Bevacizumab, Radiotherapy and Temozolomide Safety study in biopsied or resected primary GBM patients

Median survival for patients with a newly diagnosed GBM is 12.1 months after
resection of the tumor to the maximum extent, followed by 60 Gy irradiation in
30 x 2 Gy fractions. Maximal surgical resection is not feasible in a sub-group
of patients due to the localization of their tumor, resulting in poorer
prognosis. In a selected group of patients the median survival was 14.6 months
when resection was followed by radiotherapy in combination with temozolomide
during and thereafter temozolomide 6 monthly cycles. Chemoradiotherapy with
temozolomide is the current standard treatment for GBM in our center. New
combination treatments are required to lengthen survival of GBM patients. This
trial utilizes the anti-edema effect of bevacizumab and its vascular
normalization response to enhance the efficacy of chemoradiotherapy in resected
and irresectable primary GBM patients.

Primary objective is determination of safety of combination of standard
treatment with 3 bevacizumab infusions, followed by the standard adjuvant
cycles of temozolomide. Secondary objectives: determination of: efficacy,
classical response end-points, tumor imaging biomarkers and tissue samples
biomarkers.

The study will employ a prospective observational study in one tertiary
referral center for brain tumors in the Amsterdam area, the Netherlands, with
multiple time measures.

Study population will be treated with standard GBM chemoradiotherapy schedule
plus additional 3 infusions of the angiogenesis inhibitor bevacizumab at a dose
of 10 mg/kg during irradiation (e.g. one dose every 2 weeks during 6 weeks
radiotherapy).

It is safe to add bevacizumab to the current practice of chemoradiotherapy in
solid tumors, based on recent literature [Crane, 2006; Czito, 2007; Vredenburgh
2007] and preliminary results from a number of ongoing studies [Lai A et al,
submitted; Gutin PH et al, submitted; Genentech, unpublished data]. In this
study population we expect similar safety results as under standard
chemoradiotherapy *Stupp regimen*. As estimated by power analysis, for n=20
this will imply 5 or less Grade 3/4 NCI toxicity events during chemoradiation
and 10 or less Grade 3/4 NCI toxicity events during the entire treatment
schedule.