Clinical Trials Register

Summary
EudraCT Number:	2019-003765-18
Sponsor's Protocol Code Number:	AIFA-TRS-2018-00001238
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-05-24
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

2019-003765-18

A.3

Full title of the trial

Gender-related response to Tyrosine Kinase-Inhibitor drugs in hepatocellular carcinoma

Risposta genere-correlata a farmaci inibitori dei recettori tirosin kinasici (TKI) nel carcinoma epatocellulare

A.3.1

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

Evaluation of the differences in gender-related response in patients with hepatocellular carcioma treated with tyrosine-kinase inhibitor drugs

Valutare le differenze di genere nella risposta ai farmaci inibitori dei recettori per le tirosin-kinasi in pazienti con carcinoma epatocellulare

A.3.2

Name or abbreviated title of the trial where available

GReKIAH

A.4.1

Sponsor's protocol code number

AIFA-TRS-2018-00001238

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	DIPARTIMENTO AD ATTIVITà INTEGRATA CHIRURGICO, MEDICO, ODONTOIATRICO E DI SCIENZE MORFOLOGICHE
B.1.3.4	Country	Italy
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	AIFA - Italian Medicines Agency
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AIFA
B.5.2	Functional name of contact point	Ricerca Indipendente AIFA
B.5.3	Address:
B.5.3.1	Street Address	Via del Tritone, 181
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00187
B.5.3.4	Country	Italy
B.5.6	E-mail	ricercaindipendente@aifa.gov.it

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	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	Germany
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.3.2	Product code	[284461-73-0]
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	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	284461-73-0
D.3.9.2	Current sponsor code	sorafenib
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	80
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	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	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	Stivarga
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer AG
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	regorafenib
D.3.2	Product code	[755037-03-7]
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	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	REGORAFENIB
D.3.9.1	CAS number	755037-03-7
D.3.9.2	Current sponsor code	regorafenib
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	40
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	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	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.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

Patients with advanced hepatocellular carcinoma only eligible for systemic treatment

Pazienti con carcinoma epatocellulare avanzato eleggibil soltanto al trattamento sistemico

E.1.1.1

Medical condition in easily understood language

Patients with advanced hepatocellular carcinoma only eligible for systemic treatment and in sufficiently good clinical conditions

Pazienti con carcinoma epatocellulare avanzato eleggibili soltanto al trattamento sistemico e in buone condizioni cliniche generali

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	SOC
E.1.2	Classification code	10019805
E.1.2	Term	Hepatobiliary disorders
E.1.2	System Organ Class	10019805 - Hepatobiliary disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The main objective is to evaluate whether the different pharmacokinetics of the two drugs in males and females and the related pharmacogenetic variants of ADME (known to be different in male and female) are related to:
- Different clinical response to Sorafenib (part 1)
- Different clinical response to Regorafenib after failure of Sorafenib therapy (part 2)

L'obiettivo principale è valutare se la potenziale diversa farmacocinetica dei due farmaci nei due sessi e le varianti farmacogenetiche correlate ADME (note essere diverse nel maschio e nella femmina) sono relate a:
- Differente risposta clinica a Sorafenib (parte 1)
- Differente risposta clinica a Regorafenib dopo fallimento della terapia con Sorafenib (parte 2)

E.2.2

Secondary objectives of the trial

The secondary objectives of the study aim to evaluate whether gender-related outcomes, of therapy are also influenced by drug exposure (Cmin) and circulating biomarkers.(VEGF and VEGF-R, Angiopoietin-1 and Angiopoietin-2, NRP1, miRNA) chosen according with their relationship with TKI response For most of these biomarkers, demonstrable gender-related differences exist, not explored so far in relation with HCC and TKI inhibitors.

L' obiettivo secondario è valutare se i risultati della terapia correlati al genere sono influenzati anche dall'esposizione al farmaco (Cmin) e dai biomarcatori circolanti (VEGF e VEGF-R, Angiopoietin-1 e Angiopoietin-2, NRP1, miRNA) scelti in base alla loro relazione con la risposta alla TKI. Per la maggior parte di questi biomarcatori sono note differenze dimostrabili di genere, che non sono state ancora esplorate in relazione agli inibitori dell'HCC e TKI.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Sorafenib:
- Age > 18 years-old.
- Child-Pugh class 5-6 (class A);
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2;
- Patients who have a life expectancy of at least 12 weeks Child-Pugh class 5-6 (class A);
- Patients with advanced HCC: i.e. patients not eligible for or who had disease progression after local-regional therapy;
- Patients who have received local therapy;;
- Patients with an adequate adequate hematologic function (platelet count, =60×109 per liter; hemoglobin, =8.5 g per deciliter; and prothrombin time international normalized ratio, =2.3; or prothrombin time, =6 seconds above control);
- adequate hepatic function (albumin, =2.8 g per deciliter; total bilirubin, =3 mg per deciliter [51.3 µmol per liter]; and alanine aminotransferase and aspartate aminotransferase, =5 times the upper limit of the normal range);
- adequate renal function (serum creatinine, =1.5 times the upper limit of the normal range);
- Signed and dated IRB/IEC approved Informed Consent/Genetic Consent.

Regorafenib
- Age >18 years-old;
- Child-Pugh class 5-6 (class A);
- Patients with diagnosis of HCC, confirmed by histology according to AASLD/EASL criteria prior to the start of first-line therapy (sorafenib);
- Patients with advanced HCC who had documented radiological progression during sorafenib as defined in a study-specific radiology charter. They must have tolerated sorafenib (=400 mg daily for at least 20 of the 28 days before discontinuation);
- Patient must have at least one uni-dimensional measurable lesion by CT or MRI according to mRECIST which is either not previously treated by local therapy or, if treated, it has clearly progressed when the patient is recruited;
- Patients who have a life expectancy of at least 12 weeks;
- ECOG performance status of 0 or 1;
- Patients who have received local therapy (such as surgery, radiation therapy, etc...)
- Capability to swallow capsules intact (without chewing, crushing, or opening);

Sorafenib
- Età > 18 anni
- Child-Pugh (classe A)
- (ECOG) performance status 0, 1 o 2;
- Pazienti con aspettativa di vita di almeno 12 settimane;
- Pazienti con HCC avanzato;
- Pazienti sottoposti a terapia locoregionale;
- Pazienti con normale funzionalità ematologica (n° piastrine =60×109 per litro; emoglobina, =8.5 g per decilitro; tempo di protrombina in valori internazionali =2.3; o tempo di protrombina =6 secondi oltre il valore di controllo);
- Adeguata funzione epatica (albumina =2.8 g per decilitro; bilirubina totale =3 mg per decilitro [51.3 µmol per litro]; alanina aminotransferasi e aspartato aminotransferasi, =5 volte superiore al limite del valore normale);
- Adeguata funzione renale (creatinine del siero =1.5 volte superiore al limite del valore normale);
- Consenso informato approvato da un comitato etico indipendente firmato e datato dal paziente.

Regorafenib
- Età > 18 anni
- Child-Pugh classe 5-6 (classe A)
- Pazienti con HCC diagnosticata, confermata da criteri isologici AASLD/EASL prima dell’inizio della terapia con Sorafenib;
- Pazienti con HCC avanzata che abbiano progressione della malattia documentata con immagini radiologiche durante terapia con Sorafenib. Devono aver tollerato Sorafenib (=400 mg/die per almeno 20 dei 28 days prima dell’interruzione);
- I pazienti devono avere almeno una lesione misurabile unidirezionale da CT or MRI in accordo con lo studio mRECIST che non sia stata precedentemente trattata o che, se trattata, sia chiaramente peggiorata quando il paziente è in fase di reclutamento;
- Pazienti con una aspettativa di vita di almeno 12 settimane;
- ECOG performance status 0 o 1;
- Pazienti che hanno ricevuto terapia locoregionale (es. chirurgia, radioterapia, etc…)

E.4

Principal exclusion criteria

These exclusion criteria apply to both drugs:
- Prior systemic therapy for HCC;
- Active clinically serious infections (> grade 2 National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [CTCAE] version 3.0);
- Renal failure requiring hemo- or peritoneal dialysis;
- History of cardiac disease: congestive heart failure > New York Heart Association (NYHA) class 2; active coronary artery disease (CAD);
- Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta-blockers or digoxin, or uncontrolled hypertension;
- Myocardial infarction less than 6 months prior to study entry;
- Cholangiocarcinoma, hepatocholangiocarcinoma, fibrolamellar carcinoma and hepatoblastoma;
- History of moderate or severe ascites, bleeding esophageal varices, hepatic encephalopathy or pleural effusions related to liver insufficiency within 6 months of screening;
- Known significant immunodeficiency due to underlying illness (e.g. HIV/AIDS);
- Known contraindications to sorafenib according to the drug prescribing information and/or severe hypersensitivity to sorafenib or any other component of sorafenib, or known intolerance to sorafenib.

Valevoli per entrambi i farmaci
- Terapia sistemica precedente per HCC.
- Infezioni gravi attive clinicamente rilevanti (> grado 2 per il National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [CTCAE] versione 3.0).
- Insufficienza renale che richieda emodialisi o dialisi peritoneale.
- Malattie cardiache precedenti: infarto congestizio > classe 2 secondo New York Heart Association (NYHA); problematiche alle arterie coronarie (CAD).
- Aritmie che richiedano una terapia antiaritmica o altri beta-bloccanti, o digossina o ipertensione incontrollata
- Infarto del miocardio avvenuto in un periodo ti tempo inferiore ai 6 mesi prima dell’inizio dello studio
- Colangiocarcinoma, epatocolangiocarcinoma, carcinoma fibrolamellare e epatoblastoma.
- Storie di asciti da severe a moderate, varici esofagee sanguinolente, encefalopatia epatica or effusioni pleurali collegate ad insufficienza epatica entro 6 mesi.
- Nota e rilevante imunodeficienza dovuta a (per es.) HIV/AIDS;
- Infiammazione cutanea severa o storicità di eczema grave (a giudizio dello sperimentatore) che abbia richiesto un intervento terapeutico.
- Controindicazioni note alla prescrivibilità di Sorafenib e Regorafenib o a ciascuno degli altri componenti del farmaco

E.5 End points

E.5.1

Primary end point(s)

The study is divided in two consecutive parts (one primary endpoint each).

Part 1 (sorafenib)
The primary endpoint the progression free survival (PFS) to assess whether there are gender-related differences in the response to the therapy after initiation of sorafenib

Part 2 (regorafenib)
The primary endpoint of the Part 2 is overall survivals (OS) to assess whether there are gender-related differences in the response to the therapy after initiation of sorafenib, according to gender and ADME-related pharmacogenetic variants

Lo studio si divide in due parti consecutive, con un endpoint primario per ciascuna parte.

Parte 1 (sorafenib)
L'endpoint primario della prima parte è la PFS (sopravvivenza senza progressione di malattia) per valutare se ci siano differenze di genere alla risposta alla terapia.

Parte 2 (regorafenib)
L'endpoint primario della seconda parte è OS (sopravvivenza totale) dall'inizio della terapia con regorafenib per valutare se ci siano differenze di genere alla risposta alla terapia.

E.5.1.1

Timepoint(s) of evaluation of this end point

Part 1:
At disease progression, controlled with radiological imaging every 8 weeks
Part 2:
At the time of death of the patients or disease progression (disease progression, controlled with radiological imaging every 8 weeks)

Parte 1:
Alla progressione di malattia, monitorata attraverso immagigni radiologiche ogni 8 settimane
Parte 2:
Alla morte del paziente o progressione di malattia (monitorata attraverso immagini radiologiche ogni 8 settimane)

E.5.2

Secondary end point(s)

Evaluation if the association between therapy outcomes ( in terms of PFS and OS) and gender are associated to different levels of circulating biomarkers and drug exposure (Cmin).

Valutazione se l'associazione tra risultati della terapia (in termini di PFS e OS) e il genere siano associati a diverse espressioni dei biomarcatori circolanti e l'esposizione al farmaco (Cmin)

E.5.2.1

Timepoint(s) of evaluation of this end point

Consequently the achievement of primary endpoint (for both parts of the study)

Conseguente al raggiungimento dell'endpoint primario (for both parts of the study)

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

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Correlation of the indicated endpoints with gender of the patients

Correlazione delle finalità suddette con il genere del paziente

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

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

Yes

E.8.1.7.1

Other trial design description

Nel paziente, che inizia terapia secondo standard of care per HCC, verrà valutata la risposta clinic

Patients undergo pharmacological treatment following the standard of care for his disease

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

Information not present in EudraCT

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

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:

200

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

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

300

F.4.2

For a multinational trial

F.4.2.1

In the EEA

300

F.4.2.2

In the whole clinical trial

300

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)

They will be treated and followed-up based on standard of care procedures for their condition of otherwise untreatable HCC

continueranno ad essere seguiti e trattati secondo lo standard of care per la loro condizione di HCC inoperabile

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

2020-03-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-11-19

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

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