Clinical Trials Register

Summary
EudraCT Number:	2016-000085-32
Sponsor's Protocol Code Number:	TG6006.01
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:	2020-11-04
Trial results	View 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

2016-000085-32

A.3

Full title of the trial

A phase I/IIa trial to evaluate the safety and efficacy of the combination of the oncolytic immunotherapy Pexa-Vec with the PD-1 receptor blocking antibody nivolumab in the first-line treatment of advanced hepatocellular carcinoma (HCC)

Studio di fase I/IIa che mira a valutare la tollerabilità e l’efficacia della combinazione fra l’immunoterapia oncolitica Pexa-Vec e l’anticorpo inibente il recettore PD-1 nivolumab nel trattamento di prima linea del carcinoma epatocellulare (CHC) avanzato

A.3.1

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

The purpose of this study is to evaluate the safety and efficacy of the combination of two products Pexa-Vec and nivolumab for the treatment of liver cancer

L'obiettivo dello studio clinico è di valutare la sicurezza e l'efficacia della combinazione dei due prodotti Pexa-Vec e nivolumab per il trattamento del tumore del fegato

A.3.2

Name or abbreviated title of the trial where available

TG6006.01

A.4.1

Sponsor's protocol code number

TG6006.01

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03071094

A.5.4

Other Identifiers

Name:

TG6006.01

Number:

TG6006.01

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	TRANSGENE SA
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	TRANSGENE
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	TRANSGENE
B.5.2	Functional name of contact point	Medical Affairs Secretariat
B.5.3	Address:
B.5.3.1	Street Address	400 boulevard Gonthier d'Andernach - Parc d'Innovation - CS80166
B.5.3.2	Town/ city	Illkirch Graffenstaden
B.5.3.3	Post code	67405
B.5.3.4	Country	France
B.5.4	Telephone number	0033388279155
B.5.5	Fax number	0033388279141
B.5.6	E-mail	clinical.trials@transgene.fr

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	Yes
D.2.5.1	Orphan drug designation number	EMA/OD/076/09
D.3 Description of the IMP
D.3.1	Product name	pexastimogene devacirepvec
D.3.2	Product code	[Pexa-Vec]
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intratumoral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Pexastimogene devacirepvec
D.3.9.2	Current sponsor code	Pexa-Vec or TG6006 or JX-594
D.3.9.3	Other descriptive name	Vaccinia GM-CSF/TK-deactivated virus
D.3.10	Strength
D.3.10.1	Concentration unit	PFU plaque forming unit
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	999999999
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)	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	Yes
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Yes
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)	Yes
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	Yes
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	OPDIVO - 10 MG/ML- CONCENTRATO PER SOLUZIONE PER INFUSIONE- USO ENDOVENOSO- FLACONCINO (VETRO)- 4 ML- 1 FLACONCINO
D.2.1.1.2	Name of the Marketing Authorisation holder	BRISTOL-MYERS SQUIBB PHARMA EEIG
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	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.3.9.2	Current sponsor code	Nivolumab
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
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.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

Hepatocellular carcinoma

Carcinoma epatocellulare

E.1.1.1

Medical condition in easily understood language

Liver cancer

Tumore del fegato

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	10019828
E.1.2	Term	Hepatocellular carcinoma non-resectable
E.1.2	System Organ Class	100000004864

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

Phase I part: To evaluate the safety profile of intratumoral (IT) Pexa-Vec combined with intravenous (IV) nivolumab in patients with advanced HCC.
Phase IIa part: To evaluate the anti-tumor activity and efficacy of IT Pexa-Vec combined with IV nivolumab in patients with advanced hepatocellular carcinoma (HCC) with respect to Overall Response Rate (ORR) (RECIST 1.1).

Parte della fase I: Valutare il profilo di tollerabilità di Pexa-Vec per via intratumorale (IT) associato a nivolumab per via endovenosa (EV) in pazienti con CHC avanzato.
Parte della fase IIa: Valutare l’attività antitumorale e l’efficacia di Pexa-Vec IT associato a nivolumab EV in pazienti con carcinoma epatocellulare (CHC) avanzato rispetto al tasso di risposta globale (TRG) (RECIST 1.1).

E.2.2

Secondary objectives of the trial

To evaluate the efficacy of Pexa-Vec combined with nivolumab in patients with advanced HCC with respect to the following endpoints (imaging endpoints evaluated by RECIST 1.1):
• Safety (Phase IIa)
• Disease Control Rate (DCR)
• Time to Progression (TTP)
• Duration of Response (DoR)
• Progression Free Survival (PFS)
• Overall Survival (OS)
• Blood viral load (HCV, HBV when appropriate)

Valutare l’efficacia di Pexa-Vec associato a nivolumab in pazienti con CHC avanzato rispetto ai criteri seguenti (parametri di diagnostica per immagini valutati secondo i criteri RECIST 1.1):
• Tollerabilità (Fase IIa)
• Tasso di controllo della malattia (TCM)
• Tempo alla progressione (TAP)
• Durata della risposta (DR)
• Sopravvivenza libera da progressione (SLP)
• Sopravvivenza globale (SG)
• Carica virale plasmatica (HCV, HBV se necessario)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female patients, age =18 years old
2. Histological/cytological diagnosis of primary HCC, excluding cholangiocarcinoma, hepatocholangiocarcinoma, fibrolamellar carcinoma and hepatoblastoma
3. Advanced stage HCC per EASL-EORTC (European Association for the Study of the Liver-European Organisation for Research and Treatment of Cancer) guidelines, i.e. patients who are not candidates for curative interventions and not candidates for locoregional modalities
4. Patients naïve to systemic therapy for HCC
5. Tumor status (as determined by radiology evaluation): At least one measurable viable tumor in the liver, =1 cm longest diameter (LD), using a dynamic imaging technique (arterial phase of triphasic computerized tomography [CT] scan, or dynamic contrast-enhanced magnetic resonance imaging [MRI]), and injectable under imaging-guidance (CT or ultrasound)
6. At least one tumor that has not received prior local-regional treatment, or that has exhibited definitive growth of viable tumor since prior local-regional treatment of HCC undertaken at least 4 weeks prior to enrolment or 3 months prior to enrolment for radioembolization
7. Child-Pugh Class A. Note: paracentesis, albumin infusion or diuretic treatment cannot be used to downgrade Child-Pugh score (e.g., to improve from severe to moderate/mild or from moderate to mild ascites)
8. Performance status 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale

1. Pazienti di sesso maschile o femminile, di età ¿=18 anni.
2. Diagnosi istologica/citologica di CHC primitivo, all’infuori di colangioma, epatocolangiocarcinoma, carcinoma fibrolamellare ed epatoblastoma.
3. CHC di stadio avanzato secondo le direttive EASL-EORTC (European Association for the Study of the Liver-European Organisation for Research and Treatment of Cancer), vale a dire pazienti non candidati a interventi curativi e non candidati a modalità terapeutiche locoregionali.
4. Pazienti che non hanno mai ricevuto trattamenti sistemici per il CHC.
5. Stato tumorale (determinato mediante valutazione radiologica): almeno un tumore vitale misurabile nel fegato, con diametro maggiore =1 cm, valutato con una tecnica di diagnostica per immagini dinamica (fase arteriosa di una tomodensitometria trifasica [TDM] o imaging a risonanza magnetica [MRI] dinamico (con iniezione di mezzo di contrasto), che possono ricevere iniezioni guidate mediante diagnostica per immagini (TDM o ecografia).
6. Almeno un tumore che non abbia ricevuto trattamenti locoregionali precedenti, o che abbia presentato una crescita definitiva da tumore vitale dal trattamento locoregionale precedente per il CHC effettuato almeno 4 settimane prima dell’inclusione o 3 mesi prima dell’inclusione per la radioembolizzazione.
7. Classe A di Child-Pugh. Nota: non è possibile ricorrere a paracentesi, perfusione di albumina o a terapia diuretica per abbassare il punteggio di Child-Pugh (migliorare l’ascite da grave a moderata/lieve o da moderata a lieve).
8. Stato prestazionale di 0 o 1 sulla scala ECOG (Eastern Cooperative Oncology Group).

E.4

Principal exclusion criteria

1. Major surgery within 4 weeks of study treatments (minor surgical procedures are allowed e.g., intravascular access line or Port-a-Cath®)
2. Local-regional therapy of HCC within 4 weeks or radioembolization within 3 months prior to enrolment
3. Histological diagnosis of cholangiocarcinoma, hepatocholangiocarcinoma, fibrolamellar carcinoma and hepatoblastoma

1. Intervento chirurgico maggiore nelle 4 settimane precedenti i trattamenti dello studio (gli interventi chirurgici minori sono accettati; ad esempio la collocazione di un dispositivo di accesso intravascolare o di Port-a-Cath®).
2. Trattamento locoregionale del CHC nelle 4 settimane o radioembolizzazione nei 3 mesi precedenti l’inclusione.
3. Diagnosi istologica di colangioma, epatocolangiocarcinoma, carcinoma fibrolamellare o epatoblastoma.

E.5 End points

E.5.1

Primary end point(s)

Phase I part: Safety - adverse events and serious adverse events (SAE) graded according to NCI CTCAE version 4.03
Phase IIa: Overall Response Rate (ORR)

Fase I: Tollerabilità - Gli eventi avversi e gli eventi avversi gravi (SAE) saranno segnalati e registrati secondo la classificazione CTCAE del NCI (National Cancer Institute’s Common Toxicity Criteria for Adverse Events), versione 4.03
Fase IIa: Tasso di Risposta Globale (TRG)

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase I: AEs and SAEs collection at Day 1, Day 15, Day 29, Week 6, then every 2 weeks.
Phase IIa: Radiological assessments will be performed at Sreening and repeated every 6 weeks until documented progression or discontinuation of treatment beyond progression.

Fase I: eventi avversi e eventi avversi gravi (SAE) collezione al giorno 1, giorno 15, giorno 29, settimana 6, poi ogni 2 settimane.
Fase IIa: Accertamenti radiologici saranno compiuti a Rasserenando e saranno ripetuti ogni 6 settimane fino a che procedere documentato o interruzione di trattamento oltre procedere.

E.5.2

Secondary end point(s)

Safety. Disease Control Rate (DCR). Time to Progression (TTP). Duration of Response (DoR). Progression Free Survival (PFS). Overall Survival (OS). Blood viral load (HCV, HBV when appropriate).

Tollerabilità. Tasso di controllo della malattia (TCM). Tempo alla progressione (TAP). Durata della risposta (DR). Sopravvivenza libera da progressione (SLP). Sopravvivenza globale (SG). Carica virale plasmatica (HCV, HBV se necessario).

E.5.2.1

Timepoint(s) of evaluation of this end point

Safety: AEs and SAEs collection at Day 1, Day 15, Day 29, Week 6, then every 2 weeks.
Radiological assessments will be performed at Sreening and repeated every 6 weeks until documented progression or discontinuation of treatment beyond progression.

Tollerabilità: eventi avversi e eventi avversi gravi (SAE) collezione al giorno 1, giorno 15, giorno 29, settimana 6, poi ogni 2 settimane.
Accertamenti radiologici saranno compiuti a Rasserenando e saranno ripetuti ogni 6 settimane fino a che procedere documentato o interruzione di trattamento oltre procedere.

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

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Safety

Tollerabilità

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

France

Italy

United States

E.8.7

Trial has a data monitoring committee

Yes

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

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)

Not applicable - Standard treatment of HCC condition after patient study completion.

Non applicabile - trattamento standard della condizione di HCC dopo il completamento dello studio per il paziente.

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

2018-03-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-05-04

P. End of Trial
P.	End of Trial Status	Completed

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Orphan Designation Number:
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