Clinical Trials Register

Summary
EudraCT Number:	2020-001588-10
Sponsor's Protocol Code Number:	VIVA
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:	2021-08-02
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

2020-001588-10

A.3

Full title of the trial

A randomized, phase IIb study of adjuvant durvalumab (MEDI4736)
plus regorafenib vs untreated control in stage IV colorectal cancer patients with no evidence of disease (NED): VIVA trial

Studio randomizzato di fase IIb sulla associazione di durvalumab e regorafenib come terapia adiuvante nei pazienti con adenocarcinoma del colon-retto in stadio IV senza evidenza di malattia (NED): trial VIVA

A.3.1

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

Adjuvant therapy in stage IV colorectal cancer patients NED

terapia adiuvante nei pazienti con adenocarcinoma del colon-retto in stadio IV NED

A.3.2

Name or abbreviated title of the trial where available

VIVA trial

Studio VIVA

A.4.1

Sponsor's protocol code number

VIVA

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	IRCCS-A.O.U. SAN MARTINO-IST
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	AIRC
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	Astra Zeneca
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	Bayer
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 GISCAD
B.5.2	Functional name of contact point	Gestione del Regolatorio: inserimen
B.5.3	Address:
B.5.3.1	Street Address	Via Gattinoni 4
B.5.3.2	Town/ city	Vanzago
B.5.3.3	Post code	20043
B.5.3.4	Country	Italy
B.5.4	Telephone number	0284968409
B.5.5	Fax number	0284968441
B.5.6	E-mail	centrotrialgiscad@yahoo.com

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	No
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	DURVALUMAB
D.3.2	Product code	[EMEA/H/C/4771]
D.3.4	Pharmaceutical form	Concentrate for solution for injection/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.3.9.1	CAS number	1428935-60-7
D.3.9.2	Current sponsor code	MEDI4736
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	600
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	Yes
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	Comparator
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	STIVARGA
D.2.1.1.2	Name of the Marketing Authorisation holder	BAYER AG
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	REGORAFENIB (STIVARGA)
D.3.2	Product code	[BAY 73-4506]
D.3.4	Pharmaceutical form	Modified-release 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	EU/1/13/858/02
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	160
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	Yes
D.3.11.13.1	Other medicinal product type	inibitore delle protein-chinasi

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

stage IV colorectal cancer patients with no evidence of disease (NED)

nei pazienti con adenocarcinoma del colon-retto in stadio IV senza evidenza di malattia (NED)

E.1.1.1

Medical condition in easily understood language

colorectal adenocarcinoma

adenocarcinoma del colon retto

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	LLT
E.1.2	Classification code	10001172
E.1.2	Term	Adenocarcinoma of colon stage IV
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Disease Free Survival (DFS)

Sopravvivenza libera da malattia (DFS)

E.2.2

Secondary objectives of the trial

¿ 18-months Disease-Free Survival (DFS)
¿ Adverse events and Toxicity
¿ Overall Survival (OS)
¿ Compliance to the experimental treatment

¿ Sopravvivenza libera da malattia (DFS) a 18 mesi
¿ Eventi avversi e tossicità
¿ Sopravvivenza globale (OS)
¿ Compliance al trattamento sperimentale

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed ICF, after oral as well as written information;
2. = 18 years;
3. Body weight >30 kg
4. Histologically confirmed diagnosis of colorectal adenocarcinoma;
5. Patients must be in NED after completion of any treatments for stage IV CRC, including resections, RFA; RT with or without neoadjuvant/adjuvant therapies or CR after chemotherapy;
6. Patients must be randomized within 10 weeks since the achievement of the NED state. Those who have also received adjuvant therapy following the locoregional treatment are still eligible, provided they are randomized within 4 weeks since the last chemotherapy cycle;
7. NED state ascertained by means of CT scan and/or PET scan and/or MRI scan;
8. ECOG Performance Status </= 1;
9. Must have a life expectancy of at least 12 weeks
10. CEA within normal limits
11. No residual toxicity from previous chemotherapy;
12. Women of childbearing potential must use safe contraception

1. Firmare il CI, dopo adeguata informazione orale o scritta;
2. = 18 anni d’età;
3. ECOG Performance Status = 1;
4. Diagnosi istologica confermata di adenocarcinoma del colonretto;
5. I pazienti devono avere non evidenza di malattia (NED) dopo aver completato qualsiasi trattamento per lo stadio IV, incluso resezioni chirurgiche, radiofrequenze (RFA), radioterapia (RT) con o senza terapia neoadiuvante/adiuvante, o risposta completa (RC) dopo chemioterapia;
6. I pazienti devono essere randomizzati entro 10 settimane dal raggiungimento dello stato NED. Coloro che hanno ricevuto terapia adiuvante dopo trattamento locoregionale sono eleggibili, solo se possano essere randomizzati entro 4 settimane dall’ultimo ciclo della chemioterapia adiuvante.
7. Stato NED valutato con TC e/o PET e/o RM;
8. ECOG Performance Status </= 1
9. CEA entro i limiti della norma;
10. Non evidenza di lesioni sospette agli esami strumentali;
11. Esami ematochimici permissivi;
12. Donne in età fertile devono utilizzare metodi contraccettivi

E.4

Principal exclusion criteria

1. History of another primary malignancy within the last 5 years
2. Patients with microsatellite instability (MSI) or DNA Mismatch Repair Deficiency (dMMR) are not allowed.
3. Any form of systemic disease that, in the opinion of the Investigator, would make the subject unsuitable for the study
4. Adeguate Serum Creatinine
5. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control
6. Any condition that, in the opinion of the investigator, would interfere with evaluation of the study drug or interpretation of patient safety or study results
7. Participation in another clinical study

1. Presenza di qualsiasi altra neoplasia attiva o storia di neoplasia entro i 5 anni;
2. Pazienti con instabilità dei microsatelliti (MSI) o deficit del mismatch repair (dMMR) sono esclusi;
3. Qualsiasi malattia sistematica che, a giudizio del clinico, renderebbe il paziente non adeguato per lo studio (incluse malattie autoimmune);
4. Creatinina sierica > 2.0 x limite superiore della norma;
5. Donne incinta o in allattamento;
6. Malattie mentali che possano compromettere la compliance allo studio;
7. Partecipazione a qualsiasi altro trial clinico

E.5 End points

E.5.1

Primary end point(s)

Disease Free Survival (DFS)

Sopravvivenza libera da malattia (DFS)

E.5.1.1

Timepoint(s) of evaluation of this end point

the following condition will be considered DFS event: Two consecutive increases in CEA levels above upper limit level (time gap decided by the clinical investigator).

verrà considerato come evento di DFS anche due incrementi consecutivi dell’antigene carcinoembrionario (CEA) sopra il limite superiore della norma (l’intervallo temporale a cui eseguire le rilevazioni del CEA sono a decisione del clinico sperimentatore).

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

E.6.4

Safety

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

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

Yes

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

Yes

E.8.2.3.1

Comparator description

no trattamento. Crossover a Regorafenib + Durvalumab dopo recidiva.

no treatment. Crossover to Regorafenib + Durvalumab upon relapse

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

170

F.4.2

For a multinational trial

F.4.2.1

In the EEA

170

F.4.2.2

In the whole clinical trial

170

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 randomized to an inactive control vs the possibility of receiving durvalumab + regorafenib: patients randomized in control arm will receive rdurvalumab + regorafenib when relapsed (crossover) Chemotherapy is going to have a median of 4 months until Disease progression. Patients will be anyway followed for 2 years of follow-up

I pazienti vengono randomizzarli in un braccio ad un controllo senza trattamento e nell’altro a ricevere durvalumab + regorafenib: ai pazienti nel braccio di controllo verrà proposto il crossover a regorafenib e durvalumab nel momento della recidiva di malattia. La terapia avrà una durata mediana di circa 4 mesi fino a progressione di malattia. Il pazinte sarà comunque seguito per un follow-up di 2 anni

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

2021-01-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-09-27

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

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