Phase II Study of Everolimus Combined With Octreotide LAR to Treat Advanced GI NET (EVERLAR)
The underlying hypothesis of the synergistic activity of octreotide and everolimus is based on the combination of a) a direct action of everolimus over mTOR (mammalian target of rapamycin), and b) the inhibitory effect of octreotide on the IGF-I (insulin like growth factor 1) system preventing the activation of the mTOR system by this factor. Both types of inhibition would completely cancel this signal transduction pathway, which is so important in neuroendocrine tumours.
Furthermore, the biological study proposed in this protocol will allow for better establishing the relationship between the activation of the IGFR-PI3K-mTOR signal transduction pathway (i.e., the mTOR pathway stimulated by IGFR) and treatment response; this information is relevant since the IGFR-PI3K-mTOR activation status could be a response prediction factor.
This study will provide significant additional information about the efficacy of the combination treatment of everolimus with octreotide LAR® in non-functioning GI NET.
Drug: octreotide LAR
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase II Study on Everolimus, an mTOR Inhibitor (Oral Formulation), With Octreotide LAR® in Adult Patients With Advanced, Non-functioning, Well-differentiated Gastrointestinal Neuroendocrine Tumours (GI NET)|
- Percentage of patients with progression-free survival (PFS) [ Time Frame: After 12 month of study treatment ] [ Designated as safety issue: No ]Rate of patients
- Number of patients positive for insulin like growth factor 1 receptor (IGF1R) and ribosomal kinase S6 (S6K) phosphorylation. [ Time Frame: At baseline ] [ Designated as safety issue: No ]Activation status of mTOR pathway.
- Rate of patients with objective responses [ Time Frame: Each three cycles ] [ Designated as safety issue: No ]Includes duration of response
- Median and average of time for Overall survival [ Time Frame: At the end of the study ] [ Designated as safety issue: No ]
- Rate of patients with an early decrease of chromogranin A (CgA) levels [ Time Frame: Each cycle ] [ Designated as safety issue: No ]CgA levels will be measured when increased at baseline and up to its normalization.
- Percentage of patients with Adverse Events [ Time Frame: Each cycle ] [ Designated as safety issue: Yes ]
|Study Start Date:||June 2011|
|Estimated Study Completion Date:||May 2015|
|Primary Completion Date:||April 2014 (Final data collection date for primary outcome measure)|
|Experimental: Everolimus + Octreotide LAR treatment||
Other Name: AfinitorDrug: octreotide LAR
30 mg each 28 days
Other Name: Sandostatin LAR
Everolimus has been developed following two administration regimens: weekly and daily. Phase I pharmacodynamic studies recommend doses of 50 mg weekly and 10 mg/daily, based on its toxicity and inhibitory effect of the mTOR pathway in tumours; although the inhibition of this pathway has been demonstrated, the knowledge of response prediction factors has not been developed, in part due to the very low responses found in the population in phase I studies. These factors can be better outlined in a phase II study, where patients who have received fewer previous treatments can respond better, and where the profile of responders and non-responders can be identified more easily.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01567488
|Instituto Catalán de Oncologia|
|Hospitalet de Llobregat, Barcelona, Spain, 08907|
|Study Chair:||Ramón Salazar, MD, PhD||Grupo Espanol de Tumores Neuroendocrinos|