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Avastin Plus Radiotherapy in Elderly Patients With Glioblastoma

Phase 2
65 Years
Open (Enrolling)

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Trial Information

Avastin Plus Radiotherapy in Elderly Patients With Glioblastoma

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.


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.

Inclusion 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

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 (GliadelĀ®) 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

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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

median overall survival

Outcome Description:

median overall survival

Outcome Time Frame:

1 year

Safety Issue:


Principal Investigator

01 Studienregister MasterAdmins

Investigator Role:

Study Director

Investigator Affiliation:

UniversitaetsSpital Zuerich


Switzerland: Swissmedic

Study ID:




Start Date:

October 2011

Completion Date:

September 2016

Related Keywords:

  • Glioblastoma
  • Glioblastoma