An Open Label Non- Randomized Multicentric Phase II Study of Sunitinib Before and During Radiotherapy in Newly Diagnosed Biopsy-only Glioblastoma Patients
Sunitinib (SU 11248) is a small molecule with good oral bioavailability that inhibits
multiple receptor tyrosine kinases (RTKs) expressed on diverse tumour cells: VEGFR, PDGFR,
KIT, FLT3 and endothelium, pericytes, and stroma VEGFR, PDGFR. It has the potential to
inhibit directly the growth of multiple tumour types by the inhibition of multiple targets
and to act negatively on antiangiogenesis.
Glioblastoma (GB) is the most frequent brain tumour. Standard treatment after surgical
resection is radiation therapy with Temozolomide. But patients who can afford only a biopsy
of their lesion due to the location in eloquent areas of their tumour or multifocality,
don't get benefit from such treatment and their median survival is in the best case of only
9 months. These patients constitute 30% of Glioblastomas. Clinical trials in this setting
are required as patients should be treated immediately after the biopsy to prevent
These patients are ideal to test new promising therapies. Their survival is similar to
recurrent patients. The evaluation of response is easier as it's possible to avoid the
confounding post-surgical changes that interfere with the evaluation of treatment efficacy
in terms of tumour size reduction.. Furthermore, neo adjuvant treatment before radiotherapy
has shown not to worsen their survival.
Glioblastoma is a tumour rich in molecular abnormalities. PDGFRs are important in growth
signalling pathways and neoangiogenesis of gliomas. PDGF ligands and PDGFR-alfa are
expressed in most human gliomas, while PDGFR-beta is expressed in glioma cells and tumor
endothelial cells, PDFGR-α is expressed in most human gliomas. Imatinib mesylate exhibited
antiglioma activity in preclinical studies, sensitizes glioma cells to radiation injury, and
combined with hydroxyurea has shown promising results in the recurrent setting.
Moreover gliomas are among the most angiogenic cancers. VEGF/VEGFR-2 is the most prominent
angiogenic signalling pathway. Its inhibition either by a neutralizing anti-VEGF antibody,
anti-sense VEGF constructs, expression of a dominant-negative mutant form of VEGFR-2 (a
specific small molecule inhibitor of the VEGFR-2 tyrosine kinase) or neutralizing
anti-VEGFR-2 antibody has resulted in suppression of experimental malignant glioma growth.
VEGF has been the focus in the development of glioma-targeted therapies. Recently
Bevacizumab has shown to be active in phase II studies.
For these reasons, Sunitinib seems to be a promising treatment fo The objective of this
proposal is to evaluate the clinical activity of Sunitinib as first line therapy in patients
who have measurable disease and to evaluate the safety of Sunitinib with radiation therapy.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Objective response rate to Sunitinib therapy
Clinical activity in terms of clinical response (RANO criteria) after 2, 4 weeks cycles of Sunitinib treatment.
8 weeks after treatment
Carmen Balaña, Coordiantor
Hospital Germans Trias i Pujol, Badalona, Spain
Spain: Spanish Agency of Medicines