Clinical Trials Register

Summary
EudraCT Number:	2016-005126-11
Sponsor's Protocol Code Number:	D419CC00002
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Restarted
Date on which this record was first entered in the EudraCT database:	2018-11-15
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

2016-005126-11

A.3

Full title of the trial

A Randomized, Open-label, Multi-center Phase III Study of Durvalumab and Tremelimumab as First-line Treatment in Patients with Unresectable Hepatocellular Carcinoma

Studio Randomizzato, in Aperto, Multicentrico di Fase III di Durvalumab e Tremelimumab come Terapia di Prima Linea in Pazienti con Carcinoma Epatocellulare non operabile

A.3.1

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

This is a randomized, open-label, multi-center, global, Phase III study to assess the effectiveness and safety of two Immune Therapy drugs, durvalumab given by itself or with tremelimumab versus sorafenib, the standard first line treatment, to treat patients with no prior systemic therapy for liver cancer (hepatocellular carcinoma) that cannot be removed by surgery (unresectable).

Studio di Fase III randomizzato, multicentrico, multinazionale, per valutare l'efficacia e la sicurezza di due farmaci per l' immunoterapia, durvalumab somministrato da sé o con tremelimumab verso sorafenib, il trattamento standard di prima linea, per trattare pazienti senza alcuna terapia sistemica precedente per il tumore al fegato (carcinoma epatocellulare) che non può essere rimosso mediante intervento chirurgico (non resecabile).

A.3.2

Name or abbreviated title of the trial where available

HIMALAYA

A.4.1

Sponsor's protocol code number

D419CC00002

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	ASTRAZENECA AB
B.1.3.4	Country	Sweden
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	AstraZeneca AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AstraZeneca Clinical
B.5.2	Functional name of contact point	Study Information Center
B.5.3	Address:
B.5.3.1	Street Address	-
B.5.3.2	Town/ city	-
B.5.3.3	Post code	0
B.5.3.4	Country	United States
B.5.4	Telephone number	18772409479
B.5.5	Fax number	0
B.5.6	E-mail	information.center@astrazeneca.com

D. IMP Identification
D.IMP: 1
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	Nexavar
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Pharma AG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	EU/3/06/364
D.3 Description of the IMP
D.3.1	Product name	sorafenib
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	sorafenib
D.3.9.1	CAS number	284461-73-0
D.3.9.2	Current sponsor code	-
D.3.9.3	Other descriptive name	Sorafenib
D.3.9.4	EV Substance Code	-
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	200
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.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	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	MEDI4736
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
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	durvalumab
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/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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: 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	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	tremelimumab
D.3.2	Product code	MEDI1123
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
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	tremelimumab
D.3.9.1	CAS number	745013-59-6
D.3.9.2	Current sponsor code	MEDI4736
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	20
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

unresectable hepatocellular carcinoma (HCC)

Carcinoma Epatocellulare non Resecabile (HCC)

E.1.1.1

Medical condition in easily understood language

liver cancer that cannot be removed by surgery

Cancro al fegato che non può essere rimosso chirurgicamente

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	20.0
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

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the efficacy of durvalumab plus tremelimumab compared with sorafenib.

Valutare l'efficacia di durvalumab più tremelimumab rispetto a sorafenib

E.2.2

Secondary objectives of the trial

-To assess the efficacy of durvalumab monotherapy and durvalumab plus tremelimumab combination therapy compared with sorafenib
-To assess the efficacy of all immunotherapy arms compared with sorafenib by PD-L1 expression
-To assess disease-related symptoms and health-related quality of life (HRQoL) in patients treated with all immunotherapy arms compared with sorafenib
- To evaluate the population PK and pharmacodynamics of all immunotherapy arms
- To investigate the immunogenicity of all immunotherapy arms

Valutare l'efficacia di durvalumab in monoterapia e durvalumab e tremelimumab in terapia combinata rispetto a sorafenib

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- HCC (unresectable hepatocellular carcinoma) histopathological diagnosis confirmation based on tumor tissue
- No prior systemic therapy for HCC
- Barcelona Clinic Liver Cancer (BCLC) stage B (that is not eligible for locoregional therapy) or stage C
- Child-Pugh Score class A
- ECOG performance status of 0 or 1 at enrollment

- Diagnosi di Carcinoma Epatocellulare non resecabile basata su tessuto tumorale
- Nessuna terapia sistemica precedente per il Carcinoma Epatocellulare
-Stadio C secondo il Barcelona Clinic Liver Cancer
-Classificazione A secondo la classificazione di Child-Pugh delle malattie al fegato
- ECOG performance status 0 o 1 al momento dell'arruolamento

E.4

Principal exclusion criteria

- Hepatic encephalopathy within past 12 months or requirement for medication to prevent or control encephalopathy
- Ascites that requires ongoing paracentesis to control symptoms (within 6 weeks prior to the first scheduled dose)
- Main portal vein thrombosis
- Active or prior documented GI variceal bleed or history of upper GI bleeding, ulcers or esophageal varices with bleeding within 12 months
- HBV and HCV co-infection

- Encefalopatia epatica negli ultimi 12 mesi o necessità di farmaci per prevenire o controllare l'encefalopatia
- Asciti che richiedono una paracentesi continua per controllare i sintomi (entro 6 settimane prima della prima dose programmata)
- Trombosi venosa della vena porta
- Sanguinamento gastrointestinale variceale attivo o precedentemente documentato o storia di sanguinamento del tratto gastrointestinale superiore, ulcere o varici esofagee con sanguinamento entro 12 mesi
- co-infezione da HBV e HCV

E.5 End points

E.5.1

Primary end point(s)

Overall survival (OS) is defined as the time from the date of randomization until death due to any cause.

La sopravvivenza globale (OS) è definita come il tempo trascorso dalla data della randomizzazione fino alla morte, dovuta a qualsiasi causa

E.5.1.1

Timepoint(s) of evaluation of this end point

Patient level: Assessments for survival will be made every 4 weeks during treatment period and every 2 months following treatment discontinuation which will continue until the end of the study unless the patient has expressly withdrawn their consent to survival follow-up. In addition, all patients will be contacted in the week following data cutoff to confirm survival status

Livello del paziente: Le valutazioni per la sopravvivenza saranno effettuate ogni 4 settimane durante il periodo di trattamento e ogni 2 mesi dopo la sospensione del trattamento che continuerà fino alla fine dello studio a meno che il paziente non abbia espressamente ritirato il suo consenso al follow-up della sopravvivenza. Inoltre, tutti i pazienti saranno contattati nella settimana successiva al data cutoff per confermare lo stato di sopravvivenza

E.5.2

Secondary end point(s)

Other secondary efficacy endpoints include: OS (Overall survival), Time to progression (TTP), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and duration of response (DoR)

Altri endpoint secondari di efficacia includono:
OS (sopravvivenza globale), tempo di progressione (TTP), sopravvivenza libera da progressione (PFS), tasso di risposta obiettiva (ORR), tasso di controllo della malattia (DCR) e durata della risposta (DoR

E.5.2.1

Timepoint(s) of evaluation of this end point

TTP, PFS, ORR, DoR, DCR - Patient level: Efficacy for all patients will be assessed by objective tumor assessments every 8 weeks (±1 week) for the first 48 weeks (relative to the date of randomization; then every 12 weeks (±1 week) thereafter until confirmed PD as defined by RECIST 1.1 or discontinuation from study participation. OS18 and OS24 - Patient level: Assessments for survival will be made every 4 weeks during treatment period and every 2 months following treatment discontinuation which will continue until the end of the study unless the patient has expressly withdrawn their consent to survival follow-up. In addition, all patients will be contacted in the week following data cutoff to confirm survival status.

TTP, PFS, ORR, DoR, DCR - Livello del paziente: L'efficacia per tutti i pazienti sarà valutata con valutazione oggettiva del tumore ogni 8 settimane (± 1 settimana) per le prime 48 settimane (rispetto alla data di randomizzazione; ± 1 settimana) successivamente ogni 12 settimane (± 1 settimana) fino a quando non sarà stata confermata la PD come definito da RECIST 1.1 o la sospensione dalla partecipazione allo studio OS18 e OS24 - Livello del paziente: le valutazioni per la sopravvivenza verranno effettuate ogni 4 settimane durante il periodo di trattamento e ogni 2 mesi dopo la sospensione del trattamento fino alla fine dello studio, a meno che il paziente non abbia espressamente ritirato il suo consenso al follow-up della sopravvivenza. Inoltre, tutti i pazienti saranno contattati nella s

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability
Healthcare resource utilization
Quality of life

Tollerabilità
Utilizzo delle risorse sanitarie
Qualità della vita

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

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

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

Brazil

Canada

China

France

Germany

Hong Kong

India

Italy

Japan

Korea, Republic of

Russian Federation

Spain

Taiwan

Thailand

Ukraine

United States

Vietnam

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

Last patients’ treatment discontinuation.

Ultima interruzione di trattamento dei pazienti.

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

Number of subjects for this age range:

F.1.1.1

In Utero

Information not present in EudraCT

F.1.1.2

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

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

960

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

640

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

Yes

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

A legal representative may provide consent on behalf of a subject incapable of giving consent personally, where permitted by local regulations.

Un rappresentante legale può fornire il consenso per conto di un soggetto incapace di dare il consenso personalmente, se consentito dalle normative locali.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

100

F.4.2

For a multinational trial

F.4.2.1

In the EEA

348

F.4.2.2

In the whole clinical trial

1600

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)

After the final analysis, AstraZeneca will continue to supply open-label drug to patients receiving immunotherapy until confirmed PD, unacceptable toxicity, or any of the discontinuation criteria are met.

Dopo l'analisi finale, AstraZeneca continuerà a fornire i farmaci in aperto ai pazienti che ricevono l' immunoterapia fino a che non siano stati confermati PD, tossicità inaccettabile o qualsiasi criterio di sospensione.

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

2017-10-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-10-17

P. End of Trial
P.	End of Trial Status	Restarted

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