Avastin Plus Radiotherapy in Elderly Patients With Glioblastoma (ARTE)
Primary Purpose
Glioblastoma
Status
Completed
Phase
Phase 2
Locations
Switzerland
Study Type
Interventional
Intervention
Bevacizumab
Radiation therapy
Sponsored by
About this trial
This is an interventional treatment trial for Glioblastoma
Eligibility Criteria
Inclusion criteria: Diagnosis: newly diagnosed glioblastoma in elderly patients
- Signed informed consent
- Age > 65 years
- Newly diagnosed supratentorial glioblastoma
- Eligible for first infusion of bevacizumab > 28 and > 49 days after surgery for glioblastoma
- Karnofsky performance score 60 or more
- Paraffin-embedded tissue for central pathology review
- Stable or decreasing corticosteroid dose within 5 days prior to enrolment
- Adequate haematological function:
- Adequate liver function
- Adequate renal function
Exclusion criteria:
- Karnofsky performance score 50 or less
- Evidence of recent hemorrhage on postoperative brain MRI
- Tumor with infiltration of retina, optic nerve, optic chiasm or brainstem
- Any prior chemotherapy including carmustine-containing wafers (Gliadel®) or immunotherapy for glioblastoma or lower grade astrocytomas
- Any prior radiotherapy to the brain or prior radiotherapy resulting in a potential overlap in the radiation field
- Inadequately controlled hypertension
- History of hypertensive crisis or hypertensive encephalopathy
- New York Heart Association (NYHA) grade II or higher congestive heart failure
- Myocardial infarction or unstable angina within 6 months prior to enrolment
- Stroke or transitory ischemic attack within 6 months prior to enrolment
- Other significant vascular disease within 6 months prior to enrolment
- History of = grade 2 haemoptysis within 1 month prior to enrolment
- Bleeding diathesis or coagulopathy in the absence of therapeutic anticoagulation
- Major surgical procedure, open biopsy, intracranial biopsy, ventriculoperitoneal shunt or significant traumatic injury within 28 days prior to first dose of bevacizumab
- Core biopsy (excluding intracranial biopsy) or other minor surgical procedure within 7 days prior to first dose of bevacizumab
- Abdominal fistula or gastrointestinal perforation within 6 months prior to enrolment
- Intracranial abscess within 6 months prior to enrolment
- Serious non-healing wound, active ulcer or untreated bone fracture
- Pregnancy or lactation
- Fertile women < 2 years after last menstruation and men unwilling or unable to use effective means of contraception
- Active malignancy that may interfere with the study treatment at the investigator?s and PI discretion
Sites / Locations
- Department of Neurology, University Hospital Zurich
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Experimental
Arm Label
Radiotherapy
Radiotherapy plus Bevacizumab
Arm Description
Radiotherapy
Radiotherapy plus Bevacizumab
Outcomes
Primary Outcome Measures
median overall survival
median overall survival
Secondary Outcome Measures
progression-free survival
progression-free survival after 6 months
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01443676
Brief Title
Avastin Plus Radiotherapy in Elderly Patients With Glioblastoma
Acronym
ARTE
Official Title
Avastin Plus Radiotherapy in Elderly Patients With Glioblastoma
Study Type
Interventional
2. Study Status
Record Verification Date
October 2016
Overall Recruitment Status
Completed
Study Start Date
October 2011 (undefined)
Primary Completion Date
August 2015 (Actual)
Study Completion Date
August 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Zurich
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of this study is to explore the efficacy of bevacizumab combined with radiotherapy compared with radiotherapy alone in the treatment of newly diagnosed glioblastoma in the elderly.
Trial with medicinal product
Detailed Description
This is a randomized (2:1), explorative, parallel-group, open-label, phase II trial in elderly patients with newly diagnosed glioblastoma. In the control arm, patients will receive radiotherapy, in the experimental arm, patients will receive bevacizumab during and after radiotherapy until progression.
Background:
For decades, neurosurgical resection and postoperative radiotherapy have been the cornerstones of treatment for patients with glioblastoma. Most chemotherapeutic agents showed little or no activity in malignant glioma patients, with the possible exception of nitrosoureas. This has changed with the introduction of temozolomide, first shown to be active in recurrent disease (Yung et al. 2000) and more recently in newly diagnosed glioblastoma (Stupp et al. 2005, 2009). This EORTC 26981-22981 NCIC CE.3 trial demonstrated an increase in median survival from 12.1 to 14.6 months and of the 2 year survival rate from 10% to 26% in patients receiving radiotherapy plus temozolomide compared with radiotherapy alone. Notably patients with tumors exhibiting methylation of the promoter region of the O6-methylguanine DNA methyltransferase (MGMT) gene showed a striking benefit from temozolomide (Hegi et al. 2005). Yet, inclusion in this trial was limited to patients up to the age of 70, and subgroup analyses demonstrated that younger patients were more likely to derive benefit from combined modality treatment than older patients. Thus, radiotherapy alone is still the standard of care in the elderly. The value of radiotherapy has been confirmed in a small randomized trial comparing best supportive care versus radiotherapy alone: median survival was 29 weeks with radiotherapy compared with 16.9 weeks with supportive care only (Keime-Guibert et al. 2007). Based on the overall shorter survival in elderly patients, hypofractionated radiotherapy has been explored and shown to be equieffective in patients aged 65-70 years and more (Roa et al. 2004). Two randomized trials presented in abstract form at the Annual Meeting of the American Society of Clinical Oncology in June 2010 failed to show superiority of primary temozolomide chemotherapy alone over radiotherapy alone in elderly patients (Malmstrom et al. 2010, Wick et al. 2010a). In fact, the German NOA-08 trial even showed that primary temozolomide alone is not non-inferior to primary radiotherapy alone (Wick et al. 2010a). A concomitant treatment strategy is currently evaluated in a NCIC-EORTC randomized trial. Further, the Nordic trial corroborated the equieffectiveness of an accelerated radiotherapy protocol of 40 Gy administered in 15 fractions versus the standard fractionation of 30 x 2 Gy. Altogether, these clinical data justify the exploration of new, temozolomide-free first-line treatment strategies in glioblastoma.
Glioblastomas express high levels of vascular endothelial growth factor (VEGF) and are highly vascularized tumors. The VEGF antibody, bevacizumab, has recently gained approval in patients with recurrent glioblastoma in the USA and in Switzerland in 2009, but not in the EU. Its role in the first-line treatment of glioblastoma is currently being evaluated in randomized trials. There is limited data on the safety and efficacy of bevacizumab in elderly patients with glioblastoma, although the safety profile of bevacizumab in elderly patients with other types of cancer, e.g., lung cancer is favorable. There are ample rationales for combining bevacizumab with radiotherapy, including the induction of VEGF by radiotherapy and the concept of vascular normalization resulting in increased oxygenation and thus sensitivity to radiotherapy. Thus, bevacizumab is not only expected to inhibit angiogenesis, but may also exhibit additive or synergistic interactions with radiotherapy and further impair tumor growth. Altogether, this study seeks to explore, using a dedicated neuroimaging protocol, the possibility that bevacizumab enhances the effects of radiotherapy via the process of vascular normalization.
The purpose of this study is to explore the efficacy of bevacizumab combined with radiotherapy compared with radiotherapy alone in the treatment of newly diagnosed glioblastoma in the elderly.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
75 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Radiotherapy
Arm Type
Active Comparator
Arm Description
Radiotherapy
Arm Title
Radiotherapy plus Bevacizumab
Arm Type
Experimental
Arm Description
Radiotherapy plus Bevacizumab
Intervention Type
Drug
Intervention Name(s)
Bevacizumab
Other Intervention Name(s)
Avastin
Intervention Description
Bevacizumab will be added to radiotherapy
Intervention Type
Radiation
Intervention Name(s)
Radiation therapy
Intervention Description
Radiation therapy
Primary Outcome Measure Information:
Title
median overall survival
Description
median overall survival
Time Frame
1 year
Secondary Outcome Measure Information:
Title
progression-free survival
Description
progression-free survival after 6 months
Time Frame
progression-free survival after 6 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria: Diagnosis: newly diagnosed glioblastoma in elderly patients
Signed informed consent
Age > 65 years
Newly diagnosed supratentorial glioblastoma
Eligible for first infusion of bevacizumab > 28 and > 49 days after surgery for glioblastoma
Karnofsky performance score 60 or more
Paraffin-embedded tissue for central pathology review
Stable or decreasing corticosteroid dose within 5 days prior to enrolment
Adequate haematological function:
Adequate liver function
Adequate renal function
Exclusion criteria:
Karnofsky performance score 50 or less
Evidence of recent hemorrhage on postoperative brain MRI
Tumor with infiltration of retina, optic nerve, optic chiasm or brainstem
Any prior chemotherapy including carmustine-containing wafers (Gliadel®) or immunotherapy for glioblastoma or lower grade astrocytomas
Any prior radiotherapy to the brain or prior radiotherapy resulting in a potential overlap in the radiation field
Inadequately controlled hypertension
History of hypertensive crisis or hypertensive encephalopathy
New York Heart Association (NYHA) grade II or higher congestive heart failure
Myocardial infarction or unstable angina within 6 months prior to enrolment
Stroke or transitory ischemic attack within 6 months prior to enrolment
Other significant vascular disease within 6 months prior to enrolment
History of = grade 2 haemoptysis within 1 month prior to enrolment
Bleeding diathesis or coagulopathy in the absence of therapeutic anticoagulation
Major surgical procedure, open biopsy, intracranial biopsy, ventriculoperitoneal shunt or significant traumatic injury within 28 days prior to first dose of bevacizumab
Core biopsy (excluding intracranial biopsy) or other minor surgical procedure within 7 days prior to first dose of bevacizumab
Abdominal fistula or gastrointestinal perforation within 6 months prior to enrolment
Intracranial abscess within 6 months prior to enrolment
Serious non-healing wound, active ulcer or untreated bone fracture
Pregnancy or lactation
Fertile women < 2 years after last menstruation and men unwilling or unable to use effective means of contraception
Active malignancy that may interfere with the study treatment at the investigator?s and PI discretion
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
01 Studienregister MasterAdmins
Organizational Affiliation
UniversitaetsSpital Zuerich
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Michael Weller, Professor
Organizational Affiliation
University Hospital Zurich, Division of Neurology
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Neurology, University Hospital Zurich
City
Zurich
Country
Switzerland
12. IPD Sharing Statement
Citations:
PubMed Identifier
32967939
Citation
Wirsching HG, Roelcke U, Weller J, Hundsberger T, Hottinger AF, von Moos R, Caparrotti F, Conen K, Remonda L, Roth P, Ochsenbein A, Tabatabai G, Weller M. MRI and 18FET-PET Predict Survival Benefit from Bevacizumab Plus Radiotherapy in Patients with Isocitrate Dehydrogenase Wild-type Glioblastoma: Results from the Randomized ARTE Trial. Clin Cancer Res. 2021 Jan 1;27(1):179-188. doi: 10.1158/1078-0432.CCR-20-2096. Epub 2020 Sep 23.
Results Reference
derived
PubMed Identifier
29648580
Citation
Wirsching HG, Tabatabai G, Roelcke U, Hottinger AF, Jorger F, Schmid A, Plasswilm L, Schrimpf D, Mancao C, Capper D, Conen K, Hundsberger T, Caparrotti F, von Moos R, Riklin C, Felsberg J, Roth P, Jones DTW, Pfister S, Rushing EJ, Abrey L, Reifenberger G, Held L, von Deimling A, Ochsenbein A, Weller M. Bevacizumab plus hypofractionated radiotherapy versus radiotherapy alone in elderly patients with glioblastoma: the randomized, open-label, phase II ARTE trial. Ann Oncol. 2018 Jun 1;29(6):1423-1430. doi: 10.1093/annonc/mdy120.
Results Reference
derived
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Avastin Plus Radiotherapy in Elderly Patients With Glioblastoma
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