Clinical Trials Register

Summary
EudraCT Number:	2011-006194-26
Sponsor's Protocol Code Number:	EC11-185
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2012-02-13
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

2011-006194-26

A.3

Full title of the trial

A phase IV, multicenter, randomized, double-blind, placebo-controlled study of efficacy and safety of Sorafenib in patients with hepatocellular carcinoma after radiological progression

Estudio fase IV, multicéntrico, aleatorizado, doble-ciego, controlado frente a placebo, para evaluar la eficacia y seguridad de Sorafenib en pacientes con carcinoma hepatocelular avanzado con progresión radiológica.

A.3.1

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

A phase IV study of efficacy and safety of Sorafenib in patients with hepatocellular carcinoma after radiological progression

Estudio fase IV para evaluar la eficacia y seguridad de Sorafenib en pacientes con carcinoma hepatocelular avanzado con progresión radiológica.

A.3.2

Name or abbreviated title of the trial where available

SOPRAC

A.4.1

Sponsor's protocol code number

EC11-185

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	JOSE LUIS MONTERO ALVAREZ
B.1.3.4	Country	Spain
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	MINISTERIO DE SANIDAD, POLITICA SOCIAL E IGUALDAD
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	REINA SOFIA UNIVERSITARY HOSPITAL
B.5.2	Functional name of contact point	CLINICAL UNIT OF DIGESTIVE SYSTEM
B.5.3	Address:
B.5.3.1	Street Address	AV/ MENENDEZ PIDAL
B.5.3.2	Town/ city	CORDOBA
B.5.3.3	Post code	14004
B.5.3.4	Country	Spain
B.5.4	Telephone number	34957010328
B.5.5	Fax number	34957736014
B.5.6	E-mail	jlm14005623@gmail.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	Spain
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	Sorafenib
D.3.4	Pharmaceutical form	Capsule, hard
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	SORAFENIB TOSILATE
D.3.9.1	CAS number	475207-59-1
D.3.9.2	Current sponsor code	475207-59-1
D.3.9.3	Other descriptive name	SORAFENIB TOSILATE
D.3.9.4	EV Substance Code	SUB22347
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	Yes
D.3.11.13.1	Other medicinal product type	multikinase inhibitor

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Advanced stage hepatocellular carcinoma (stage C of BCLC classification)

Carcinoma hepatocelular avanzado (estadio C de la clasificación BCLC)

E.1.1.1

Medical condition in easily understood language

Hepatocellular carcinoma

Carcinoma hepatocelular

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	14.1
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	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 determine efficacy of Sorafenib in advanced hepatocellular carcinoma (stage C of BCLC classification) after radiological progression.

Determinar eficacia de Sorafenib en pacientes con carcinoma hepatocelular (estadio C de la clasificación de BCLC) tras la progresión radiológica.

E.2.2

Secondary objectives of the trial

-To determine safety of Sorafenib in advanced hepatocellular carcinoma (stage C of BCLC classification) after radiological progression.
-To assess quality of life.
-To evaluate adherence to Sorafenib treatment.

ADDITIONAL EXPLORATORY OBJECTIVE:
To determine if growth factors related to neoangiogenesis, as EGF,FGF-2,VEGF and PDGF, could be biomarkers of respond to Sorafenib treatment in advanced hepatocellular carcinoma.

- Determinar seguridad de Sorafenib en el carcinoma hepatocelular avanzado (estadio C de la BCLC) tras la progresión radiológica.
- Valorar la calidad de vida.
- Evaluar la adherencia al tratamiento con Sorafenib.

OBJETIVO EXPLORATORIO ADICIONAL:
Determinar si factores de crecimiento relacionados con la neoangiogénesis, como EGF, FGF-2, VEGF y PDGF, pueden ser biomarcadores de respuesta del carcinoma hepatocelular avanzado al tratamiento con Sorafenib.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female patient older than 18 years old.
2. Diagnosis of advanced HCC according to the AASLD Guidelines.
3. HCC stage B with contraindication to transarterial chemoembolization (TACE) or stage C according to Barcelona Clinic Liver Cancer (BCLC) staging classification.
4. Sorafenib treatment-naive patient.
5. Child-Pugh class A (5-6 points) or class B (7 points), without ascites (mild ascites controlled with diuretics is allowed) and encephalopathy. Child-Pugh status must be calculated based on clinical findings and laboratory results during 30 days before inclusion in the study.
6. ECOG Performance Status lower than 2.
7. Adequate liver, renal and bone marrow function as shown by:
AST y ALT lower than 5 x ULN (upper limit of normal); bilirubin lower than 2 mg/dL; INR lower than 2; absolute neutrophil count (ANC) higher than 1.2 x 103 per ml ; platelets higher than 70 x 103 per ml ; serum creatinine lower than 1.5 mg/dL.
8. Written informed consent.
9. Women of chilbearing potential (WOCBP) must have a negative serum pregnancy test performed in the screening visit.
WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilizatiion (hysterectomy, bilateral tubal ligation or bolateral oophorectomy) or is not postmenopausal. Post menopause is defined as an amenorrhea state longer than 12 consecutive months.
10. Men and women enrolled in this trial must used adequate barrier bith control measure since two weeks prior to the start of investigational product, during the course of the trial and two weeks after the last dose of investigational product.

1. Pacientes hombres o mujeres mayores de edad.
2. Diagnóstico de hepatocarcinoma celular avanzado según los criterios de la AASLD.
3. CHC en estadio B de la BCLC con contraindicación a quimioembolización transarterial o estadio C de la BCLC sin contraindicación alguna a Sorafenib.
4. Paciente que vaya a iniciar tratamiento con Sorafenib por primera vez.
5. Child-Pugh de clase A (5-6) y B-7 como máximo, sin encefalopatía. Se permitirá ascitis controlada con dieta y/o diuréticos.
6. ECOG menor de 2.
7. Función hepática, renal y de médula ósea adecuada confirmada con una analítica local realizada no más de 21 días previos a la inclusión del paciente en el estudio:
AST y ALT < 5 x LSN (límite superior de normalidad)
Bilirrubina < 2 mg/dL
INR < 2
Hemoglobina > 9.0 g/dL
Neutrófilos absoluto > 1.2 x 103 /mL
Plaquetas > 70 x 103 /mL
Creatinina sérica < 1.5 mg/dL x LSN
8. Consentimiento informado otorgado por escrito.
9. Mujeres en edad fértil deberán obtener un reusltado negativo en la prueba de embarazo en suero, en la visita de selección.
Como mujer en edad fértil se define cualquier mujer que haya experimentado la menarquía, no se haya sometido a una intervención quirúrgica de esterilización (histerectomía, ligadura bilateral de trompas u ovariohisterectomia) y no es post- menopausica. La post-menopausia se define como amenorrea durante más de 12 meses consecutivos.
10. Los hombres y mujeres participantes en este estudio deben usar medidas anticoceptivas desde dos semanas antes de iniciar la toma del fármaco en estudio, durante la duración del estudio y dos semanas después de la última dosis del medicamento de investigación.

E.4

Principal exclusion criteria

1. Prior liver transplantation.
2. Known history of HIV infection.
3. Previous/concurrent cancer (distinct from HCC) known during the last 3 years, except for cervical carcinoma in situ, basal cells carcinoma and superficial bladder tumors.
4. History of cardiovascular disease:
- uncontrolled hypertension, defined as systolic blood pressure higher than 150 mmHg or diastolic pressure higher than 90 mmHg despite optimal medical management.
- active coronary disease, unstable or newly diagnosed angina or myocardial infarction less than 12 months prior to study entry.
- cardiac arrhythmias requiring anti-arrhytmic therapy other than beta blockers or digoxin.
- congestive heart failure higher than NYHA class 2.
5. Subjects with history of bleeding diathesis.
6. History of gastrointestinal bleeding within 30 days of randomizaion.
7. Subjects with a history of esophageal varices bleeding without efffective therapy and/or treatment to prevent bleeding recurrence.
8. Abuse to drugs, clinical or psychological states that might interfere in the participation or evaluation of study results.
9. Subjects on warfarin, acenocumarol, fenprocumone.
10.Female patients who are pregnant or breast feeding.
11.Unable or unwilling subjects to give informed consent.

1. Trasplante hepático previo.
2. Antecedentes conocidos de infección por VIH.
3. Tumores previos/actuales (diferentes del HCC) conocidos durante los 3 últimos años, excepto carcinoma cervical in situ, carcinoma de células basales y tumores superfciales de vejiga.
4. Historial de enfermedad cardiovascular:
- hipertensión descontrolada, definida como una presión sistólica mayor de 150 mmHg o una presión diastólica mayor de 90 mmHg pese a un manejo médico óptimo.
- enfermedad coronaria activa, angina de reciente diagnóstico o inestable, o infarto de miocardio durante los últimos 12 meses antes de la inclusión en el estudio.
- Arritmias cardiacas que requieren terapia anti- arritmia diferente de beta-boqueantes o digoxina.
- Fallo cardiaco congestivo mayor de la clase 2 de la NYHA.
5. Sujetos con historial de diatesis hemorrágicas.
6. Historial de hemorragias gastrointestinales en los 30 días anteriores a la randomización.
7. Sujetos con historial de varices esofágicas sin terapia eficaz para prevenir la recurrencia del sangrado.
8. Drogas de abuso, estados psicológicos o clínicos que pudieran interferiren la participación o evaluación de los resultados del estudio.
9. Sujetos en tratamiento con warfarina, acenocumarol o fenprocumona.
10. Mujeres embarazadas o en periodo de lactancia.
11. Incapacidad o reticencia para dar consentimiento informado.

E.5 End points

E.5.1

Primary end point(s)

Overall Survival (OS)

Supervivencia global (SG)

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end of the clinical trial

Al finalizar el ensayo clínico

E.5.2

Secondary end point(s)

1. Safety Variables.
All subjects who receive at least one dose of Sorafenib will be valid for safety analysis.
- Adverse Events (AEs): according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 of National Cancer Institute (NCI).
All adverse events occurring after the subject included in the study until 30 days last treatment just as adverse event causality relationship with study drug, must be recorded in the subject?s clinical informs and subject?s case record form.
The intensity or severity of adverse event should be documented using the NCI-CTCAE; version 3.0.If CTCAE grading does not exist for an AE, the severity of mild, moderate, severe and life-threatening, or grades 1-4, will be used.
- Safety assessments: Results of blood test (hematology, serum chemistry, coagulation tests), vital signs data (heart rate, blood pressure, respiration rate and body temperature), weight, 12-lead electrocardiogram (ECG) and physical examinations.
2. - Adherence to treatment.
Drug Accountability: Sorafenib tablets accountability and the patient?s information in terms of lost of forgotten doses will be recorded in the subject?s clinical informs at each study visit.
3. - Quality of life.
Patient Questionnaires: the patient reports outcomes through EQ-5D questionnaire (or EuroQol Questionnaire: a generic utility measure used to characterize current health states) and FACT-Hep questionnaire (The Functional Assessment of Cancer Therapy- Hepatobiliary Questionnaire: measuring health-related quality of life in patients with hepatobiliary cancers).

Exploratory Variable:
Determine serological levels of growth factor related to neoangiogenesis, as EGF, FGF-2,VEGF and PDGF, by Bioplex technology.

1.- Variables de seguridad.
Todos los pacientes que reciban al menos una dosis de Sorafenib serán válidos para el análisis de seguridad.
- Acontecimientos adversos (AAs) según los Criterios de Terminología Común de Eventos Adversos (NCI-CTCAE) versión 3.0 del Instituto Nacional de Cáncer (NCI).
Todos los acontecimientos adversos que ocurran después de la inclusión de un paciente en el estudio hasta 30 días después del fin del tratamiento con Sorafenib así como la relación causal con el fármaco de estudio de cada uno de ellos, serán recogidos en el informe clínico del paciente en cada visita y en el cuaderno de recogida de datos (CRD).
La intensidad o severidad del acontecimiento adverso se documentará usando el NCI-CTCAE versión 3.0. Si no existe el grado para un AA se utilizará leve, moderado, grave y amenaza a la vida, o los grados de 1 a 4.
- Medidas de seguridad: resultados de análisis de sangre (hematología, bioquímica, coagulación), datos de constantes vitales (frecuencia cardiaca, presión arterial, frecuencia respiratoria y temperatura corporal), peso, electrocardiograma de 12 derivaciones y examen físico.
2.- Adherencia al tratamiento.
- Contabilidad de medicación: se hará un recuento de comprimidos de Sorafenib en cada visita del estudio y se anotará la información proporcionada por el paciente en cuanto a olvido o pérdida de dosis en el informe clínico del paciente en cada visita del estudio.
3.- Calidad de vida.
Cuestionarios al paciente: la calidad de vida en nuestro estudio nos vendrá determinada por los resultados notificados por los pacientes mediante el cuestionario de salud general (EQ-5D) y el cuestionario de ?Evaluación funcional de la terapia contra el cáncer- subescala hepatobiliar? (FACT- Hep) [11].

Variable exploratoria:
Determinar, mediante tecnología Bioplex, los niveles serológicos de factores de crecimiento relacionados con la neoangiogénesis, como EGF, FGF-2, VEGF y PDGF.

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of study

Al finalizar el estudio

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

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

Yes

E.6.13.1

Other scope of the trial description

Serological biomarkers

Biomarcadores serológicos

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)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

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

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

At the end of the follow-up of the last included patient in the study because the main endpoint is overall survival.

Al final del seguimiento del último paciente incluido en el estudio porque la variable principal es supervivencia global.

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

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

126

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)

the expected normal treatment

El tratamiento habitual en la practica clínica

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

2012-06-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-05-22

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

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