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

• ClinicalTrials.gov Identifier: NCT02685605
• Recruitment Status: Recruiting
• First Posted: February 19, 2016
• Last Update Posted: May 11, 2023
• Sponsor: Universitätsmedizin Mannheim
• Collaborators: Carl Zeiss Meditec AG; University of California, Los Angeles
• Information provided by (Responsible Party): Frank A. Giordano, University Hospital, Bonn

Tracking Information

• First Submitted Date: February 5, 2016
• First Posted Date: February 19, 2016
• Last Update Posted Date: May 11, 2023
• Actual Study Start Date: December 9, 2016
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (submitted: February 14, 2016)

Median Progression-Free Survival [ Time Frame: 24 Months ]

Determined according to updated Response Assessment in Neuro-Oncology (RANO) criteria

Current Secondary Outcome Measures (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 (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: Intraoperative Radiotherapy in Newly Diagnosed Glioblastoma Multiforme
• Official Title: 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: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: 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.
  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

• 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
  • 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
  • Radiation: Radiochemotherapy
  • Drug: Temozolomide

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.
• Alvarez DSA, Watson PGF, Popovic M, Heng VJ, Evans MDC, Panet-Raymond V, Seuntjens J. Evaluation of Dosimetry Formalisms in Intraoperative Radiotherapy of Glioblastoma: Dosimetry formalisms in IORT of glioblastoma. Int J Radiat Oncol Biol Phys. 2023 May 5:S0360-3016(23)00439-X. doi: 10.1016/j.ijrobp.2023.04.031. Online ahead of print.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 14, 2016): 314
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 2024
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: Brazil, Canada, China, Germany, Korea, Republic of, Spain, United Kingdom, United States
• Removed Location Countries: Peru

Administrative Information

• NCT Number: 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) )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Frank A. Giordano, University Hospital, Bonn
• Original Responsible Party: Frederik Wenz, Universitätsmedizin Mannheim, Co-PI
• Current Study Sponsor: Universitätsmedizin Mannheim
• Original Study Sponsor: Same as current

Collaborators

• Carl Zeiss Meditec AG
• University of California, Los Angeles

Investigators

• 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

• PRS Account: Universitätsmedizin Mannheim
• Verification Date: May 2023