • Procedure: Standard surgery (neuronavigation-guided)
    • Radiation: Radiochemotherapy
    • Drug: Temozolomide
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 14, 2016)
314
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 2021
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Anke Keller +49621383 ext 6020 studien.strahlen@medma.uni-heidelberg.de
Contact: Anette Kipke +49621383 ext 6020 studien.strahlen@medma.uni-heidelberg.de
Listed Location Countries  ICMJE Canada,   Germany,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02685605
Other Study ID Numbers  ICMJE INTRAGO-II
ARO-2016-1 ( Other Identifier: Working Party for Radiation Oncology (ARO) of the German Cancer Society (DKG) )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Frank A. Giordano, Universitätsmedizin Mannheim
Study Sponsor  ICMJE Universitätsmedizin Mannheim
Collaborators  ICMJE
  • Carl Zeiss Meditec AG, Oberkochen, Germany
  • Brain Tumor Imaging, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Investigators  ICMJE
Principal Investigator: Frank A. Giordano, MD Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
Principal Investigator: Kevin Petrecca, MD Department of Neurosurgery, Montréal Neurological, Institute and Hospital, Montréal, Canada
PRS Account Universitätsmedizin Mannheim
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP