Clinical Trials Register

Summary
EudraCT Number:	2013-001244-56
Sponsor's Protocol Code Number:	LiCTOP-C-001
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-05-29
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

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A. Protocol Information

A.1

Member State Concerned

Sweden - MPA

A.2

EudraCT number

2013-001244-56

A.3

Full title of the trial

An open, multicenter, single dose, parallel study, evaluating the
pharmacokinetics of doxorubicin and its active metabolite (doxorubicinol)
after a hepatic intra-arterial injection of either a lipiodol emulsion
containing doxorubicin or doxorubicin loaded into DC Beads in patients
with intermediate stage hepatocellular carcinoma (HCC).

A.3.1

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

An open, multicenter, single dose, parallel study, evaluating the release
and disposition of doxorubicin and its active metabolite (doxorubicinol)
after an intra-arterial injection into the liver of an emulsion containing
doxorubicin or doxorubicin loaded into microparticulate beads in patients
with intermediate stage primary liver cancer.

A.4.1

Sponsor's protocol code number

LiCTOP-C-001

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	Department of Pharmacy, Uppsala University
B.1.3.4	Country	Sweden
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	Deparment of Pharmacy, Uppsala University
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Department of Pharmacy
B.5.2	Functional name of contact point	Biopharmaceutical research group
B.5.3	Address:
B.5.3.1	Street Address	Box 580
B.5.3.2	Town/ city	Uppsal
B.5.3.3	Post code	SE-75123
B.5.3.4	Country	Sweden
B.5.4	Telephone number	0046184714337
B.5.5	Fax number	0046184714223
B.5.6	E-mail	hans.lennernas@farmaci.uu.se

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	DC Bead
D.2.1.1.2	Name of the Marketing Authorisation holder	Biocompatibles UK
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	DC Bead
D.3.2	Product code	DEB
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraarterial use
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	Yes
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	Lipodol ultra fluide
D.2.1.1.2	Name of the Marketing Authorisation holder	Guerbet (Aulnay-sous-Bois, France)
D.2.1.2	Country which granted the Marketing Authorisation	Ireland
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	iodine
D.3.4	Pharmaceutical form	Emulsion and suspension for emulsion for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraarterial use
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	Doxorubicin Teva
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva Sweden AB
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
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	doxorubicin hcl
D.3.2	Product code	DOX
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	Intraarterial use
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: 4
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	doxorubicin hydrochloride for injection (Adriamycine)
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer inc
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	doxorubicin hcl
D.3.2	Product code	DOX
D.3.4	Pharmaceutical form	Powder for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraarterial use
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

Intermediate hepatocellular carcinoma

E.1.1.1

Medical condition in easily understood language

intermediate primary liver cancer

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	16.0
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.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the plasma pharmacokinetics of doxorubicin and its active
metabolite doxorubicinol after a single dose of doxorubicin-loaded DC
bead or doxorubicin-lipiodol emulsion

E.2.2

Secondary objectives of the trial

• To evaluate the anti-tumor effect defined as tumor size and amount
of necrosis using magnetic resonance imaging (MRI) 4-6 weeks after a
single dose of one these two formulations.
• To evaluate safety (liver function and adverse events) of the two
products after a single dose of one these two formulations.
• To evaluate the urinary excretion of doxorubicin and doxorubicinol 24
hours after a single dose of one these two formulations.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Adult (> 18 years),
2. Diagnosis of HCC: based on the Guidelines issued by AASLD
(American Association for the Study of Liver Diseases) (latest diagnostic
radiological imaging performed within 1 month from enrolment),
3. HCC for which transplantation, surgical resection or percutaneous
ablation are not indicated,
4. Child-Pugh class A or B,
5. Performance status: ECOG 0-2 (WHO),
6. Life expectancy of at least 3 months in absence of treatments,
7. The following laboratory parameters must be met:
Creatinine ≤ 115 μmol/L, Bilirubin ≤ 20.5 μmol/L, Albumin >= 35 g/L,
White blood cells >= 1.5 x 109/L, INR >= 1.7,
8. Signature of informed consent obtained from the patient

E.4

Principal exclusion criteria

1. Infiltrative HCC,
2. Liver tumor is undefined, immeasurable or not assessable,
3. Portal vein thrombosis, with the exception of thrombosis of a
segment branch of the portal vein,
4. Extra-hepatic cancer involvement,
5. Contraindications to arteriography,
6. Use of doxorubicin and other anthracyclines in the last three months
prior to inclusion into the study,
7. Previous or ongoing transarterial chemoinfusion (TAI) and/or
chemoembolization (TACE) treatment of the same liver tumor (i.e. same
lobular or segmental target area),
8. Known or suspect hypersensitivity to the investigational drug or to
the investigational pharmacological class,
9. Ascites grade 2 or 3,
10. Patients presenting with severe clinical conditions which in the
opinion of the investigator contraindicate patient participation in the
study,
11. Presence of localized or systemic infections (with the exception of
HIV infection responsive to therapy, HBV and HCV),
12. Pregnant women (women of child-bearing potential will have a
pregnancy test done) and breastfeeding women,
13. Patients who are not capable of complying with the procedures
established by the protocol and of signing the informed consent. In case
of incapacitated patients unable to release their informed consent to
take part in the study, the consent must be released and signed also by
the parents/guardian or by the legal representative. Incapacitated
patients must as well sign the informed consent to the best of their
ability.

E.5 End points

E.5.1

Primary end point(s)

Primary pharmacokinetic parameters:
AUC, Cmax, tmax, t1/2 of doxorubicin and its active metabolite
doxorubicinol in plasma from two sampling sites (vena cava and
peripheral vein)

E.5.1.1

Timepoint(s) of evaluation of this end point

PK parameters will be collected during 24 h after the performed
treatment

E.5.2

Secondary end point(s)

Secondary variables to be assessed:
Secondary effect variables:
Anti-tumor response of treated lesion
Secondary safety variables:
A complete physical examination in addition to adverse events caused by
the study and abnormal, clinically relevant, laboratory parameters
assessed by liver function tests and α-fetoprotein to assess biohumoral
levels of the disease.
Secondary pharmacokinetic variables:
Fraction excreted of doxorubicin and doxorubicinol in urine

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary effect variables:
at 4-6 weeks post treatment assessed with MRI according to modified
Response Evaluation Criteria in Solid Tumors (mRECIST).
Secondary safety variables:
A complete physical examination will be performed at screening and at
the end of the study (at 4-6 weeks, after MRI).
Blood samples including aminotransferases, bilirubin, alkaline
phosphatase, CRP, albumin, creatinine, urea, electrolytes, hemoglobin,
leukocytes and thrombocytes will be taken at screening, and 24 hours
and 5-7 days after treatment.
Secondary pharmacokinetic variables:
urine will be collected during the first 24 h after treatment.

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

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

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

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

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

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

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)

Patients continue with the clinical routine at the specific clinical site

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

2013-07-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-07-17

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

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