Study of Sunitinib Before and During Radiotherapy in Newly Diagnosed Biopsy-only Glioblastoma Patients
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||An Open Label Non- Randomized Multicentric Phase II Study of Sunitinib Before and During Radiotherapy in Newly Diagnosed Biopsy-only Glioblastoma Patients|
- Objective response rate to Sunitinib therapy [ Time Frame: 8 weeks after treatment ] [ Designated as safety issue: No ]Clinical activity in terms of clinical response (RANO criteria) after 2, 4 weeks cycles of Sunitinib treatment.
- Safety of Sunitinib with Radiation therapy [ Time Frame: 14 weeks ] [ Designated as safety issue: Yes ]Percentage of patients without neurological damage after the first 14 weeks of the treatment
- Assess the number of patients without neurological deterioration before radiation [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
- Evaluation of progression free survival [ Time Frame: participants are followed until progression ] [ Designated as safety issue: No ]After radiation therapy, Sunitinib will be continued until progression. (Evaluation of progression free survival)
- Overall survival [ Time Frame: participants are followed until death ] [ Designated as safety issue: No ]
|Study Start Date:||June 2009|
|Study Completion Date:||January 2012|
|Primary Completion Date:||December 2011 (Final data collection date for primary outcome measure)|
Experimental: Sunitinib plus radiothery
Sunitinib 37.5mg/m2/dRadiation: Radiation
Radiation therapy (60Gy) 2 Gy per day during 30 days
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 neurological deterioration.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01100177
|Grupo Español de Investigacion en Neurooncologia|
|Madrid, Spain, 28001|
|Study Chair:||Carmen Balaña, Coordiantor||Hospital Germans Trias i Pujol, Badalona, Spain|