Clinical Trials Register

Summary
EudraCT Number:	2010-022620-77
Sponsor's Protocol Code Number:	AB10006
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2015-05-25
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

Czechia - SUKL

A.2

EudraCT number

2010-022620-77

A.3

Full title of the trial

A prospective, multicentre, open-label, randomised, uncontrolled, phase 1/2 study to evaluate efficacy and safety of masitinib in combination with etoposide, or masitinib in combination with irinotecan in patients with advanced hepatocellular carcinoma and who relapsed after a first line therapy with sorafenib.

Prospektivní, multicentrická, otevřená, randomizovaná, nekontrolovaná, studie fáze 1/2, ke zhodnocení účinnosti a bezpečnosti masitinibu v kombinaci s etoposidem, nebo masitinibu v kombinaci s irinotecanem pro pacienty s pokročilým hepatocelulárním karcinomem, kteří relabovali po první linii léčby sorafenibem.

A.3.1

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

Evaluation of safety and efficacy of masitinib combined with etoposide or irinotecan in patients with relapsing liver cancer

Zhodnocení bezpečnosti a účinnosti masitinibu v kombinaci s etoposidem nebo irinotekanem u pacientů s opětovným výskytem rakoviny jater

A.4.1

Sponsor's protocol code number

AB10006

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	AB Science
B.1.3.4	Country	France
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	AB Science
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AB Science
B.5.2	Functional name of contact point	Valérie Brakni
B.5.3	Address:
B.5.3.1	Street Address	3 avenue George V
B.5.3.2	Town/ city	Paris
B.5.3.3	Post code	75008
B.5.3.4	Country	France
B.5.4	Telephone number	+ 33 1 47 20 66 76
B.5.5	Fax number	0147202411
B.5.6	E-mail	valerie.brakni@ab-science.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	masitinib
D.3.2	Product code	AB1010
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	masitinib mesylate
D.3.9.1	CAS number	790-29979-5
D.3.9.2	Current sponsor code	AB1010
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	100
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	masitinib mesylate
D.3.9.1	CAS number	790-299-79-5
D.3.9.2	Current sponsor code	AB1010
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	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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	etoposide
D.3.4	Pharmaceutical form	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	ETOPOSIDE PHOSPHATE
D.3.9.1	CAS number	117091642
D.3.9.3	Other descriptive name	ETOPOSIDE PHOSPHATE
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	60
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ETOPOSIDE PHOSPHATE
D.3.9.1	CAS number	117091642
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	45
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: 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	Yes
D.2.1.1.1	Trade name	IRINOTECAN HOSPIRA
D.2.1.1.2	Name of the Marketing Authorisation holder	HOSPIRA FRANCE
D.2.1.2	Country which granted the Marketing Authorisation	France
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	irinotecan
D.3.4	Pharmaceutical form	Concentrate for solution for injection/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	IRINOTECAN
D.3.9.1	CAS number	136572-09
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	180
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	IRINOTECAN
D.3.9.1	CAS number	136572-09
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	135
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.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

Hepatocelulární karcinom

E.1.1.1

Medical condition in easily understood language

Hepatic cancer

Rakovina jater

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	10019829
E.1.2	Term	Hepatocellular carcinoma recurrent
E.1.2	System Organ Class	100000004864

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.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10019830
E.1.2	Term	Hepatocellular carcinoma 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

Overall Survival (OS)

Celkové přežití (OS)

E.2.2

Secondary objectives of the trial

• Survival rate at week 6, 12, 18, 24 and every 12 weeks after
• Overall Progression Free Survival (PFS) according to RECIST version 1.1 and according to Modified RECIST (mRECIST) assessment for hepatocellular carcinoma
• PFS rate at week 6, 12, 18, 24 and every 12 weeks after, according to RECIST version 1.1. and to mRECIST assessment for hepatocellular carcinoma
• Tumour assessment, first according to RECIST version 1.1. and secondly according to mRECIST assessment for hepatocellular carcinoma:
o Overal Time to progression (TTP)
o TTP rate at week 6, 12, 18, 24 and every 12 wks after
o Objective response rate (CR + PR) at week 6, 12, 18, 24 and every 12 weeks after
o Control disease rate (CR + PR + SD) at week 6, 12, 18, 24 and every 12 weeks after
o Best response during study treatment
o Alpha fetoprotein dosage at week 6, 12, 18, 24 and every 12 weeks after
• Safety profile using the NCI CTC v4.02 classification
• Pharmacokinetics
• Phenotypic Analysis of selected genes

• Míra přežití v týdnech 6, 12, 18, 24 a poté každých 12 týdnů
• Celková míra přežití bez progrese onemocnění (PFS) vzhledem k RECIST verze 1.1 a vzhledem k modifikovanému RECIST (mRECIST) hodnocení hepatocelulárních karcinomů
• Hodnocení nádoru, prvně dle RECIST verze 1.1 a sekundárně dle mRECIST hodnocení hepatocelulárních karcinomů:
o Celkový čas do progrese
o Míra TTP v týdnech 6, 12, 18, 24 a poté každých 12 týdnů
o Objektivní škála odpovědi (CR+PR) v týdnech 6, 12, 18, 24 a poté každých 12 týdnů
o Nejlepší odezva během léčby
o Hladina alfa-fetoproteinu v týdnech 6, 12, 18, 24 a poté každých 12 týdnů
o Bezpečnostní profil pomocí klasifikace NCI CTC v4.02
o Farmakokinetika
o Analýza fenotypů vybraných genů

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. histologically or cytologically confirmed advanced-stage hepatocellular carcinoma (HCC) (unresectable, and/or metastatic) or responding to the Barcelona diagnostic criteria
2. Patient who has received sorafenib single agent as 1st line treatment and had discontinued from this treatment for any reason (ie, tumor disease progression, intolerance) at least 14 days prior to baseline (A line of treatment is defined as at least 1 prior therapeutic regimen consisting of chemotherapy or biologic agent). Requirement for sorafenib treatment is not applicable to patients who have not been previously treated with sorafenib for any reason (e.g., contra-indication to sorafenib, patient refusal to sorafenib treatment due to expected toxicity, etc.)
3. Patient who has recovered from any significant sorafenib-related treatment toxicities prior to baseline (≤Grade 2)
4. Patient with at least 1 untreated target lesion that could be measured in 1 dimension:
• according to the RECIST 1.1
• and according to Modified RECIST assessment for hepatocellular carcinoma
5. Patient who has received local therapy prior to sorafenib administration (surgery, hepatic arterial embolization, chemoembolization, radioembolisation, radiofrequency ablation, percutaneous ethanol injection or cryoablation) are eligible. Local therapy must be completed at least 4 weeks prior to the baseline scan
6. Adequate antiviral systemic therapy in symptomatic and asymptomatic HBV Ag carriers
7. Patient eligible for receiving etoposide and irinotecan (either as a 2nd line treatment after sorafenib or 1st line for patient not previously treated with sorafenib)
8. Child-Pugh liver function class A
9. Barcelona Clinic Liver Cancer classification: class C
10. ECOG Performance Status ≤ 2
11. Patient with adequate organ function:
• A N C ≥ 1.5 x 109/L
• Hb ≥ 10 g/dL
• Platelets ≥ 75 x 109/L
• AST/ALT ≤ 5 x ULN
• Gamma-GT ≤ 5 x ULN
• Total bilirubin ≤ 3 x ULN
• Normal Creatinine or if abnormal creatinine, creatinine clearance ≥ 50 mL/min (Cockcroft and Gault formula)
• Albumin ≥ 0.75 x LLN
• Urea < 2 x ULN
• Proteinuria < 30 mg/mL (1+) on the dipstick. If proteinuria is ≥ 1+ on the dipstick, 24 hours proteinuria must be < 1.5g/24 hour
12. Patient with life expectancy > 3 months
13. ≥ 18 years
14. weight > 40 kg and BMI > 18 kg/m²
15. Female patient of childbearing potential, who agrees to use 2 highly effective methods (1 for the patient and 1 for the partner) of medically acceptable forms of contraception during the study and for 3 months after the last treatment intake. Acceptable forms of contraception include:
• A documented placement of an IUD or IUS and the use of a barrier method used with spermicidal
foam/gel/film/cream/suppository)
• Documented tubal ligation (female sterilization). In addition, a barrier method should also be used
• Double barrier method: Condom and occlusive cap with spermicidal foam/gel/film/cream/suppository
• Any other contraceptive method with a documented failure rate of <1% per year
• Abstinence
Male patients must use medically acceptable methods of contraception if your female partner is pregnant, from the time of the 1st administration of the study drug until 3 months following administration of the last dose of study drug. Acceptable methods include:
• Condom;
• If you have undergone surgical sterilization (vasectomy with documentation of azoospermia) a condom should also be used.
Male patients must use 2 highly effective methods (1 for the patient and 1 for the partner) of medically acceptable forms of contraception during the study and for 3 months after the last treatment intake. The acceptable methods of contraception are as follows:
• Condom and occlusive cap with spermicidal foam/gel/film/cream/suppository;
• Surgical sterilization and a barrier method (condom or occlusive cap used with spermicidal foam/gel/film/cream/suppository);
• Your female partner uses oral contraceptives, injectable progesterone or subdermal implants and a barrier method
• Medically prescribed topically-applied transdermal contraceptive patch and a barrier method
• Your female partner has undergone documented tubal ligation (female sterilization). In addition, a barrier method should also be used;
• Your female partner has undergone documented placement of an IUD or IUS and the use of a barrier method used with spermicidal foam/gel/film/cream/suppository);
• Abstinence.
16. Patient able and willing to comply with study visits and procedures
17. Patient able to understand, sign, and date the written informed consent form at the screening visit prior to any protocol-specific procedures are performed.
18. Patient affiliated to a social security regimen
19. Patient able to understand and to follow the patient card procedures in case of signs or symptoms of severe neutropenia or severe cutaneous toxicity druing the first 2 months of treatment.

1. Pacient s histologicky nebo cytologicky potvrzeným pokročilým hepatocelulárním karcinomem (HCC) (neresekovatelného, a/nebo metastatického) nebo reagujícím na barcelonská diagnostická kritéria
2. Pacient, který užíval monoterapii sorafenibem jako první linii léčby a přerušil ji z jakéhokoliv důvodu (např. progrese rakoviny, intolerance) alespoň 14 dní před zařazující návštěvou (linie léčby je definována jako alespoň jedna terapeutická fáze skládající se z chemoterapie nebo biologického činitele). Požadavky pro léčbu sorafenibem nejsou aplikovatelné na pacienty, kteří nebyli v minulosti léčeni sorafenibem z jakýchkoliv příčin (např. kontraindikace na sorafenib, pacientovo odmítnutí sorafenibu z důvodu předpokládané toxicity a další)
3. Pacient, který se zotavil z jakýchkoliv signifikantních projevů toxicity souvisejících se sorafenibem před zařazující návštěvou (≤ Třída 2)
4. Pacienti s alespoň jednou neléčenou cílovou lézí, která může být jednorozměrně změřena:
• dle Odpověď hodnotících kritérií v solidních tumorech (RECIST 1.1)
• a dle modifikovaného RECIST (mRECIST) hodnocení pro hepatocelulární karcinom
5. Pacient, který byl léčen lokální léčbou před podáním sorafenibu (operace, hepatická arteriální embolizace, chemoembolizace, radioembolizace, radiofrekvenční ablace, perkutánní etanolové injekce (PEI) nebo kryoablace). Lokální terapie musí být ukončena alespoň 4 týdny před zařazující návštěvou.
6. Adekvátní antivirová systemická léčba u symptomatických a asymptomatických HBV Ag přenašečů.
7. Pacienti vhodní pro příjem etoposidu a irinotekanu (buďto jako druhou linii léčby po sorafenibu, nebo jako první linii léčby pro pacienty dříve neléčené sorafenibem)
8. Child-Pughova funkce jater třídy A
9. Barcelonská klinická klasifikace rakoviny jater (BCLC): třída C
10. Eastern Cooperative Oncology Group (ECOG) výkonnostní stav ≤ 2
11. Pacient s odpovídající funkcí orgánů:
• Absolutní počet neutrofilů (ANC) ≥ 1.5 x 109/L
• Hemoglobin ≥ 10 g/dL
• Trombocyty (PTL) ≥ 75 x 109/L
• AST/ALT ≤ 5 x ULN
• Gamma-GT ≤ 5 x ULN
• Celkový bilirubin ≤ 3x ULN
• Normální hodnota kreatininu nebo, je-li kreatinin abnormální, clearance kreatininu ≥ 50 mL/min (vzorec Cockcrofta a Gaulta)
• Albumin > 0.75 x LLN
• Proteinurie < 30 mg/mL (1+) na testovacím proužku. Pokud je proteinurie na testovacím proužku ≥1+, proteinurie za 24 hodin musí být < 1.5g/24 hodin
12. Pacient s očekávanou délkou života > 3 měsíce
13. Muži nebo ženy ≥ 18 let
14. Váha pacienta > 40 kg a BMI > 18 kg/m²
15. Žena v plodném věku (vstupující do studie po menstruaci s negativním těhotenským testem), která souhlasí s použitím dvou metod (jedné pro pacientku a druhé pro partnera) lékařsky přijatelných forem antikoncepce během studie a po dobu 3 měsíců po posledním užití studijního léku:
• Zdokumentované umístění nitroděložního tělíska (IUD), nebo nitroděložního systému (IUS) s dodatečným použitím bariérových metod (kondom nebo poševní pesar [diafragma nebo cervikální klobouček] použitých se spermicidní pěnou/gelem/filmem/krémem/čípkem.
• Zdokumentované oboustranné podvázaní vejcovodů (ženská sterilizace) s dodatečným použitím bariérových metod (kondom nebo poševní pesar [diafragma nebo cervikální klobouček ] použitých se spermicidní pěnou/gelem/filmem/krémem/čípkem
• Kondom nebo poševní pesar [diafragma nebo cervikální klobouček] použitých se spermicidní pěnou/gelem/filmem/krémem/čípkem.
• Abstinenci pouze, pokud jde o běžný a preferovaný životní styl pacienta.
• Jakoukoliv další antikoncepční metodu s prokázanou mírou selhání <1% ročně
• Abstinence
Muži musí užívat lékařsky akceptovatelné typy antikoncepce, pokud je jejich partnerka těhotná, od první administrace studijního léku až po tři měsíce po poslední přijaté dávce. Přijatelné formy antikoncepce zahrnují:
• Kondom;
• Chirurgická sterilizace (vasektomie se zdokumentovanou azoospermií) s dodatečným použitím kondomu
Muži musí během studie a po další tři měsíce po poslední dávce léku používat dvě vysoce účinné metody (jednu samotný pacient a druhou jeho partnerka) lékařsky uznávaných forem antikoncepce.
Přijatelné formy antikoncepce:
• Kondom nebo poševní pesar [diafragma nebo cervikální klobouček] použitých se spermicidní pěnou/gelem/filmem/krémem/čípkem.
• Zdokumentovanou chirurgickou sterilizaci (vasektomii se zdokumentovanou azoospermií) a bariérové metody (kondom nebo poševní pesar [diafragma nebo cervikální klobouček] použitých se spermicidní pěnou/gelem/filmem/krémem/čípkem.

E.4

Principal exclusion criteria

1. Patient intolerant to etoposide or irinotecan
2. Patient who has received a liver transplant
3. Patient with clinically significant symptoms of hepatic encephalopathy
4. Patient who has previously received more than two line of systemic therapy. One previous therapy must at least be with sorafenib monotherapy unless the patient has not been treated with sorafenib for any reason (e.g. contra-indication to sorafenib, patient refusal to sorafenib due to expected toxicity, etc.) (See Inclusion Criterion 2). Patients participating in surveys or observational studies are eligible to participate in this study.
5. Patient with previous or concurrent cancer that is distinct in primary site or histology from HCC, EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1). Any cancer curatively treated > 5 years prior to entry is permitted
6. Patient presenting with cardiac disorders defined by at least one of the following conditions:
• Patient with recent cardiac history (within 6 months) of:
- Acute coronary syndrome
- Acute heart failure (class III or IV of the NYHA classification)
- Significant ventricular arrhythmia (persistent ventricular tachycardia, ventricular fibrillation, resuscitated sudden death)
• Patient with cardiac failure class III or IV of the NYHA classification
• Patient with severe conduction disorders which are not prevented by permanent pacing (atrio-ventricular block 2 and 3, sino-atrial block)
• Syncope without known aetiology within 3 months
• Uncontrolled severe hypertension, according to the judgement of the investigator, or symptomatic hypertension
7. Pregnant or nursing female patient
8. Patient with active central nervous system (CNS) metastasis or with history of CNS metastasis
9. Patient with history of poor compliance, or current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent.
WASH OUT
10. Patient treated with any investigational agent within 4 weeks prior baseline
11. Patient who has had treatment with any of the following within the specified timeframe prior to baseline:
• Any sorafenib within the 14 days prior to baseline
• Major surgery within the 4 weeks prior to baseline
• Any transfusion, treatment with blood component preparation, received erythropoietin, albumin preparation, and granulocyte colony-stimulating factor (G CSF) within the 2 weeks prior to baseline

1. Pacient je intolerantní na etoposid nebo irinotekan
2. Pacient prodělal transplantaci jater
3. Pacient s klinicky signifikantními příznaky hepatické encefalopatie
4. Pacient, který již dříve prošel dvěma liniemi systematické léčby. Jedna předchozí léčba musí být alespoň sorafenibová monoterapie, pokud už pacient nebyl dříve z jakéhokoliv důvodu léčen sorafenibem (např. kontraindikace na sorafenib, pacientovo odmítnutí sorafenibu z důvodu možné toxicity atd.) (viz zařazovací kritéria 2). Pacienti účastnící se průzkumů nebo pozorovacích studií se mohou účastnit této studie.
5. Pacienti s předešlým nebo souběžným rakovinným onemocněním, které se liší v primární lokalitě, nebo histologii oproti HCC, KROMĚ cervikálního karcinomu in situ, léčeného karcinomu bazálních buněk, povrchových nádorů močového měchýře (Ta, Tis & T1). Je povolena jakákoliv rakovina medicínsky vyléčená > 5 let před vstupem do studie.
6. Pacient trpící srdečními chorobami definovanými alespoň jednou z následujících podmínek:
• Pacient s nedávnou anamnézou srdeční příhody (během posledních 6ti měsíců):
- Akutní koronární syndrom
- Akutní selhání srdce (třída III nebo IV podle NYHA klasifikace)
- Výrazná srdeční arytmie (přetrvávající komorová tachykardie, fibrilace komor, resuscitovaná náhlá srdeční smrt)
• Pacient se srdečním selháním třídy III nebo IV podle NYHA klasifikace
• Pacient se závažnými poruchami vodivosti, kterým nelze zabránit permanentní regulací srdečního rytmu (atrioventrikulární blokáda II. a III. stupně, sinoatriální blokáda).
• Synkopa bez známé etiologie během posledních 3 měsíců.
7. Těhotná nebo kojící pacientka
8. Pacient s aktivní metastázou do centrálního nervového systému (CNS) nebo s historií CNS metastáz
9. Pacient s historií špatné spolupráce nebo současným či minulým psychiatrickým onemocněním, které by mohlo narušit dodržování protokolu studie, nebo poskytnutí informovaného souhlasu

WASH-OUT (VYMÝVÁNÍ) OBDOBÍ PŘEDCHOZÍ LÉČBY
10. Pacient léčený jakýmkoliv studijním přípravkem během posledních 4 týdnů předcházejících zařazující návštěvě
11. Pacient, který byl léčen jakoukoliv z následujících medikací během specifikované doby před zařazující návštěvou:
• Jakýkoliv sorafenib během 14 dnů před zařazující návštěvou
• Rozsáhlý chirurgický zákrok během 4 týdnů před zařazující návštěvou
• Jakákoliv transfúze, léčba preparátem s krevními komponenty, erytropoetin, albuminové preparáty, a faktory stimulující kolonie granulocytů (G CSF) během dvou týdnů před zařazující návštěvou.

E.5 End points

E.5.1

Primary end point(s)

Overall Survival (OS) defined as the time from randomisation to the date of death from any cause

Celkové přežití (OS) definované jako čas od randomizace do data úmrtí z jakékoli příčiny

E.5.1.1

Timepoint(s) of evaluation of this end point

from randomisation to the date of death from any cause

od randomizace do data úmrtí z jakékoli příčiny

E.5.2

Secondary end point(s)

- Survival rate at week 6, 12, 18, 24 and every 12 weeks
- Overall PFS according to Modified RECIST (mRECIST) assessment for hepatocellular carcinoma
- PFS rate at week 6, 12, 18, 24 and every 12 weeks according to RECIST version 1.1. and to mRECIST assessment for hepatocellular carcinoma
- Tumour assessment, first according to RECIST version 1.1. and secondly according to mRECIST assessment for hepatocellular carcinoma:
- Overall Time to progression (TTP)
- Objective response rate (CR + PR) at week 6, 12, 18, 24 and every 12 weeks
- Control disease rate (CR + PR + SD) at week 6, 12, 18, 24 and every 12 weeks
- Best response during study treatment
- Alpha fœto protein dosage at week 6, 12, 18, 24 and every 12 weeks
- Safety profile using the NCI CTC v4.02 classification
- Pharmacokinetics
- Phenotypic analysis

-• Míra přežití v týdnech 6, 12, 18, 24 a poté každých 12 týdnů
• Celková míra přežití bez progrese onemocnění (PFS) vzhledem k RECIST verze 1.1 a vzhledem k modifikovanému RECIST (mRECIST) hodnocení hepatocelulárních karcinomů
• Hodnocení nádoru, prvně dle RECIST verze 1.1 a sekundárně dle mRECIST hodnocení hepatocelulárních karcinomů:
o Celkový čas do progrese
o Míra TTP v týdnech 6, 12, 18, 24 a poté každých 12 týdnů
o Objektivní škála odpovědi (CR+PR) v týdnech 6, 12, 18, 24 a poté každých 12 týdnů
o Nejlepší odezva během léčby
o Hladina alfa-fetoproteinu v týdnech 6, 12, 18, 24 a poté každých 12 týdnů
o Bezpečnostní profil pomocí klasifikace NCI CTC v4.02
o Farmakokinetika
o Analýza fenotypů vybraných genů

E.5.2.1

Timepoint(s) of evaluation of this end point

W6, W12, W18, W24 and every 12 weeks

T6, T12, T18, T24 a každých 12 týdnů

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

safety and pharmacokinetic

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

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)

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

Czech Republic

Greece

Slovakia

Spain

United States

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

Patient could be treated until disease progression without clinical benefit confirmed on CT scan by RECIST version 1.1 and Modified RECIST (mRECIST) assessment for hepatocellular carcinoma, limiting toxicity, or consent withdrawal

Pacient může být léčen do progrese nemoci bez klinického přínosu potvrzeného CT snímkem podle RECIST verze 1.1 a Modifikovaného RECIST (mRECIST) hodnocení pro hepatocelulární karcinom, limitující toxicity, nebo odvolání souhlasu pacienta

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

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

NOT DIFFERENT

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

2015-05-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-03-04

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

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Orphan Designation Number:
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