Phase II Study of Everolimus Combined With Octreotide LAR to Treat Advanced GI NET

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Gastrointestinal Neoplasms

Intervention / Treatment
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* Drug: Everolimus
* Drug: octreotide LAR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of non-operable or metastatic non-functioning, well differentiated advanced GI NET, confirmed by cytology or histology. In case of liver metastasis, neuroendocrine tumours of unknown origin are accepted. Confirmation of diagnosis of neuroendocrine carcinoma of low to intermediate histology grade Radiologically documented disease progression within 12 months prior to inclusion in the study. If the patient received anticancer treatment within the past 12 months, disease progression must be documented by radiology during or after taking this medication Adequate bone marrow. liver and renal function Exclusion Criteria: Previous treatment with mTOR inhibitors (sirolimus, temsirolimus, everolimus, deforolimus). Patients with any serious disease and/or an uncontrolled clinical condition Patients on chronic treatment with corticosteroids or any other immunosuppressive agent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus + Octreotide LAR treatment<br> | Drug: Everolimus<br>* Everolimus 10mg/day<br>* Other names: Afinitor;Drug: octreotide LAR<br>* 30 mg each 28 days<br>* Other names: Sandostatin LAR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with progression-free survival (PFS) | Rate of patients | After 12 month of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients positive for insulin like growth factor 1 receptor (IGF1R) and ribosomal kinase S6 (S6K) phosphorylation. | Activation status of mTOR pathway. | At baseline | 
| Rate of patients with objective responses | Includes duration of response | Each three cycles | 
| Median and average of time for Overall survival | Time from inclusion date up to date of death for any reason. | At the end of the study | 
| Rate of patients with an early decrease of chromogranin A (CgA) levels | CgA levels will be measured when increased at baseline and up to its normalization. | Each cycle | 
| Percentage of patients with Adverse Events | Ocurred during the trial and up to 30 days after the last dose. | Each cycle | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced, Non functioning, Well differentiated