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.
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Predictive molecular markers of response to sunitinib
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.
Eric Raymond, Professor
Assistance Publique - Hôpitaux de Paris
France: Ministry of Health