Clinical Trials Register

Summary
EudraCT Number:	2020-005268-71
Sponsor's Protocol Code Number:	ML42600
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:	2024-12-13
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2020-005268-71

A.3

Full title of the trial

A PHASE IIIB, SINGLE ARM, MULTICENTER STUDY OF ATEZOLIZUMAB IN COMBINATION WITH BEVACIZUMAB TO INVESTIGATE SAFETY AND EFFICACY IN SPANISH PATIENTS WITH UNRESECTABLE OR UNSUITABLE FOR LOCOREGIONAL TREATMENTS HEPATOCELLULAR CARCINOMA NOT PREVIOUSLY TREATED WITH SYSTEMIC THERAPY.

Estudio Fase IIIB, multicéntrico, de un solo brazo de atezolizumab en combinación con bevacizumab para investigar la seguridad y la eficacia en pacientes españoles diagnosticados de carcinoma hepatocelular irresecable o no suspectible de tratamientos locorregionales no tratado previamente con terapia sistémica.

A.3.1

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

Study with Atezolizumab in combination with Bevacizumab in patients with hepatocellular carcinoma not prevously treated with systemic therapy.

Estudio con Atezolizumab en combinación con Bevacizumab para pacientes diagnosticados de carcinoma hepatocelular no tratado previamente con terapia sistemica.

A.4.1

Sponsor's protocol code number

ML42600

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	Roche Farma S.A.
B.1.3.4	Country	Spain
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	Roche Farma S.A.
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	Roche Farma S.A.
B.5.2	Functional name of contact point	Head of Spain
B.5.3	Address:
B.5.3.1	Street Address	Ribera del Loira 50
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28042
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34913253700
B.5.6	E-mail	spain.start_up_unit@roche.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	Yes
D.2.1.1.1	Trade name	Tecentriq.
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Atezolizumab
D.3.2	Product code	RO5541267/F03
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	ATEZOLIZUMAB
D.3.9.2	Current sponsor code	RO5541267
D.3.9.4	EV Substance Code	SUB178312
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	60
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)	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	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	Yes
D.2.1.1.1	Trade name	Avastin
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Bevacizumab
D.3.2	Product code	RO4876646
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	BEVACIZUMAB
D.3.9.2	Current sponsor code	RO4876646
D.3.9.4	EV Substance Code	SUB16402MIG
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	25
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

Treatment for patients with unresectable HCC who have received no prior systemic treatment and are considered unsuitable for locoregional therapy.

Tratamiento en pacientes con carcinoma hepatocelular irresecable que no han recibido tratamiento sistémico previo y no se consideran aptos para tratamiento locorregional.

E.1.1.1

Medical condition in easily understood language

Treatment for patients with unresectable hepatocelular carcinoma not previously treated.

Tratamiento pacientes con carcinoma hepatocelular irresecable no tratados previamente.

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Main objective is to evaluate the safety of atezolizumab in combination with bevacizumab in patients with unresectable HCC who have received no prior systemic treatment and are considered unsuitable for locoregional therapy.

En este estudio se evaluará la seguridad del atezolizumab en combinación con bevacizumab en pacientes con carcinoma hepatocelular irresecable que no han recibido tratamiento sistémico previo y no se consideran aptos para tratamiento locorregional.

E.2.2

Secondary objectives of the trial

- To evaluate the efficacy of atezolizumab + bevacizumab. OS, defined as the time from initiation of study treatment to death from any cause.
- To further evaluate the safety of atezolizumab + bevacizumab. - Adverse Event severity according to NCI CTCAE v5.0 during patient’s treatment.
- To further evaluate the efficacy of atezolizumab + bevacizumab, According to RECIST 1.1:
*PFS.
* Objective response rate (ORR), defined as a complete or partial response, on two consecutive occasions ≥ 4 weeks apart.
* Time to progression (TTP), defined as the time from initiation of study treatment to the first occurrence of disease progression.
* Duration of Response (DOR), defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first)
* Number/Rate of patients starting second line treatment.
- To evaluate deterioration of Liver function during the treatment

- Evaluar la eficacia de atezolizumab + bevacizumab. Supervivencia global (SG), el tiempo desde el inicio del tratamiento del estudio hasta la muerte.
- Evaluar más a fondo la seguridad. La intensidad de los acontecimientos adversos de acuerdo a CTCAE del NCI, versión 5.0.
- Evaluar más a fondo la eficacia, de acuerdo a los criterios RECIS v1.1
* SSP, tiempo desde la aleatorización hasta el primer episodio de progresión de la enfermedad o la muerte por cualquier causa (lo que antes ocurra).
* (TRO); respuesta completa o parcial en dos ocasiones consecutivas con ≥ 4 semanas de intervalo.
*Tiempo hasta la progresión (THP); el tiempo desde el inicio del tratamiento del estudio hasta el primer episodio de progresión de la enfermedad.
* Duración de la respuesta (DR); el tiempo desde el primer episodio de una respuesta objetiva documentada hasta la progresión de la enfermedad o la muerte por cualquier causa ..
* Evaluar el deterioro de la función hepática.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Signed ICF, Age ≥ 18 years, Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by histology or radiologically.
- Not amenable to curative surgical and/or locoregional therapies, or progressive disease after surgical and /or locoregional therapies.
- No prior systemic therapy for HCC
- One measurable (per RECIST 1.1) untreated lesion detected by CT scan.
- 3 months to be included for those patients who received external beam radiotherapy as prior locoregional therapy.
- ECOG Performance Status of 0 or 1 within 7 days prior to recruitment
- Pre-treatment tumor tissue or a new tumor sample with
specimen associated pathology report.
- Patients with prior local therapy eligible provided the target lesion(s) have not been previously treated with local therapy or the target lesion(s) within the field of local therapy have subsequently progressed in accordance with RECIST version 1.1:
-Adequate hematologic and end-organ function, obtained within 7 days prior to recruitment.
- Resolution of any acute, toxicity from prior therapy to Grade ≤ 1 prior to study entry.
- Negative HIV test at screening. Documented virology status of hepatitis, as confirmed by screening HBV and HCV serology test
- For women of childbearing potential: agreement to remain abstinent Women must refrain from donating eggs during this same period.
- For men: agreement to remain abstinent.

- Firma del documento ICF, Edad ≥ 18 años, CHC localmente avanzado, metastásico o irresecable con diagnóstico confirmado mediante histología o radiológicamente.
- Enfermedad no susceptible de tratamiento quirúrgico o locorregional curativo, o progresión de la enfermedad después de tratamientos quirúrgicos o locorregionales.
- Ausencia de tratamiento sistémico previo.
- Al menos una lesión no tratada mensurable (según los RECIST 1.1) detectada mediante TC.
- Elegibles pacientes que hayan recibido tratamiento local previo siempre que las lesiones diana no se hayan sometido previamente a tratamiento local o las lesiones diana situadas dentro del campo de tratamiento local hayan progresado posteriormente según los RECIST, versión 1.1.
- Estado funcional del ECOG de 0 o 1 en los 7 días previos al reclutamiento.
-Los pacientes deben facilitar una muestra de tejido tumoral previa al tratamiento, si está disponible. Esta muestra debe ir acompañada del informe anatomopatológico asociado.
-Función hematológica y orgánica adecuada, definida por los resultados analíticos siguientes, obtenidos en los 7 días previos al reclutamiento.
- Resolución de cualquier toxicidad aguda de importancia clínica relacionada con tratamiento previo hasta un grado ≤ 1 antes de la entrada en el estudio.
- Prueba del VIH negativa en la selección. Estado virológico documentado de hepatitis, confirmado por pruebas serológicas de VHB y VHC en la selección.
- En las mujeres en edad fértil: compromiso de mantener abstinencia. También deberán abstenerse de donar óvulos durante ese mismo período.
- En los varones: compromiso de mantener abstinencia (de relaciones heterosexuales) o de utilizar métodos anticonceptivos y de abstenerse de donar semen.

E.4

Principal exclusion criteria

Patients who meet any of the following criteria will be excluded from entry:
- Active or history of autoimmune disease or immune deficiency EXCEPT Patients with a history of autoimmune-related hypothyroidism , with controlled Type 1 diabetes mellitus and with eczema, psoriasis, lichen simplex chronicus, or vitiligo.
- History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest (CT) scan.
- Significant cardiovascular disease.
- History of congenital long QT syndrome or corrected QT interval >500 ms at screening.
- History of uncorrectable electrolyte disorder.
- Major surgical procedure, other than for diagnosis.
- History of malignancy other than HCC within 5 years prior to screening
- Severe infection within 4 weeks prior to initiation of study treatment
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
- Prior allogeneic stem cell or solid organ transplantation
- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding
-Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment,
-Pregnancy or breastfeeding, or intention of becoming pregnant.
- Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding.
- At least one clinically evident episode of encephalopathy in the past three months .
- Co-infection of HBV and HCV.
-Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.
- Uncontrolled tumor-related pain.
-Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures .
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to initiation of study treatment
- If a diagnosis of COVID-19 infection is confirmed

Se excluirá del estudio a los pacientes:
- Presencia o antecedentes de enfermedades autoinmunitarias o inmunodeficiencia, EXCEPTO con antecedentes de hipotiroidismo autoinmunitario, pacientes con diabetes mellitus de tipo 1 y los pacientes con eccema, psoriasis, liquen simple crónico o vitíligo.
- Antecedentes de fibrosis pulmonar idiopática.
- Enfermedad cardiovascular importante.
- Antecedentes de síndrome de QT largo congénito o intervalo QT corregido > 500 ms.
- Antecedentes de trastorno electrolítico no corregible.
- Intervención de cirugía mayor, excepto si es con fines diagnósticos.
-Antecedentes de un proceso maligno distinto del CHC en los 5 años previos.
- Infección grave en las 4 semanas previas al inicio del tratamiento del estudio.
- Tratamiento con antibióticos terapéuticos por vía oral o IV en las 2 semanas previas al inicio del tratamiento del estudio.
- Alotrasplante de células progenitoras o trasplante de órgano sólido previo.
- Cualquier otra enfermedad, disfunción metabólica.
- Tratamiento con una vacuna de microorganismos vivos atenuados en las 4 semanas previas.
- Antecedentes de reacciones alérgicas anafilácticas graves a anticuerpos quiméricos o humanizados o a proteínas de fusión.
- Un episodio hemorrágico previo por varices esofágicas o gástricas en los 6 meses previos al inicio del tratamiento del estudio
-Al menos un episodio clínicamente evidente de encefalopatía en los tres últimos meses
-Infección conjunta por el VHB y el VHC.
- Metástasis en el sistema nervioso central (SNC) sintomáticas, no tratadas o en progresión activa
- Embarazo o lactancia, o intención de quedarse embarazada.
- Dolor no controlado relacionado con el tumor.
- Derrame pleural, derrame pericárdico o ascitis no controlados.
- Intervención de cirugía mayor, biopsia abierta o lesión traumática importante.
- Si se confirma diagnostico por Covid-19.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the incidence and severity of adverse events of grade ≥ 3 that lead to discontinuation of study treatment.

Incidencia e intensidad de los acontecimientos adversos de grado ≥ 3 causantes de interrupción del atezolizumab o el bevacizumab.

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end of the study.

Al final del estudio.

E.5.2

Secondary end point(s)

- secondary endpoints of severity of AEs (determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 [NCI CTCAE v5.0]), as well as changes from baseline in targeted vital signs and clinical laboratory test results will be evaluated during the patients’ treatment.
- overall survival ([OS] defined as the time from initiation of study treatment to death from any cause

- La intensidad de los acontecimientos adversos se determinará de acuerdo con los CTCAE del NCI, versión 5.0, durante el tratamiento del paciente. Cambio de las constantes vitales de interés respecto al momento basal. Cambio de los resultados analíticos de interés respecto al momento basal.
- SSP, definida como el tiempo desde la aleatorización hasta el primer episodio de progresión de la enfermedad o la muerte por cualquier causa (lo que antes ocurra).

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of the study.

Al final del 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

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

- Genomic analysis Tissue & Blood Biomarker Plan to identify biomarkers that might be potentially associated with response patterns
- CT-radiomics analysis

- Plan de análisis genómico de biomarcadores tisulares y sanguíneos.
- Se ha incluido un análisis radiómico por TC

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

E.8.1.1

Randomised

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)

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

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

The end of study will occur when all enrolled patients have either died, withdrawn consent, are lost to follow up, or have been followed for 24 months since the last study patient is enrolled, whichever occurs first.

El estudio finalizará cuando todos los pacientes incluidos hayan fallecido, hayan retirado el consentimiento, se hayan perdido al seguimiento o se hayan seguido durante 24 meses desde el reclutamiento del último paciente del estudio, lo que antes ocurra.

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:

100

F.1.3

Elderly (>=65 years)

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

100

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

2021-03-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-12-30

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-04-26

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials