Well Differentiated Pancreatic Endocrine TumorPhase 2MetNET1NCT02294006
Activity and Safety of Everolimus+Octreotide LAR+Metformin in Advanced Pancreatic Well-differentiated NETs
A Phase 2 study testing Everolimus plus Octreotide LAR plus Metformin in people with Well Differentiated Pancreatic Endocrine Tumor, run by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano at 1 site in Italy.
Trial summary
Abnormal PI3K-Akt-mTOR (mammalian target of rapamycin) pathway signaling and autocrine activation of the mTOR pathway, mediated through insulin-like growth factor 1 (IGF1), has been implicated in the proliferation of pNET ( primitive neuroectodermal tumor) cells. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Well Differentiated Pancreatic Endocrine Tumor
- What is being tested?
- Everolimus plus Octreotide LAR plus Metformin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 26 participants
- Where
- 1 siteItaly
- Study dates
- Jun 2014to Oct 2021
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Signature of written informed consent (approved by the Institutional Ethics Committee Independent ) obtained after a careful study of screening procedures
- Age >= 18 years old.
- Patients with histological evidence of pNET well-differentiated G1 -G2
- Configurable tumor disease (according to RECIST (Response Evaluation Criteria In Solid Tumors) ) .
- Karnofsky Performance Status >= 60%.
- Life expectancy greater than 6 months.
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- Is permitted to enroll patients who have not received any treatment for advanced disease or patients pretreated with surgery , chemotherapy or somatostatin analogues .
- Basal blood tests :
- Counts of neutrophils in absolute value > 1.5 x 109 / L.
- Platelet count > 100 x 109 / L.
- Hemoglobin > 9 g / dl .
- Total Bilirubin < 1.5 times the upper limit of normal .
- AST( aspartate aminotransferase), ALT (alanine aminotransferase)<2.5 times the upper limit of normal in patients without evidence of liver metastases.
- AST, ALT <2.5 times the upper limit of normal in patients with evidence of liver metastases.
- Alkaline phosphatase <2.5 times the upper limit of normal in patients with evidence of hepatic metastases
- Values of serum creatinine < 1.5 mg / dl. - CCr ( Creatinine Clearance rate) ≥ 60 mL / min 9 . During the study of male and female patients must use adequate contraceptive methods .
Who cannot join
- Patients with histological evidence of malignant insulinoma ( pNET )
- Surgeries performed within 28 days prior to the start of treatment.
- Evidence of metastasis at the level of the central nervous system or spinal cord compression . Patients should be subjected to a recent study MRI or CT scan at least 28 days from the date of randomization.
- Clinically significant cardiovascular disease , such as cardiovascular accidents occurred in less than 6 months, unstable angina , congestive heart failure grade greater than or equal to II according to the classification of the New York Heart Association (NYHA) series cardiac arrhythmias that require treatment.
- Important comorbidities , metabolic disorders , clinical examination or laboratory investigations , which contraindicate the use of drugs to study, or patients at high risk of complications from the treatment.
- Active or uncontrolled severe infections .
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- Cirrhosis , acute hepatitis or chronic active hepatitis .
- Poor control of diabetes HbA1c > = 8.0 % .
- Diabetic patients who are treated with metformin are eligible if they have enabled the treatment with metformin for less than 6 months. Are excluded diabetic patients who make use of other hypoglycemic agents such as sulfonylureas, insulin , glinides as monotherapy or in combination with metformin.
- Using anti - IL6 (Interleukin 6) or IGF1 .
- Uncontrolled high blood pressure , atrial fibrillation .
- History of immunosuppression included positive HIV test .
- No previous or concomitant oncological pathology , except: basal cell skin cancer, in situ , as long as every other cancer patient diseasefree for at least 5 years.
- They excluded patients with a condition of metabolic acidosis , acute or chronic , including ketoacidosis .
- History of alcohol abuse , or habitual intake of alcohol (≥ 3 glasses of alcoholic drinks / day) sufficient to cause hepatotoxicity.
- Prolonged fasting .
- Severe states of dehydration.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Activity and Safety of Everolimus in Combination With Octreotide LAR and Metformin in Patients With Advanced Pancreatic Well-differentiated Neuroendocrine Tumors (pWDNETs): a Phase II, Open, Monocentric, Prospective Study
Abnormal PI3K-Akt-mTOR (mammalian target of rapamycin) pathway signaling and autocrine activation of the mTOR pathway, mediated through insulin-like growth factor 1 (IGF1), has been implicated in the proliferation of pNET ( primitive neuroectodermal tumor) cells. Everolimus ,an mTOR inhibitor (a central regulator of growth/proliferation, cellular metabolism and angiogenesis) has shown antitumor benefit in pNETs alone and in combination with Octreotide LAR in RADIANT-1 and RADIANT-3 studies.
Despite EVE-based phase II/III trials improve progression-free survival (PFS) for pNETs, they are limited to significantly prolong overall survival (OS). Metformin has recently shown some anti-cancer activity, both in vitro and in vivo studies by antisecretory properties to decrease insulin and IGF1 levels; and by antitumor effect due to AMPK (adenosine monophosphate kinase) activation and consequently inhibition to TSC1(tuberous sclerosis complex 1) -2/mTOR complex, mediated to LKB1 oncogene expression. The investigators retrospective experience, despite in a limited group of pWDNET, highlights the role of MET to improve clinical benefit in diabetic pts receiving EVE-OCT (octreotide) combination.
Read more
This study will investigate the antiproliferative potential of MET in combination with EVE and OCT in pWDNETs. MetNET1 prospective trial (EudraCT 2014-000888-41) may be helpful to either confirm or discard these preliminary findings.
The main objective of this study is to evaluate progression free survival rate at 12 months of treatment. The secondary objectives are safety, overall survival, response rate evaluation.
A sub-study analysis will evaluate circulant biomarkers levels (IL 6, IGF1) in blood samples.
Read the detailed description
Abnormal PI3K-Akt-mTOR (mammalian target of rapamycin) pathway signaling and autocrine activation of the mTOR pathway, mediated through insulin-like growth factor 1 (IGF1), has been implicated in the proliferation of pNET ( primitive neuroectodermal tumor) cells. Everolimus ,an mTOR inhibitor (a central regulator of growth/proliferation, cellular metabolism and angiogenesis) has shown antitumor benefit in pNETs alone and in combination with Octreotide LAR in RADIANT-1 and RADIANT-3 studies.
Despite EVE-based phase II/III trials improve progression-free survival (PFS) for pNETs, they are limited to significantly prolong overall survival (OS). Metformin has recently shown some anti-cancer activity, both in vitro and in vivo studies by antisecretory properties to decrease insulin and IGF1 levels; and by antitumor effect due to AMPK (adenosine monophosphate kinase) activation and consequently inhibition to TSC1(tuberous sclerosis complex 1) -2/mTOR complex, mediated to LKB1 oncogene expression. The investigators retrospective experience, despite in a limited group of pWDNET, highlights the role of MET to improve clinical benefit in diabetic pts receiving EVE-OCT (octreotide) combination.
This study will investigate the antiproliferative potential of MET in combination with EVE and OCT in pWDNETs. MetNET1 prospective trial (EudraCT 2014-000888-41) may be helpful to either confirm or discard these preliminary findings.
The main objective of this study is to evaluate progression free survival rate at 12 months of treatment. The secondary objectives are safety, overall survival, response rate evaluation.
A sub-study analysis will evaluate circulant biomarkers levels (IL 6, IGF1) in blood samples.
- Being tested
- Everolimus plus Octreotide LAR plus Metformin
- Keywords
- pancreatic, neuroendocrine, everolimus, metformin, octreotide
- Medical subject headings
- Adenoma, Islet Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Everolimus plus Octreotide LAR plus MetforminDrug
Everolimus plus Octreotide LAR plus Metformin
| Study group | Role | What they receive |
|---|---|---|
| everolimus+octreotide LAR+metformin | Experimental | everolimus+octreotide LAR+metformin Receives: Drug: Everolimus plus Octreotide LAR plus Metformin |
What is being measured
The primary outcome is the main question the study is designed to answer.
to determine the progression free survival rate (PFS) at 12 months from the first drug administration in patients with advanced pancreatic neuroendocrine tumors
progression free survival rate at 12th month of treatment, according to RECIST criteria version 1.0
Measured: 1 year
Secondary outcomes (4)
to determine the safety and tolerability of the combination of Everolimus, Octreotide LAR and Metformin as measured according to the National cancer Institute-Common Toxicity Criteria v. 3.0 guidelines
safety is measured according to the National cancer Institute-Common Toxicity Criteria v. 3.0 guidelines
Measured: 1 year
to determine the overall survival of the combination of Everolimus, Octreotide LAR and Metformin.
overall survival is defined as the time interval between enrollment and the date of the death from any cause.
Measured: 3 years
to determine the response rate of the combination of Everolimus, Octreotide LAR and Metformin.
response rate is defined as the percentage of patients presenting objective responce of the disease, according to RECIST Criteria version 1.0.
Measured: 1 year
to determine the biochemical response of the combination of Everolimus, Octreotide LAR and Metformin.
the biochemical response is defined as the impact of study treatment on general neuroendocrine tumors biomarkers, Chromogranine A and Enolase neuron specific and circulating plasma IL6, IL8 and IGF-1 levels.
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Nov 2014 (estimated)
- Study startJun 2014
- Primary completionJun 2021
- Study completionOct 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Well Differentiated Pancreatic Endocrine TumorStudies of the same condition, open and under way.
- More trials run by Fondazione IRCCS Istituto Nazionale dei Tumori, MilanoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 26 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Filippo De Braud, MD, Principal investigator, INT MILANORoberto Buzzoni, MD, Principal investigator, INT MILANOSara Pusceddu, MD, Principal investigator, INT MILANO
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02294006
- Sponsor's protocol ID
- Ist Nazionale Tumori Milano
- Acronym
- MetNET1
- Status last verified
- Sep 2021
- First submitted
- 29 Oct 2014
- Last updated
- 9 Sep 2021
- Results posted
- No
- Data monitoring committee
- No
Publications
Pusceddu S, de Braud F, Concas L, Bregant C, Leuzzi L, Formisano B, Buzzoni R. Rationale and protocol of the MetNET-1 trial, a prospective, single center, phase II study to evaluate the activity and safety of everolimus in combination with octreotide LAR and metformin in patients with advanced pancreatic neuroendocrine tumors. Tumori. 2014 Nov-Dec;100(6):e286-9. doi: 10.1700/1778.19298.
PubMed 25688512
Study at a glance
From the registry record, last updated by the sponsor on 9 Sep 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Activity and Safety of Everolimus in Combination With Octreotide LAR and Metformin in Patients With Advanced Pancreatic Well-differentiated Neuroendocrine Tumors (pWDNETs): a Phase II, Open, Monocentric, Prospective Study
- ClinicalTrials.gov ID
- NCT02294006
- Acronym / sponsor ID
- MetNET1 / Ist Nazionale Tumori Milano
- Keywords
- pancreatic, neuroendocrine, everolimus, metformin, octreotide
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 26 participants (actual)
- Lead sponsor
- Fondazione IRCCS Istituto Nazionale dei Tumori, MilanoUniversity, hospital or other
- Study start
- Jun 2014
- Primary completion
- Jun 2021 (actual)
- Study completion
- Oct 2021 (estimated)
- First posted
- 19 Nov 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Abnormal PI3K-Akt-mTOR (mammalian target of rapamycin) pathway signaling and autocrine activation of the mTOR pathway, mediated through insulin-like growth factor 1 (IGF1), has been implicated in the proliferation of pNET ( primitive neuroectodermal tumor) cells. Everolimus ,an mTOR inhibitor (a central regulator of growth/proliferation, cellular metabolism and angiogenesis) has shown antitumor benefit in pNETs alone and in combination with Octreotide LAR in RADIANT-1 and RADIANT-3 studies.
Despite EVE-based phase II/III trials improve progression-free survival (PFS) for pNETs, they are limited to significantly prolong overall survival (OS). Metformin has recently shown some anti-cancer activity, both in vitro and in vivo studies by antisecretory properties to decrease insulin and IGF1 levels; and by antitumor effect due to AMPK (adenosine monophosphate kinase) activation and consequently inhibition to TSC1(tuberous sclerosis complex 1) -2/mTOR complex, mediated to LKB1 oncogene expression. The investigators retrospective experience, despite in a limited group of pWDNET, highlights the role of MET to improve clinical benefit in diabetic pts receiving EVE-OCT (octreotide) combination.
This study will investigate the antiproliferative potential of MET in combination with EVE and OCT in pWDNETs. MetNET1 prospective trial (EudraCT 2014-000888-41) may be helpful to either confirm or discard these preliminary findings.
The main objective of this study is to evaluate progression free survival rate at 12 months of treatment. The secondary objectives are safety, overall survival, response rate evaluation.
A sub-study analysis will evaluate circulant biomarkers levels (IL 6, IGF1) in blood samples.
Detailed description
Abnormal PI3K-Akt-mTOR (mammalian target of rapamycin) pathway signaling and autocrine activation of the mTOR pathway, mediated through insulin-like growth factor 1 (IGF1), has been implicated in the proliferation of pNET ( primitive neuroectodermal tumor) cells. Everolimus ,an mTOR inhibitor (a central regulator of growth/proliferation, cellular metabolism and angiogenesis) has shown antitumor benefit in pNETs alone and in combination with Octreotide LAR in RADIANT-1 and RADIANT-3 studies.
Despite EVE-based phase II/III trials improve progression-free survival (PFS) for pNETs, they are limited to significantly prolong overall survival (OS). Metformin has recently shown some anti-cancer activity, both in vitro and in vivo studies by antisecretory properties to decrease insulin and IGF1 levels; and by antitumor effect due to AMPK (adenosine monophosphate kinase) activation and consequently inhibition to TSC1(tuberous sclerosis complex 1) -2/mTOR complex, mediated to LKB1 oncogene expression. The investigators retrospective experience, despite in a limited group of pWDNET, highlights the role of MET to improve clinical benefit in diabetic pts receiving EVE-OCT (octreotide) combination.
This study will investigate the antiproliferative potential of MET in combination with EVE and OCT in pWDNETs. MetNET1 prospective trial (EudraCT 2014-000888-41) may be helpful to either confirm or discard these preliminary findings.
The main objective of this study is to evaluate progression free survival rate at 12 months of treatment. The secondary objectives are safety, overall survival, response rate evaluation.
A sub-study analysis will evaluate circulant biomarkers levels (IL 6, IGF1) in blood samples.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| everolimus+octreotide LAR+metformin | Experimental | Drug: Everolimus plus Octreotide LAR plus Metformineverolimus+octreotide LAR+metformin |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- Signature of written informed consent (approved by the Institutional Ethics Committee Independent ) obtained after a careful study of screening procedures
- Age >= 18 years old.
- Patients with histological evidence of pNET well-differentiated G1 -G2
- Configurable tumor disease (according to RECIST (Response Evaluation Criteria In Solid Tumors) ) .
- Karnofsky Performance Status >= 60%.
Key exclusion criteria (17 listed)
- Patients with histological evidence of malignant insulinoma ( pNET )
- Surgeries performed within 28 days prior to the start of treatment.
- Evidence of metastasis at the level of the central nervous system or spinal cord compression . Patients should be subjected to a recent study MRI or CT scan at least 28 days from the date of randomization.
- Clinically significant cardiovascular disease , such as cardiovascular accidents occurred in less than 6 months, unstable angina , congestive heart failure grade greater than or equal to II according to the classification of the New York Heart Association (NYHA) series cardiac arrhythmias that require treatment.
- Important comorbidities , metabolic disorders , clinical examination or laboratory investigations , which contraindicate the use of drugs to study, or patients at high risk of complications from the treatment.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Everolimus plus Octreotide LAR plus MetforminEverolimus plus Octreotide LAR plus Metformin | Drug | everolimus+octreotide LAR+metformin |
Primary outcome
to determine the progression free survival rate (PFS) at 12 months from the first drug administration in patients with advanced pancreatic neuroendocrine tumors
Time frame: 1 year
progression free survival rate at 12th month of treatment, according to RECIST criteria version 1.0
4 secondary outcomes
to determine the safety and tolerability of the combination of Everolimus, Octreotide LAR and Metformin as measured according to the National cancer Institute-Common Toxicity Criteria v. 3.0 guidelines
Time frame: 1 year
to determine the overall survival of the combination of Everolimus, Octreotide LAR and Metformin.
Time frame: 3 years
to determine the response rate of the combination of Everolimus, Octreotide LAR and Metformin.
Time frame: 1 year
to determine the biochemical response of the combination of Everolimus, Octreotide LAR and Metformin.
Time frame: 1 year
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Sep 2021.
- Derived from this study: PubMed 25688512Pusceddu S, de Braud F, Concas L, Bregant C, Leuzzi L, Formisano B, Buzzoni R. Rationale and protocol of the MetNET-1 trial, a prospective, single center, phase II study to evaluate the activity and safety of everolimus in combination with octreotide LAR and metformin in patients with advanced pancreatic neuroendocrine tumors. Tumori. 2014 Nov-Dec;100(6):e286-9. doi: 10.1700/1778.19298.
Related trials for Well Differentiated Pancreatic Endocrine Tumor
RecruitingPhase 1
Study of RYZ401 in Subjects With Solid Tumors Expressing SSTRs.
GEP-NET, Gastroenteropancreatic Neuroendocrine Tumor
Active, not recruitingPhase 2
Comparing Capecitabine and Temozolomide in Combination to Lutetium Lu 177 Dotatate in Patients With Advanced Pancreatic Neuroendocrine Tumors, the ComPareNET Trial
Metastatic Pancreatic Neuroendocrine Tumor, Unresectable Pancreatic Neuroendocrine Carcinoma
Active, not recruitingPhase 3
Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy
GEP-NET, Gastroenteropancreatic Neuroendocrine Tumor
RecruitingPhase 4
Surgical Debulking Prior to Peptide Receptor Radionuclide Therapy in Well Differentiated Gastroenteropancreatic Neuroendocrine Tumors
Digestive System Neuroendocrine Tumor G1, Digestive System Neuroendocrine Tumor G2
Active, not recruitingPhase 2
Abemaciclib in Treating Patients With Advanced, Refractory, and Unresectable Digestive System Neuroendocrine Tumors
Advanced Digestive System Neuroendocrine Neoplasm, Digestive System Neuroendocrine Tumor
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Filippo De Braud, MD principal investigator
INT MILANO
Roberto Buzzoni, MD principal investigator
INT MILANO
Sara Pusceddu, MD principal investigator
INT MILANO
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Everolimus plus Octreotide LAR plus Metformin in people with Well Differentiated Pancreatic Endocrine Tumor, run by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 9 Sep 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
to determine the progression free survival rate (PFS) at 12 months from the first drug administration in patients with advanced pancreatic neuroendocrine tumors (time frame: 1 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02294006, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Sep 2021.