Predictive Biomarkers of Response to Sunitinib in the Treatment of Poorly-differentiated NEURO-Endocrine Tumors (NET)
The purpose of this study is to identify predictive molecular markers of response to continuous daily sunitinib at dose of 37.5 mg used in patients with poorly-differentiated Advanced/Inoperable NEURO-Endocrine Tumors.
- To distinguish molecular markers based on their expression at the initial biopsy, their detection by proteomic analysis and demonstrating that tumor or vascular cells are straightaway sensitive to sunitinib (markers sensitivity).
- The presence of these markers at the initial biopsy predict the sensitivity to sunitinib(Positive predictive value of markers)
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Multicenter Phase II Open Study Coupled With a Translational Assessment of Biomarkers Predictive of Response to Sunitinib in Patients With Poorly-differentiated Advanced/Inoperable NEURO-Endocrine Tumors.|
- Predictive molecular markers of response to sunitinib [ Time Frame: 1 year ] [ Designated as safety issue: No ]to assess the correlation between the expression of biomarkers and CT scan response. Patients are considered as responders when objective response (Partial or complete response) is showed on CT scan.
- The antitumor activity of sunitinib [ Time Frame: 1 year ] [ Designated as safety issue: No ]
- Objective response according to RECIST criteria (Time Frame: duration of study Safety issue: No).
- Overall Survival (Time Frame: 6 months. Safety issue: No).
- Progression-free survival (PFS)
- Correlation between overall survival, PFS and tumor necrosis assessed on CT scan
- Residual concentration [ Time Frame: 2 months ] [ Designated as safety issue: Yes ]correlation between the concentration of sunitinib and its major active metabolite, SU012662, and objective response and /or toxicity.
|Study Start Date:||October 2008|
|Estimated Study Completion Date:||December 2014|
|Primary Completion Date:||December 2013 (Final data collection date for primary outcome measure)|
Experimental: patient treated
patient who receive sunitinib (SUTENT)
sunitinib 37.5 mg/day (per os) for 6 months
Other Name: Sutent
Neuroendocrine tumors (NET) are rare malignancies (1-2% of digestive cancers); and there is, in recent years, a slow but steady increase in their incidence. Despite the joint efforts of several research groups, which led to the new WHO classification (2002), the natural history of the disease remains heterogene and the resistance to conventional cytotoxic treatment remains the common denominator of these tumors.
Indeed, the prognosis of patients with metastatic disease remains poor despite numerous treatments (including: IFN, DTIC, 5-FU, doxorubicin, somatostatin analogues, etc.).
None of which showed a benefit in terms of survival. The main therapeutic objective is still to get a palliative effect on the symptoms and / or limit a few months tumor progression.
There are many publications showing that angiogenesis is one of the major mechanisms of tumor progression in TNE. But the multiple signaling pathways involved, the existence of alternative routes and their relationship to apoptosis inducing molecules remain unknown. Sunitinib is a new molecule in the family of tyrosine kinase inhibitors targeting multiple receptors which VEGFR, KIT, PDGF-R, FLT3 and RET. Since 2006 year, Sunitinib has been approved to treat advanced kidney cancer also called advanced renal cell carcinoma (a typically chemoresistant disease for which there was no active treatment available).
Many retrospective studies in patients showing that the TNE overexpress one or more targets of sunitinib. In Phase I trial, an antitumor activity has been identified in neuroendocrine tumors. In a phase II trial including 100 patients with well-differentiated TNE and carcinoids, sunitinib is associated with a response rate of 10%, and 82% of clinical benefit in the form of tumor stability.
Currently, an international randomised phase III trial initiated in well differentiated forms, but no studies are underway for poorly-differentiated TNE.
All of this suggests that sunitinib could represent an important therapeutic option for moderate, or poorly differentiated inoperable TNE and needs to be explored in this pathology by identifying predictive biomarkers of response.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01215578
|Clichy, Hauts de Seine, France, 92110|
|Principal Investigator:||Eric Raymond, Professor||Assistance Publique - Hôpitaux de Paris|