Clinical trial NCT01567488: Phase II Study of Everolimus Combined With Octreotide LAR to Treat Advanced GI NET
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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Gastrointestinal Neoplasms
Keywords: Advanced
Non functioning
Well differentiated
Lead sponsor: Grupo Espanol de Tumores Neuroendocrinos
Sponsor class: OTHER
First posted: 2012-03-30
Enrollment: 43
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Percentage of patients with progression-free survival (PFS)
timeFrame: After 12 month of study treatment
Secondary outcomes:
measure: Number of patients positive for insulin like growth factor 1 receptor (IGF1R) and ribosomal kinase S6 (S6K) phosphorylation.
timeFrame: At baseline
measure: Rate of patients with objective responses
timeFrame: Each three cycles
measure: Median and average of time for Overall survival
timeFrame: At the end of the study
measure: Rate of patients with an early decrease of chromogranin A (CgA) levels
timeFrame: Each cycle
measure: Percentage of patients with Adverse Events
timeFrame: Each cycle
Other outcomes:
Locations:
city: Hospitalet de Llobregat
country: Spain
facility: Instituto Catalán de Oncologia
state: Barcelona
Study officials:
affiliation: Grupo Espanol de Tumores Neuroendocrinos
name: Ramón Salazar, MD, PhD
role: STUDY_CHAIR
References:
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.