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Avastin Plus Radiotherapy in Elderly Patients With Glioblastoma (ARTE)

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ClinicalTrials.gov Identifier: NCT01443676
Recruitment Status : Completed
First Posted : September 30, 2011
Last Update Posted : November 1, 2016
Sponsor:
Information provided by (Responsible Party):
University of Zurich

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

Condition or disease Intervention/treatment Phase
Glioblastoma Drug: Bevacizumab Radiation: Radiation therapy Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 75 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Avastin Plus Radiotherapy in Elderly Patients With Glioblastoma
Study Start Date : October 2011
Actual Primary Completion Date : August 2015
Actual Study Completion Date : August 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Bevacizumab

Arm Intervention/treatment
Active Comparator: Radiotherapy
Radiotherapy
Radiation: Radiation therapy
Radiation therapy

Experimental: Radiotherapy plus Bevacizumab
Radiotherapy plus Bevacizumab
Drug: Bevacizumab
Bevacizumab will be added to radiotherapy
Other Name: Avastin




Primary Outcome Measures :
  1. median overall survival [ Time Frame: 1 year ]
    median overall survival


Secondary Outcome Measures :
  1. progression-free survival [ Time Frame: progression-free survival after 6 months ]
    progression-free survival after 6 months



Information from the National Library of Medicine

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Ages Eligible for Study:   65 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria: Diagnosis: newly diagnosed glioblastoma in elderly patients

  1. Signed informed consent
  2. Age > 65 years
  3. Newly diagnosed supratentorial glioblastoma
  4. Eligible for first infusion of bevacizumab > 28 and > 49 days after surgery for glioblastoma
  5. Karnofsky performance score 60 or more
  6. Paraffin-embedded tissue for central pathology review
  7. Stable or decreasing corticosteroid dose within 5 days prior to enrolment
  8. Adequate haematological function:
  9. Adequate liver function
  10. Adequate renal function

Exclusion criteria:

  1. Karnofsky performance score 50 or less
  2. Evidence of recent hemorrhage on postoperative brain MRI
  3. Tumor with infiltration of retina, optic nerve, optic chiasm or brainstem
  4. Any prior chemotherapy including carmustine-containing wafers (Gliadel®) or immunotherapy for glioblastoma or lower grade astrocytomas
  5. Any prior radiotherapy to the brain or prior radiotherapy resulting in a potential overlap in the radiation field
  6. Inadequately controlled hypertension
  7. History of hypertensive crisis or hypertensive encephalopathy
  8. New York Heart Association (NYHA) grade II or higher congestive heart failure
  9. Myocardial infarction or unstable angina within 6 months prior to enrolment
  10. Stroke or transitory ischemic attack within 6 months prior to enrolment
  11. Other significant vascular disease within 6 months prior to enrolment
  12. History of = grade 2 haemoptysis within 1 month prior to enrolment
  13. Bleeding diathesis or coagulopathy in the absence of therapeutic anticoagulation
  14. Major surgical procedure, open biopsy, intracranial biopsy, ventriculoperitoneal shunt or significant traumatic injury within 28 days prior to first dose of bevacizumab
  15. Core biopsy (excluding intracranial biopsy) or other minor surgical procedure within 7 days prior to first dose of bevacizumab
  16. Abdominal fistula or gastrointestinal perforation within 6 months prior to enrolment
  17. Intracranial abscess within 6 months prior to enrolment
  18. Serious non-healing wound, active ulcer or untreated bone fracture
  19. Pregnancy or lactation
  20. Fertile women < 2 years after last menstruation and men unwilling or unable to use effective means of contraception
  21. Active malignancy that may interfere with the study treatment at the investigator?s and PI discretion

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01443676


Locations
Switzerland
Department of Neurology, University Hospital Zurich
Zurich, Switzerland
Sponsors and Collaborators
University of Zurich
Investigators
Study Director: 01 Studienregister MasterAdmins UniversitaetsSpital Zuerich
Principal Investigator: Michael Weller, Professor University Hospital Zurich, Division of Neurology

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: University of Zurich
ClinicalTrials.gov Identifier: NCT01443676     History of Changes
Other Study ID Numbers: ARTE
First Posted: September 30, 2011    Key Record Dates
Last Update Posted: November 1, 2016
Last Verified: October 2016

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
Bevacizumab
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents