Clinical Trials Register

Summary
EudraCT Number:	2015-004626-34
Sponsor's Protocol Code Number:	MetNET2
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-12-17
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

2015-004626-34

A.3

Full title of the trial

Safety of Lanreotide 120 mg ATG in combination with Metformin in patients with progressive advanced Well-differentiated gastro-intestinal (GI) or lung carcinoids.
A pilot, one-arm, open-label, prospective study:
the MetNET-2 trial.

VALUTAZIONE DELLA SICUREZZA DELLA COMBINAZIONE LANREOTIDE ATG 120 mg E METFORMINA IN PAZIENTI AFFETTI DA TUMORI NEUROENDOCRINI GASTRO-INTESTINALI (GI) O CARCINOIDI POLMONARI AVANZATI, BEN DIFFERENZIATI E/O NON RESECABILI.
STUDIO DI FATTIBILITA’, IN APERTO, PROSPETTICO: MetNET-2 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

MetNET2

A.4.1

Sponsor's protocol code number

MetNET2

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN00000000

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00000000

A.5.3

WHO Universal Trial Reference Number (UTRN)

U0000-0000-0000

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	IPSEN S.P.A.
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 Tumori
B.5.2	Functional name of contact point	Clinical Trial Center
B.5.3	Address:
B.5.3.1	Street Address	Via Giacomo Venezian 1
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20133
B.5.3.4	Country	Italy
B.5.4	Telephone number	0223903251
B.5.5	Fax number	0223903992
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	METFORMINA TEVA - 30 CPR RIVESTITE IN BLISTER BIANCO OPACO PVC/PVDC/AL DA 850 MG
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA ITALIA S.R.L.
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	[Metformina]
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.3.9.2	Current sponsor code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	850 to 2550
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	IPSTYL - 30 MG/2 ML POLVERE E SOLVENTE PER SOSPENSIONE INIETTABILE A RILASCIO PROLUNGATO PER USO INTRAMUSCOLARE1 FLACONE POLVERE + 1 FIALA SOLVENTE 2 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	IPSEN S.P.A
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	IPSTYL
D.3.2	Product code	[IPSTYL]
D.3.4	Pharmaceutical form	Powder and solvent for solution for 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	LANREOTIDE
D.3.9.2	Current sponsor code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	120
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Patients with progressive advanced Well-differentiated gastro-intestinal (GI) or lung carcinoids.

Tumore neuroendocrino gastro-intestinale (GI) o carcinoide polmonare ben differenziato in stadio avanzato e/o non resecabile

E.1.1.1

Medical condition in easily understood language

Advanced neuroendocrine tumor

Tumore neuroendocrino in stadio avanzato

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10071542
E.1.2	Term	Neuroendocrine carcinoma 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

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the safety of Lanreotide ATG 120 mg in combination with Metformin as number of AEs and SAEs.

Valutare la Safety (profilo di tollerabilità) in termini di incidenza di AEs e SAEs

E.2.2

Secondary objectives of the trial

To evaluate the time to progression (TTP) to Lanreotide ATG 120 mg in combination with Metformin; To evaluate the symptomatic responses to Lanreotide ATG 120 mg in combination with Metformin in symptomatic patients; To evaluate the biochemical responses to Lanreotide ATG 120 mg in combination with Metformin.

Valutare l’efficacia di Lanreotide ATG 120 mg in combinazione con Metformina sul tempo alla progressione (TTP); Valutare l’efficacia di Lanreotide ATG 120 mg in combinazione con Metformina sulla risposta sintomatica (RR); Valutare l’efficacia di Lanreotide ATG 120 mg in combinazione con Metformina sulla risposta biochimica; Valutare la correlazione prognostica e predittiva di risposta al trattamento dei biomarcatori genetici analizzati

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

(a) Adult patients (male or female, age > 18 years)
(b) Patients with a histologically documented diagnosis of advanced well differentiated (G1 and G2) GI or lung carcinoids, defined according to the last WHO Classification criteria for NET
(c) Tumor tissue available for analysis
(d) Measurable disease and disease progression in the 6 months before study inclusion (according to RECIST vs 1.1), documented and appropriate imaging
(e) Patient who has received prior treatment with surgery or chemotherapy or somatostatin analogues or m-TOR inhibitors or other systemic antineoplastic/target therapies
(f) Functioning or non-functioning NETs
(g) Type-2 Diabetic or normoglycaemic patient
(h) Documented Octreoscan/PET Ga68 uptake/IHC stain of SSTR2 receptor, within 6 months before study entry
(i) Basal blood tests:
- Counts of neutrophils in absolute value> 1.5 x 103 / L
- Platelet count> 100 x 103 / 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
- Alkaline phosphatase <2.5 times the upper limit of normal
- Values of serum creatinine <1.5 mg / dl. - CCr = 60 mL / min
(j) ECOG performance status = 2
(j) Life expectancy > 12 months
(k) Written informed consent

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 tumore neuroendocrino gastrointestinale (GI) o carcinoidi polmonari ben differenziati G1-G2.
4. Tessuto tumorale disponibile per l’analisi.
5. E’ ammesso l’arruolamento di pazienti che non hanno ricevuto nessun trattamento per la malattia avanzata o pazienti pretrattati con chirurgia, con chemioterapia, analoghi della somatostatina, inibitori di m-TOR.
6. Tumori funzionanti o non funzionanti.
7. Pazienti normoglicemici o iperglicemici (Diabete tipo-2)
8. Documentata captazione Octreoscan/PET Ga68 /IHC positive per recettori SSTR2 , entro 6 mesi prima dell’ingresso nello studio.
9. 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
10. ECOG Performance Status = 2
11. Malattia tumorale parametrabile (in accordo ai criteri RECIST).
12. Aspettativa di vita superiore ai 12 mesi.
13. In fase di studio i pazienti di sesso maschile e femminile devono utilizzare metodi contraccettivi idonei.

E.4

Principal exclusion criteria

(a) Surgery performed within 28 days prior to the beginning of study treatment
(b) Brain metastasis or spinal cord compression
(c) 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
(d) Uncontrolled high blood pressure, atrial fibrillation
(e) Cardio-vascular, lung, kidney or hepatic disorders not treated/controlled
(f) Cirrhosis, acute hepatitis or chronic active hepatitis
(g) 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
(h) Active or uncontrolled severe infections
(i) Patients with a condition of metabolic acidosis, acute or chronic, including ketoacitosi
(j) History of POTUS (alcohol abuse), or habitual intake of alcohol (= 3 glasses of alcoholic drinks / day) sufficient to cause hepatotoxicity
(k) Severe states of dehydration
(l) Prolonged fasting
(m) History of immunosuppression, including positive HIV test
(n) 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
(o) Serious neurological or psychiatric disorders
(p) Pregnancy or lactation
(q) Patients that do not use appropriate methods of contraception.

1. Interventi chirurgici effettuati entro 28 giorni prima dell’inizio del trattamento.
2. Evidenza di metastasi a livello del sistema nervoso centrale o di compressione midollare.
3. 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.
4. 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.
5. Attive o incontrollate infezioni di grado severo.
6. Cirrosi, epatiti acute, o epatiti croniche attive.
7. Sono esclusi pazienti che presentano una condizione di acidosi metabolica, acuta o cronica, inclusa ketoacitosi.
8. Anamnesi di potus (abuso alcolico), o abituale introito di sostanze alcoliche ( = 3 bicchieri di bevande alcoliche/die) sufficiente per causare epatotossicità.
9. Gravi stati di disidratazione
10. Digiuno prolungato.
11. Storia di immunodepressione incluso test HIV positivo.
12. 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.
13. I pazienti diabetici che sono in trattamento con metformina sono eleggibili purchè abbiano attivato il trattamento con metformina da meno di 6 mesi.
14. Ipertensione arteriosa non controllabile, fibrillazione atriale.
15. Seri disordini neurologici o psichiatrici
16. Gravidanza o allattamento
17. Pazienti che non utilizzano appropriati metodi contraccettivi

E.5 End points

E.5.1

Primary end point(s)

To evaluate the incidence of AEs and SAEs, physical examination output, laboratory tests results, and cardiologic assessment

Valutazione: dell'incidenza di eventi avversi e eventi avversi seri, esame fisico, risultati di esami di laboratorio, esami cardiologici

E.5.1.1

Timepoint(s) of evaluation of this end point

During treatment study period

Durata del trattemento in studio

E.5.2

Secondary end point(s)

To evaluate the efficacy of Lanreotide ATG 120 mg in combination with Metformin on the time to progression (TTP); To evaluate the efficacy of Lanreotide ATG 120 mg in combination with Metformin on symptomatic response.; To evaluate the efficacy of Lanreotide ATG 120 mg in combination with Metformin on Biochemical Response; To evaluate the prognostic and predictive role of genetic biomarkers in patients treated with Lanreotide ATG 120 mg and Metformin combination

Valutazione dell'efficacia di lanreotide in combinazione con metformina fino alla progressione.; Valutazione dell'efficacia di lanreotide in combinazione con metformina alla risposta sintomatica.; Valutazione dell'efficacia di lanreotide in combinazione con metformina alla risposta biochimica.; Valutazione della correlazione prognostica e predittiva di risposta al trattamento dei biomarcatori genetici analizzati

E.5.2.1

Timepoint(s) of evaluation of this end point

At baseline and every 4 months.; Weekly; Every 4 months; At baseline

Al basale e ogni 4 mesi.; Settimanalmente; Ogni 4 mesi; Al basale

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

Yes

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)

Yes

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.8.4.1

Number of sites anticipated in 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

Information not present in EudraCT

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

Follow up of 12 months for last enrolled patient

Follow up di 12 mesi dall'ultimo paziente arruolato

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

the standard of care in prectice at the investigator site

standard terapeutico utlizzato nella normale pratica clinica

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

2016-03-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-11-26

P. End of Trial
P.	End of Trial Status	Ongoing

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