Clinical Trials Register

Summary
EudraCT Number:	2015-001663-39
Sponsor's Protocol Code Number:	D4190C00022
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-10-05
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

Spain - AEMPS

A.2

EudraCT number

2015-001663-39

A.3

Full title of the trial

A Study of Safety, Tolerability, and Clinical Activity of MEDI4736 and Tremelimumab Administered as Monotherapy and in Combination to Subjects with Unresectable Hepatocellular Carcinoma

Estudio de seguridad, tolerabilidad y actividad clínica de MEDI4736 y tremelimumab administrados en monoterapia y en combinación a pacientes con carcinoma hepatocelular no resecable

A.3.1

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

A clinical trial in patients with liver cancer that cannot be removed by surgery, investigating the safety, tolerability, and clinical activity of investigational drugs MEDI4736 and tremelimumab. The study will look at the effect of these two drugs either as a single agents (monotherapy) or as combination therapy (when given together to patients).

Ensayo clínico en pacientes con cáncer de hígado que no se puede extirpar mediante cirugía, en el que se investiga la seguridad, tolerabilidad y actividad clínica de los medicamentos en investigación MEDI4736 y tremelimumab. En el estudio se investigará el efecto de estos dos medicamentos administrados solos (monoterapia) o en combinación (cuando se administran los dos juntos a los pacientes).

A.4.1

Sponsor's protocol code number

D4190C00022

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02519348

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	MedImmune
B.1.3.4	Country	United States
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	Medimmune, Limited
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	MedImmune, LLC
B.5.2	Functional name of contact point	Clinical Trial Enquiries
B.5.3	Address:
B.5.3.1	Street Address	One MedImmune Way
B.5.3.2	Town/ city	Gaithersburg
B.5.3.3	Post code	20878
B.5.3.4	Country	United States
B.5.4	Telephone number	00800-4573-0011
B.5.6	E-mail	clinicaltrialenquiries@medimmune.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	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	Intravenous use
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	MEDI1123
D.3.9.3	Other descriptive name	Human cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody
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	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	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	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.3.2	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	Intravenous use
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.3.9.3	Other descriptive name	Immunoglobulin G1, anti-(human CD antigen
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	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	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 hepatocelular

E.1.1.1

Medical condition in easily understood language

Liver Cancer

Cancer de hígado

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	18.1
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 safety and tolerability of MEDI4736 and tremelimumab administered as monotherapy and in combination to subjects with unresectable HCC

Evaluar la seguridad y la tolerabilidad de MEDI4736 y tremelimumab administrados en monoterapia y en combinación a pacientes con carcinoma hepatocelular (CHC) no resecable.

E.2.2

Secondary objectives of the trial

1. To evaluate the preliminary clinical activity of MEDI4736 and tremelimumab administered as monotherapy and in combination to subjects with unresectable HCC.
2. To evaluate the relationship between candidate biomarkers (eg, programmed cell death ligand 1 [PD-L1] expression in the tumor microenvironment) and measures of clinical outcome of MEDI4736 and tremelimumab administered as monotherapy and in combination in subjects with unresectable HCC.

1. Evaluar la actividad clínica preliminar de MEDI4736 y tremelimumab administrados en monoterapia y en combinación a pacientes con carcinoma hepatocelular (CHC) no resecable.
2. Evaluar la relación entre los biomarcadores candidatos (p. ej., expresión del ligando de muerte celular programada 1 [PD-L1] en el microentorno tumoral) y las determinaciones de la respuesta clínica obtenida con MEDI4736 y tremelimumab administrados en monoterapia y en combinación a pacientes con carcinoma hepatocelular (CHC) no resecable.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female subjects
2. 18 years and older
3. Confirmed diagnosis of unresectable hepatocellular carcinoma with or without concomitant viral hepatits B or hepatitis C infection.
4. Subjects must have either: progressed on, are intolerant to, or refused treatment with sorafenib.

1. Pacientes hombres o mujeres 2. 18 años o más 3. Diagnóstico confirmado de carcinoma hepatocelular no resecable con o sin infección concomitante por el virus de la hepatitis B o la hepatitis C 4. Los pacientes deben bien presentar progresión de la enfermedad o intolerancia al sorafenib, o bien haber rechazado el tratamiento con sorafenib.

E.4

Principal exclusion criteria

1. Prior exposure to immune-mediated therapy
2. Hepatic encephalopathy characterized by asterixis
3. Active or prior documented gastrointestinal variceal bleed
4. Any concurrent chemotherapy, immunotherapy, or biologic or hormonal therapy for cancer treatment
6. Active or prior documented autoimmune or inflammatory disease with some exceptions
7. Current or prior use of immunosuppressive medication within 14 days with some exceptions

1. Exposición previa a la inmunoterapia 2. Encefalopatía hepática caracterizada por asterixis 3. Hemorragia digestiva varicosa activa o anterior documentada 4. Cualquier quimioterapia, inmunoterapia o terapia biológica u hormonal concomitante para el tratamiento del cáncer 6. Trastornos autoinmunitarios o inflamatorios activos o anteriores documentados, con algunas excepciones 7. Uso previo o actual de medicamentos inmunosupresores en los 14 días anteriores, con algunas excepciones.

E.5 End points

E.5.1

Primary end point(s)

Number (percentage) of subjects reporting adverse events and number (percentage) of subjects reporting serious adverse events.
Changes from baseline in laboratory parameters (including liver and viral laboratory tests),
electrocardiograms and vital signs.

Número (porcentaje) de pacientes que notifiquen acontecimientos adversos y número (porcentaje) de pacientes que notifiquen acontecimientos adversos graves. Cambios con respecto al momento basal en los parámetros de laboratorio (incluidas las pruebas de función hepática y detección de virus), electrocardiogramas y constantes vitales.

E.5.1.1

Timepoint(s) of evaluation of this end point

Evaluation of AEs, SAEs, discontinuation of IP, changes in Lab parameters, ECG etc will be assessed at Screening (baseline) AEs, SAEs and lab changes; Day1± 3 days every other week to week 25 then week 29,33,37,41,45 and 49, EoT & approx Day 30, 60 and 90 post last dose. ECG: baseline and week 9.

Evaluación de los AA, AAG, interrupción del MI, cambios en los parámetros analíticos, ECG, etc. en la fase de selección (línea basal) AA, AAG y cambios en los parámetros analíticos; Día 1 ± 3 días, cada dos semanas hasta la semana 25 y en las semanas 29, 33, 37, 41, 45 y 49, en el FdT y aproximadamente en los días 30, 60 y 90 después de la última dosis. ECG: línea basal y semana 9.

E.5.2

Secondary end point(s)

Objective response (OR), disease control (DC), duration of response (DoR), time to progression (TTP), and progression-free survival (PFS) based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and overall survival (OS).

La respuesta objetiva (RO), el control de la enfermedad (CE), la duración de la respuesta (DdR), el tiempo hasta la progresión (ThP)y la supervivencia sin progresión (SSP) de acuerdo con los criterios de evaluación de la respuesta en tumores sólidos (RECIST) v.1.1 y la supervivencia global (SG).

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Clinical outcome (OR, DC, DoR, TTP, PFS, and OS): Screening, weeks 9, 17, 25, 33, 41, 49 and then every 8 weeks until end of trial and then every 3 months to 12 months post last dose.

1. Resultado clínico (RO, CE, DR, THP, SSP, SG): selección, semanas 9, 17, 25, 33, 41, 49 y cada 8 semanas hasta el final del ensayo y, posteriormente, cada 3 meses durante los 12 meses después de la última dosis.

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

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

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

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

Hong Kong

Italy

Japan

Korea, Republic of

Singapore

Spain

Taiwan

United States

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

As per protocol: 'The end of the study (?study completion?) is 3 years after the final subject is enrolled or the date the study is closed by the sponsor, whichever occurs first.'

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:

110

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

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, where permitted.

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

120

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)

None

Ninguno

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

2015-11-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-11-13

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

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