An Open Label Non- Randomized Multicentric Phase II Study of Sunitinib Before and During Radiotherapy in Newly Diagnosed Biopsy-only Glioblastoma Patients
18 Years
75 Years
Both
Glioblastoma
Trial Information
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
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.
Inclusion Criteria:
1. Patients with glioblastoma, non resectable, who have only a biopsy as surgical
treatment.
2. Measurable disease and with contrast capture of 2cm
3. Stable doses of DXM during the week before the inclusion
4. Performance status 0-1-2
5. Age < 75 years
6. MMS > 25/30
7. Barthel index > 50%
8. Surgical incision must have healed before the inclusion
9. Basal MRI done 3 weeks at the most before the beginning of the treatment which has
specified conditions at the protocol.
10. FEVI > 50%
11. Suitable medullar reserve (neutrophils _2000x109/L, platelets _ 100x109/L,
Haemoglobin _ 10 g/dl.)
12. Not previous chemotherapy or radiation treatment.
13. Creatinin < 1,5 times the superior standard limit of the laboratory in charged of
the analysis.
14. Serum Bilirubin < 1, 5/ULN, SGOT y SGPT _ 2,5 times the superior standard limit of
the laboratory in charged of the analysis. Serum alkaline phosphatases < 3/ULN.
15. Effective contraception method in patients and their couple.
16. Informed consent.
Exclusion Criteria:
1. Previous radiation or chemotherapy for the glioma´s treatment.
2. Less than 5 years time from any previous infiltrant neoplasia
3. Serious Cerebral haemorrhage after biopsy
4. Anticomital treatment inducting / inhibiting the CYP3A4 enzyme: fenitoin,
carbamacepzin, phenobarbitone or other drugs that interact with sunitinib metabolism
and that could not be replaced by another drug without interactions with Sunitinib.
5. Pregnancy or lactation.
6. Active or not controlled cardiovascular disease such as hypertension, angor instable,
cardiac congestive failure IInd degree (NYHA), cardiac arrhythmia, previous
myocardium heart attack, up to 1 year before the randomization
7. Currently treatment established with therapeutic doses of derivated anticoagulants of
coumarin (coumarin, warfarin) or a week before the beginning of sunitinib. The
administration of heparins of low molecular weight for TVP's control is allowed
8. Patient with TVP
9. HTA with higher values than 150/100 and not controllable with antihypertensive
standard drugs
10. Not healed scars, sores or bone fractures
11. Hemorrhagic diathesis or coagulate illnesses
Type of Study:
Interventional
Study Design:
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Objective response rate to Sunitinib therapy
Outcome Description:
Clinical activity in terms of clinical response (RANO criteria) after 2, 4 weeks cycles of Sunitinib treatment.
Outcome Time Frame:
8 weeks after treatment
Safety Issue:
No
Principal Investigator
Carmen Balaña, Coordiantor
Investigator Role:
Study Chair
Investigator Affiliation:
Hospital Germans Trias i Pujol, Badalona, Spain
Authority:
Spain: Spanish Agency of Medicines
Study ID:
GENOM-008
NCT ID:
NCT01100177
Start Date:
June 2009
Completion Date:
January 2012
Related Keywords:
- Glioblastoma
- Patients with non resectable Glioblastoma who have only a
- biopsy as surgical treatment
- Glioblastoma
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