Clinical trial NCT02685605: 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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Glioblastoma
Keywords: Glioblastoma
Intraoperative Radiotherapy
Radiotherapy Dose Escalation
Lead sponsor: Universitätsmedizin Mannheim
Sponsor class: OTHER
Collaborators: name: Carl Zeiss Meditec AG
name: University of California, Los Angeles
First posted: 2016-02-19
Enrollment: 314
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Median Progression-Free Survival
timeFrame: 24 Months
Secondary outcomes:
measure: Median Overall Survival
timeFrame: 24 Months
measure: PFS within a 1-2 cm margin around the cavity
timeFrame: 24 Months
measure: OS with respect to Age
timeFrame: 24 Months
measure: PFS with respect to Age
timeFrame: 24 Months
measure: OS with respect to KPS
timeFrame: 24 Months
measure: PFS with respect to KPS
timeFrame: 24 Months
measure: OS with respect to thickness of anticipated T1-Gd-enhancing (remaining) tumor margin
timeFrame: 24 Months
measure: PFS with respect to thickness of anticipated T1-Gd-enhancing (remaining) tumor margin
timeFrame: 24 Months
measure: OS with respect to extent of resection
timeFrame: 24 Months
measure: PFS with respect to extent of resection
timeFrame: 24 Months
measure: OS with respect to MGMT promoter methylation status
timeFrame: 24 Months
measure: PFS with respect to MGMT promoter methylation status
timeFrame: 24 Months
measure: Quality of Life (QoL) questionnaire
timeFrame: 24 Months
measure: Activities of daily living (ADL), assessed using the Barthel Index (Mahoney & Barthel, 1965).
timeFrame: 24 Months
measure: Radiation-related (acute / early delayed / late) neurotoxicity
timeFrame: 24 Months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Barrow Neurological Institute (SJHMC)
state: Arizona
city: Maywood
country: United States
facility: Stritch School of Medicine Loyola University
state: Illinois
city: Lake Success
country: United States
facility: Long Island Jewish Medical Center, North Shore University Hospital
state: New York
city: New York
country: United States
facility: Lenox Hill Hospital, Hofstra Northwell School of Medicine
state: New York
city: Morgantown
country: United States
facility: West Virginia University
state: West Virginia
city: São Paulo
country: Brazil
facility: Hospital Alemão Oswaldo Cruz
city: Montréal
country: Canada
facility: Montreal Neurological Institute and Hospital
state: Quebec
city: Beijing
country: China
facility: Beijing Tian Tan Hospital, Capital Medical University
city: Augsburg
country: Germany
facility: University Hospital Augsburg
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin
city: Leipzig
country: Germany
facility: St. Georg Hospital
city: Mannheim
country: Germany
facility: University Hospital Mannheim
city: Munich
country: Germany
facility: Technical University of Munich (TUM), Department of Radiation Oncology
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart
city: Wuppertal
country: Germany
facility: Helios University Hospital Wuppertal
city: Seoul
country: Korea, Republic of
facility: Gangnam Severance Hospital, Yonsei University College of Medicine
city: Barcelona
country: Spain
facility: Catalan Institute of Oncology (ICO)
city: Córdoba
country: Spain
facility: Hospital Reina Sofia
city: London
country: United Kingdom
facility: The London Clinic
Study officials:
affiliation: Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Germany
name: Frank A. Giordano, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Neurosurgery, Montréal Neurological, Institute and Hospital, Montréal, Canada
name: Kevin Petrecca, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.