Clinical Trials Register

Summary
EudraCT Number:	2019-004916-76
Sponsor's Protocol Code Number:	TWINS-GU002
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-10-21
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

2019-004916-76

A.3

Full title of the trial

A phase II study of nivolumab combined with metformin in pre-treated metastatic renal cell carcinoma (mRCC) patients.

Studio di fase II di nivolumab in combinazione con metformina in pazienti con carcinoma del rene metastatico pretrattato.

A.3.1

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

Combination study between nivolumab and metformin in advanced kidney cancer.

Studio di combinazione tra nivolumab e metformina nel tumore del rene avanzato.

A.3.2

Name or abbreviated title of the trial where available

NivoMet

A.4.1

Sponsor's protocol code number

TWINS-GU002

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 POLICLINICO UNIVERSITARIO AGOSTINO GEMELLI IRCCS UNIVERSITA' CATTOLICA DEL SACRO CUORE
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Direzione scientifica Fondazione Policlinico A.Gemelli IRCCS
B.5.2	Functional name of contact point	Direzione Scientifica Fondazione Po
B.5.3	Address:
B.5.3.1	Street Address	Largo Agostino Gemelli 8
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00168
B.5.3.4	Country	Italy
B.5.4	Telephone number	0630155701
B.5.5	Fax number	0630155701
B.5.6	E-mail	direzione.scientifica@policlinicogemelli.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	Opdivo
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	Nivolumab
D.3.2	Product code	[Nivolumab]
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NIVOLUMAB
D.3.9.1	CAS number	946414-94-4
D.3.9.2	Current sponsor code	946414-94-4
D.3.9.3	Other descriptive name	NIVOLUMAB
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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)	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	Yes
D.3.11.13.1	Other medicinal product type	anticorpo monoclonale
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.2.5	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
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.3.8	INN - Proposed INN	METFORMINA
D.3.9.1	CAS number	657-24-9
D.3.9.2	Current sponsor code	657-24-9
D.3.9.3	Other descriptive name	METFORMINA
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	1000
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 advanced renal cell carcinoma pre-treated with VEGFR inhibitors.

Pazienti con carcinoma renale avanzato pre-trattati con farmaci inibitori del VEGFR.

E.1.1.1

Medical condition in easily understood language

Patients with advanced renal cell carcinoma pre-treated with VEGFR inhibitors.

Pazienti con carcinoma renale avanzato pre-trattati con farmaci inibitori del VEGFR.

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	21.0
E.1.2	Level	PT
E.1.2	Classification code	10073251
E.1.2	Term	Clear cell renal cell carcinoma
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 investigate if the addiction of metformin increases the activiti of nivolumab in metastatic kidney cancer.

Valutare se la metformina aumenta l'attività di nivolumab nel carcinoma renale metastatico.

E.2.2

Secondary objectives of the trial

To investigate the safety, activity and quality of life of patients who received the combination of metformin and nivolumab for metastatic kidney cancer.

Valutare la sicurezza, l'attività e la qualità della vita dei pazienti che hanno ricevuto la combinazione di metformina e nivolumab per carcinoma renale metastatico.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Willing and able to provide written informed consent
2. Male aged 18 years and above
3. Histological confirmation of RCC with a clear cell component
4. Advanced or metastatic RCC
5. Measurable disease as defined by RECIST1.1criteria
6. Must have received at least one prior systemic treatment regimen in the advanced or metastatic setting, and must have evidence of progression on or after the last treatment regimen received
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2
8. Adequate bone marrow and chemistry values defined as:
a. Hemoglobin = 9.0 g/dL independent of transfusion
b. Platelet count =100.000/µL
c. Serum creatinine < 1.5 x ULN or a calculated creatinine clearance = 40 mL/min
d. Liver function:
i. Serum bilirubin < 1.5 x ULN (except for patients with documented Gilbert’s disease)
ii. AST or ALT < 2.5 x ULN
9. Life expectancy of at least 6 months
10. Patients who have partners of childbearing potential must be willing to use a method of birth control with adequate barrier protection as determined to be acceptable by the principal investigator and sponsor during the study and for 13 weeks after last study drug administration.

1. Pazienti in grado di fornire il consenso informato scritto
2. Età di 18 anni e oltre
3. Carcinoma a cellule renali con componente a cellule chiare istologicamente o citologicamente confermato
4. Malattia avanzata o metastatica
5. Malattia misurabile documentata da TC total body (e/o RMN addome e TC torace) secondo i criteri RECIST 1.1
6. Progressione radiografica del carcinoma renale secondo i criteri RECIST ad almeno una precedente linea di terapia
7. Stato di prestazione del gruppo di oncologia cooperativa orientale (ECOG) ¿ 2
8. Valori adeguati del midollo osseo e della chimica definiti come:
a. Emoglobina = 9.0 g/dL indipendente da trasfusione
b. Conta piastrinica =100.000/µL
c. Creatinina sierica <1,5 x ULN o clearance della creatinina calcolata = 40 ml/min
d. Funzione epatica:
¿ Bilirubina sierica <1,5 x ULN (ad eccezione dei pazienti con malattia di Gilbert documentata)
¿ AST o ALT <2,5 x ULN
9. Aspettativa di vita di almeno 6 mesi
10. I pazienti che hanno partner in età fertile devono essere disposti a utilizzare un metodo di controllo delle nascite con un'adeguata protezione barriera durante lo studio e per 13 settimane dopo l’ultima somministrazione del farmaco in studio.

E.4

Principal exclusion criteria

1. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection
2. Any active known or suspected autoimmune disease
3. Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to the first dose of study drug. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease
4. Uncontrolled adrenal insufficiency
5. Evidence of active pneumonitis during screening, except for pulmonary fibrosis induced by prior thoracic irradiation
6. Dialitic patients
7. Diabetes mellitus
8. Any history of biguanide-based therapy within 1 year prior to enrollment
9. Current severe, uncontrolled systemic disease
10. Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction measurement of < 50% at baseline
11. Other malignancy with a previous diagnosis within 5 years (with the exclusions of NMIBC, CIN).
12. Prior treatment with an anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.

1. Epatite virale B o C attiva o cronica, o infezione da HIV
2. Malattie autoimmuni
3. Patologie che richiedano un trattamento corticostereoideo sistemico (> 10 mg/die di prednisone o equivalente) o altri farmaci immunosoppressivi entro 14 giorni prima della randomizzazione. Steroidi inalatori e terapia steroidea sostitutiva surrenalica > 10 mg di prednisone equivalente giornaliero sono consentiti in assenza di malattia autoimmune attiva.
4. Insufficienza surrenalica non controllata
5. Riscontro di polmonite attiva durante lo screening, ad eccezione di fribrosi polmonare indotta da precedente RT a livello toracico
6. Pazienti in dialisi
7. Diabete Mellito in terapia farmacologica
8. Qualsiasi storia di terapia a base di biguanidi entro un anno prima dall’arruolamento
9. Patologie concomitanti severe, non sotto controllo farmacologico e/o clinico
10. Cardiopatia clinicamente significativa come evidenziato da infarto miocardico, o eventi trombotici arteriosi negli ultimi 6 mesi, angina grave o instabile, o cardiopatia di classe II-IV di New York Heart Association (NYHA) o misurazione della frazione di eiezione cardiaca <50%.
11. Altri tumori maligni con una precedente diagnosi entro 5 anni (con le esclusioni di NMIBC, CIN).
12. Precedente trattamento con anti-PD-1 o PD-L1 o anti-CTLA4

E.5 End points

E.5.1

Primary end point(s)

To evaluate the Progression-Free Survival (PFS) rate at 9 months of the combination of nivolumab plus metformin in mRCC patients previously treated with at least one anti-angiogenic therapy.

Valutare il tasso di sopravvivenza libera da progressione (PFS) a 9 mesi dalla combinazione di nivolumab più metformina in pazienti con mRCC precedentemente trattati con almeno una terapia anti-angiogenica.

E.5.1.1

Timepoint(s) of evaluation of this end point

9 months

9 mesi

E.5.2

Secondary end point(s)

Objective response rate; Median progression free surival; Overall survival; Safety of the combination; Quality of life

Tasso di risposte obiettive; Tempo mediano alla progressione; Sopravvivenza complessiva; Sicurezza della combinazione; Qualità della vita

E.5.2.1

Timepoint(s) of evaluation of this end point

9 months; 9 months; 9 months; 9 months; 9 months

9 mesi; 9 mesi; 9 mesi; 9 mesi; 9 mesi

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

E.6.5

Efficacy

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

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

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

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

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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)

Patients will be treated according to clinical practice.

I pazienti verranno trattati secondo la 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

2020-07-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-07-16

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2023-09-13

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