Clinical Trials Register

Summary
EudraCT Number:	2014-000888-41
Sponsor's Protocol Code Number:	MetNET1trial
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-03-10
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2014-000888-41

A.3

Full title of the trial

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.

VALUTAZIONE DELL’ATTIVITÀ E DELLA SICUREZZA DELLA COMBINAZIONE EVEROLIMUS, OCTREOTIDE LAR E METFORMINA IN PAZIENTI AFFETTI DA TUMORI NEUROENDOCRINI DEL PANCREAS BEN DIFFERENZIATI IN STADIO AVANZATO E/O NON RESECABILI. STUDIO CLINICO-BIOLOGICO DI FASE II, MetNET 1 Trial.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A.3.2

Name or abbreviated title of the trial where available

MetNET1 trial

A.4.1

Sponsor's protocol code number

MetNET1trial

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Fondazione IRCCS Istituto Nazionale dei tumori
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Not applicable
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fondazione IRCCS Istituto Nazionale dei tumori
B.5.2	Functional name of contact point	Trials center
B.5.3	Address:
B.5.3.1	Street Address	Via Venezian 1
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20133
B.5.3.4	Country	Italy
B.5.6	E-mail	trialcenter@istitutotumori.mi.it

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Afinitor
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Afinitor
D.3.2	Product code	039398045
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Afinitor
D.3.9.1	CAS number	159351-69-6
D.3.9.3	Other descriptive name	EVEROLIMUS
D.3.9.4	EV Substance Code	SUB02065MIG
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Sandostatina lar 30
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Sandostatina lar 30
D.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	OCTREOTIDE
D.3.9.1	CAS number	83150-76-9
D.3.9.3	Other descriptive name	octreotide lar 30
D.3.9.4	EV Substance Code	SUB09417MIG
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Metformina teva
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Metformina teva
D.3.2	Product code	035195205
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METFORMIN
D.3.9.1	CAS number	657-24-9
D.3.9.4	EV Substance Code	SUB08831MIG
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

advanced/ or not resectable well differnciated pancreatic neuroendocrin tumor

Tumore neuroendocrino del pancreas ben differenziato avanzato e/o non resecabile

E.1.1.1

Medical condition in easily understood language

advanced/ or not resectable well differnciated pancreatic neuroendocrin tumor

Tumore neuroendocrino del pancreas ben differenziato avanzato e/o non resecabile

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10067518
E.1.2	Term	Pancreatic neuroendocrine tumor
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	PT
E.1.2	Classification code	10068909
E.1.2	Term	Pancreatic neuroendocrine tumour metastatic
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate progression free survival

Valutare la sopravvivenza libera da progressione

E.2.2

Secondary objectives of the trial

safety, overall survival, response rate

sicurezza, sopravvivenza totale e tassi di risposte obiettive

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

to evaluate circulant biomarkers levels (IL 6, IGF1)

Valutazione dei livelli di biomarcatori circolanti (IL 6, IGF1)

E.3

Principal inclusion criteria

Signature of written informed consent (approved by the Institutional Ethics Committee Independent ) obtained after a careful study of screening procedures .
2 . Age >= 18 years old.
3 . Patients with histological evidence of pNET well-differentiated G1 -G2 .
4 . Configurable tumor disease (according to RECIST ) .
5 . Karnofsky Performance Status >= 60%.
6 . Life expectancy greater than 6 months.
7 . Is permitted to enroll patients who have not received any treatment for advanced disease or patients pretreated with surgery , chemotherapy or somatostatin analogues .
8 . 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, ALT <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 ≥ 60 mL / min

9 . During the study of male and female patients must use adequate contraceptive methods .

1. Firma del consenso informato scritto (approvato dal Comitato Etico indipendente Istituzionale) ottenuto dopo un attento studio delle procedure di screening.
2. Età >=18 anni.
3. Pazienti con evidenza istologica di pNET ben differenziato G1-G2.
4. Malattia tumorale parametrabile (in accordo ai criteri RECIST).
5. Performance Status secondo Karnofsky >=60%.
6. Aspettativa di vita superiore ai 6 mesi.
7. E’ ammesso l’arruolamento di pazienti che non hanno ricevuto nessun trattamento per la malattia avanzata o pazienti pretrattati con chirurgia, con chemioterapia o analoghi della somatostatina.
8. Esami ematochimici basali:
- Conta dei granulociti neutrofili in valore assoluto > 1.5 x 109/L.
- Conta piastrinica > 100 x 109/L.
- Emoglobina > 9 g/dl.
- Bilirubina Totale <1.5 volte il limite superiore della norma.
- AST, ALT< 2.5 volte il limite superiore della norma in pazienti senza evidenza di metastasi epatiche.
- AST, ALT< 2.5 volte il limite superiore della norma in pazienti con evidenza di metastasi epatiche.
- Fosfatasi alcalina < 2.5 volte il limite superiore della norma in pazienti con evidenza di metastasi epatiche
- Valori di creatinina sierica < 1.5 mg/dl. - CCr ≥ 60 mL/min

9. In fase di studio i pazienti di sesso maschile e femminile devono utilizzare metodi contraccettivi idonei.

E.4

Principal exclusion criteria

1 . Patients with histological evidence of malignant insulinoma ( pNET )
2 . Surgeries performed within 28 days prior to the start of treatment.
3 . 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.
4 . 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.
5 . 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.
6 . Active or uncontrolled severe infections .
7 . Cirrhosis , acute hepatitis or chronic active hepatitis .
8 . Poor control of diabetes HbA1c > = 8.0 % .
9 . 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.
10 . Using anti - IL6 or IGF1 .
11 . Uncontrolled high blood pressure , atrial fibrillation .
12 . History of immunosuppression included positive HIV test .
13 . No previous or concomitant oncological pathology , except: basal cell skin cancer, in situ , as long as every other cancer patient disease-free for at least 5 years.
14 . They excluded patients with a condition of metabolic acidosis , acute or chronic , including ketoacitosi .
15 . History of alcohol abuse , or habitual intake of alcohol (≥ 3 glasses of alcoholic drinks / day) sufficient to cause hepatotoxicity.
16 . Prolonged fasting .
17 . Severe states of dehydration.

1. Pazienti con evidenza istologica di Insulinoma maligno (pNET)
2. Interventi chirurgici effettuati entro 28 giorni prima dell’inizio del trattamento.
3. Evidenza di metastasi a livello del sistema nervoso centrale o di compressione midollare. I pazienti devono essere sottoposti ad uno studio RMN o TC dell’encefalo recente di almeno 28 giorni dalla data di randomizzazione.
4. Malattie cardiovascolari clinicamente significative, per esempio accidenti cardiovascolari verificatesi in meno di 6 mesi: angina instabile, insufficienza cardiaca congestizia di grado superiore o uguale a II (in accordo alla classificazione del New York Heart Association NYHA), serie aritmie cardiache che richiedono trattamento.
5. Comorbidità importanti, disfunzioni metaboliche, obiettività clinica o laboratoristica, che controindicano l’uso dei farmaci da studio, o pazienti ad alto rischio di complicazioni dal trattamento.
6. Attive o incontrollate infezioni di grado severo.
7. Cirrosi, epatiti acute, o epatiti croniche attive.
8. Scarso controllo del diabete HbA1C >= 8.0%.
9. I pazienti diabetici che sono in trattamento con metformina sono eleggibili purchè abbiano attivato il trattamento con metformina da meno di 6 mesi. Sono esclusi pazienti diabetici che fanno uso di altri ipoglicemizzanti come sulfoniluree, insulina, glinidi in monoterapia o in associazione alla metformina.
10. Utilizzo di anti IL6-IGF1.
11. Ipertensione arteriosa non controllabile, fibrillazione atriale.
12. Storia di immunodepressione incluso test HIV positivo.
13. Nessuna precedente o concomitante patologia oncologica, eccetto: basalioma della cute, cancro in situ, ogni altro cancro purchè paziente libero da malattia da almeno 5 anni.
14. Sono esclusi pazienti che presentano una condizione di acidosi metabolica, acuta o cronica, inclusa ketoacitosi.
15. Anamnesi di potus (abuso alcolico), o abituale introito di sostanze alcoliche ( ≥ 3 bicchieri di bevande alcoliche/die) sufficiente per causare epatotossicità.
16. Digiuno prolungato.
17. Gravi stati di disidratazione

E.5 End points

E.5.1

Primary end point(s)

safety, overall survival, response rate

Valutare la sopravvivenza libera da progressione

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months

1 anno

E.5.2

Secondary end point(s)

to evaluate circulant biomarkers levels (IL 6, IGF1)

Valutazione dei livelli di biomarcatori circolanti (IL 6, IGF1)

E.5.2.1

Timepoint(s) of evaluation of this end point

1 year

1 anno

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

follow up according to international giudelines

Controlli clinico strumentali in accordo alle linee guida internazionali

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-06-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-06-05

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-09-27

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