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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2017 by Universitätsmedizin Mannheim
Sponsor:
Collaborator:
Carl Zeiss Meditec AG, Oberkochen, Germany
Information provided by (Responsible Party):
Frederik Wenz, Universitätsmedizin Mannheim
ClinicalTrials.gov Identifier:
NCT02685605
First received: February 5, 2016
Last updated: March 16, 2017
Last verified: March 2017
  Purpose
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 Intervention Phase
Glioblastoma
Procedure: Standard surgery (neuronavigation-guided)
Radiation: Intraoperative radiotherapy
Radiation: Radiochemotherapy
Drug: Temozolomide
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Multicenter Randomized Phase III Trial on INTraoperative RAdiotherapy in Newly Diagnosed GliOblastoma Multiforme (INTRAGO II)

Resource links provided by NLM:


Further study details as provided by Universitätsmedizin Mannheim:

Primary Outcome Measures:
  • 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:
  • 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


Estimated Enrollment: 314
Study Start Date: June 2016
Estimated Study Completion Date: February 2021
Estimated Primary Completion Date: June 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 (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).
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 (neuronavigation-guided) 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).

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥18 and ≤ 70 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 informed consent 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 ≥ 145.000/μL
    • WBC ≥ 4.000/μL
    • Hemoglobin ≥ 12.0 g/dL

    Liver Function:

    • ASAT and ALAT ≤ 1.5 times ULN
    • ALP ≤ 2.5 times ULN
    • Total Serum Bilirubin < 1 times ULN

    Renal Function:

    • Serum Creatinine ≤ 1.5 times ULN

    Inclusion Criteria Related to Surgery:

  8. IORT must be technically feasible
  9. Histologically confirmed (frozen section) GBM (WHO grade IV)

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. Use of alternating electrical fields (e.g., Novo-TTF)
  5. History of cancers or other comorbidities that limit life expectancy to less than five years
  6. Previous therapy with anti-angiogenic substances (such as bevacizumab)
  7. Technical impossibility to use MRI or known allergies against MRI and/or CT contrast agents
  8. Participation in other clinical trials testing cancer-derived investigational agents/procedures.
  9. Pregnant or breast feeding patients
  10. Fertile patients refusing to use safe contraceptive methods during the study

    Exclusion Criteria Related to Surgery:

  11. Active egress of fluids from a ventricular defect
  12. In-field risk organs and/or IORT dose >8 Gy to any risk organ
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02685605

Contacts
Contact: Anke Keller +49621383 ext 6020 studien.strahlen@medma.uni-heidelberg.de
Contact: Anette Kipke +49621383 ext 6020 studien.strahlen@medma.uni-heidelberg.de

Locations
United States, New York
Lenox Hill Hospital, Hofstra Northwell School of Medicine Not yet recruiting
New York, New York, United States, 10028
Contact: Tamika A Wong, MPH    212-434-4836    twong4@northwell.edu   
Principal Investigator: John A. Boockvar, MD         
United States, West Virginia
West Virginia University Not yet recruiting
Morgantown, West Virginia, United States, 26506-9260
Contact: Joseph Brunetti    304-293-7360      
Principal Investigator: Christopher P Cifarelli, MD, PhD, FAANS, FACS         
Germany
Department of Radiotherapy University Hospital Mannheim Recruiting
Mannheim, Germany, 68167
Contact: Frederik Wenz, Prof. Dr. med.    00496213834960    frederik.wenz@medma.uni-heidelberg.de   
Sponsors and Collaborators
Universitätsmedizin Mannheim
Carl Zeiss Meditec AG, Oberkochen, Germany
Investigators
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
  More Information

Publications:
Responsible Party: Frederik Wenz, Co-PI, Universitätsmedizin Mannheim
ClinicalTrials.gov Identifier: NCT02685605     History of Changes
Other Study ID Numbers: INTRAGO-II
ARO-2016-1 ( Other Identifier: Working Party for Radiation Oncology (ARO) of the German Cancer Society (DKG) )
Study First Received: February 5, 2016
Last Updated: March 16, 2017

Keywords provided by Universitätsmedizin Mannheim:
Glioblastoma
Intraoperative Radiotherapy
Radiotherapy Dose Escalation

Additional relevant MeSH terms:
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
Dacarbazine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents

ClinicalTrials.gov processed this record on March 28, 2017