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

Primary Purpose

Gastrointestinal Neoplasms

Status
Completed
Phase
Phase 2
Locations
Spain
Study Type
Interventional
Intervention
Everolimus
octreotide LAR
Sponsored by
Grupo Espanol de Tumores Neuroendocrinos
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Gastrointestinal Neoplasms focused on measuring Advanced, Non functioning, Well differentiated

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Instituto Catalán de Oncologia

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Everolimus + Octreotide LAR treatment

Arm Description

Outcomes

Primary Outcome Measures

Percentage of patients with progression-free survival (PFS)
Rate of patients

Secondary Outcome Measures

Number of patients positive for insulin like growth factor 1 receptor (IGF1R) and ribosomal kinase S6 (S6K) phosphorylation.
Activation status of mTOR pathway.
Rate of patients with objective responses
Includes duration of response
Median and average of time for Overall survival
Time from inclusion date up to date of death for any reason.
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.
Percentage of patients with Adverse Events
Ocurred during the trial and up to 30 days after the last dose.

Full Information

First Posted
March 26, 2012
Last Updated
January 2, 2018
Sponsor
Grupo Espanol de Tumores Neuroendocrinos
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1. Study Identification

Unique Protocol Identification Number
NCT01567488
Brief Title
Phase II Study of Everolimus Combined With Octreotide LAR to Treat Advanced GI NET
Acronym
EVERLAR
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)
Study Type
Interventional

2. Study Status

Record Verification Date
May 2017
Overall Recruitment Status
Completed
Study Start Date
June 8, 2011 (Actual)
Primary Completion Date
September 1, 2014 (Actual)
Study Completion Date
June 7, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Grupo Espanol de Tumores Neuroendocrinos

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Gastrointestinal Neoplasms
Keywords
Advanced, Non functioning, Well differentiated

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
43 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Everolimus + Octreotide LAR treatment
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Everolimus
Other Intervention Name(s)
Afinitor
Intervention Description
Everolimus 10mg/day
Intervention Type
Drug
Intervention Name(s)
octreotide LAR
Other Intervention Name(s)
Sandostatin LAR
Intervention Description
30 mg each 28 days
Primary Outcome Measure Information:
Title
Percentage of patients with progression-free survival (PFS)
Description
Rate of patients
Time Frame
After 12 month of study treatment
Secondary Outcome Measure Information:
Title
Number of patients positive for insulin like growth factor 1 receptor (IGF1R) and ribosomal kinase S6 (S6K) phosphorylation.
Description
Activation status of mTOR pathway.
Time Frame
At baseline
Title
Rate of patients with objective responses
Description
Includes duration of response
Time Frame
Each three cycles
Title
Median and average of time for Overall survival
Description
Time from inclusion date up to date of death for any reason.
Time Frame
At the end of the study
Title
Rate of patients with an early decrease of chromogranin A (CgA) levels
Description
CgA levels will be measured when increased at baseline and up to its normalization.
Time Frame
Each cycle
Title
Percentage of patients with Adverse Events
Description
Ocurred during the trial and up to 30 days after the last dose.
Time Frame
Each cycle

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ramón Salazar, MD, PhD
Organizational Affiliation
Grupo Espanol de Tumores Neuroendocrinos
Official's Role
Study Chair
Facility Information:
Facility Name
Instituto Catalán de Oncologia
City
Hospitalet de Llobregat
State/Province
Barcelona
ZIP/Postal Code
08907
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
Undecided
IPD Sharing Plan Description
As per Spanish local regulations
Citations:
PubMed Identifier
29794066
Citation
Capdevila J, Teule A, Barriuso J, Castellano D, Lopez C, Manzano JL, Alonso V, Garcia-Carbonero R, Dotor E, Matos I, Custodio A, Casanovas O, Salazar R; EVERLAR study investigators. Phase II Study of Everolimus and Octreotide LAR in Patients with Nonfunctioning Gastrointestinal Neuroendocrine Tumors: The GETNE1003_EVERLAR Study. Oncologist. 2019 Jan;24(1):38-46. doi: 10.1634/theoncologist.2017-0622. Epub 2018 May 23.
Results Reference
derived

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

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