Clinical Trials Register

Summary
EudraCT Number:	2011-001690-62
Sponsor's Protocol Code Number:	HE2016
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2014-09-25
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

UK - MHRA

A.2

EudraCT number

2011-001690-62

A.3

Full title of the trial

A randomised phase II clinical trial of conditioning cyclophosphamide and chemoembolisation with or without vaccination with dendritic cells pulsed with HepG2 lysate ex vivo in patients with Hepatocellular Carcinoma

A.3.1

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

A study comparing the standard treatment of transarterial chemoembolisation (TACE)plus low doses of chemotherapy (cyclophosphamide) with an immune cell derived vaccine

A.3.2

Name or abbreviated title of the trial where available

IMMUNOTACE

A.4.1

Sponsor's protocol code number

HE2016

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN11889464

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	University of Birmingham
B.1.3.4	Country	United Kingdom
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	NIHR-EME program
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	Cyclophosphamide
D.2.1.1.2	Name of the Marketing Authorisation holder	Generic
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Cyclophosphamide
D.3.4	Pharmaceutical form	Powder for solution for injection
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	Cyclophosphamide monohydrate BP
D.3.9.1	CAS number	6055-19-2
D.3.9.4	EV Substance Code	AS2
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	20
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	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	Autologous dendritic cells pulsed with HepG2 lysate matured with monophosphoryl lipid A
D.3.2	Product code	not applicable
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 Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Autologous matured Dendritic cells HepG2 pulsed vaccine
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	RG_10-148
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	AS3
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	1000000 to cells
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)	Yes
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.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Hepatocellular carcinoma

E.1.1.1

Medical condition in easily understood language

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10049010
E.1.2	Term	Carcinoma hepatocellular
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 determine whether activity due to the addition of DC vaccine to chemoembolisation and preconditioning cyclophosphamide warrants further investigation defined by 12 months progression free survival.

E.2.2

Secondary objectives of the trial

To determine whether the addition of DC vaccine to chemoembolisation and preconditioning is superior to chemoembolisation and preconditioning alone in:

1) Improvement in overall survival
2) Reduction in markers of cancer progression
3) Reduction in size of the tumour as defined by radiological imaging
4) Activation of anti-cancer immune responses
5) Toxicity
6) Progression free survival at 12 months

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Histological or cytological diagnosis or meet the AASLD criteria for
diagnosis of HCC and at least one uni-dimensional lesion measurable
according to the RECIST 1.1 criteria by CT-scan or MRI.
2. Suitable for TACE
3. Aged ≥ 18 years and estimated life expectancy ≥ 6 months
4. Not a candidate for surgical resection or transplantation
5. No previous chemotherapy, radiotherapy, immunotherapy or other experimental
treatment for HCC prior to entry into the trial
6. ECOG performance status ≤ 2
7. Adequate haematological function: Hb ≥ 90g/L, Absolute neutrophil count
≥ 1.5x109/L, platelet count ≥ 50x10^9/L
8. Bilirubin ≤ 50 µmol/L, AST or ALT ≤ 5 x ULN
9. Adequate renal function: Cockroft and Gault estimation ≥ 40ml/min
10. INR ≤ 1.5
11. Child-Pugh score ≤ 7
12. Women of child-bearing potential should have a negative pregnancy test prior
to trial entry
13. Women of child-bearing potential and men who have partners of child-bearing
potential must be willing to practise effective contraception for the
duration of the study and for three months after the completion of
treatment.
14. Written informed consent
15. Suitable veins for access with 17G fistula needle

E.4

Principal exclusion criteria

1. Extra-hepatic metastasis
2. Prior embolisation, systemic or radiation therapy for HCC
3. Investigational therapy or major surgery within 4 weeks of trial entry
4. Any ablative therapy (RFA or PEI) for HCC (this should not exclude patients
if target lesion(s) have not been treated and occurred >6 weeks prior trial
entry)
5. Child Pugh score >7
6. Hepatic encephalopathy
7. Ascites refractory to diuretic therapy
8. Documented invasion of the main portal vein
9. Hypersensitivity to intravenous contrast agents
10. Active clinically serious infection > grade 2 CTCAE version 4 within
preceding 2 weeks
11. Pregnant or lactating women
12. History of second malignancy except those treated with curative intent more
than three years previously without relapse and non-melanotic skin cancer or
cervical carcinoma in situ
13. Evidence of severe or uncontrolled systemic diseases, congestive cardiac
failure > NYHA class 2, Myocardial Infection within 6 months or laboratory
finding that in the view of the investigator makes it undesirable for the
patient to participate in the trial
14. Psychiatric or other disorder likely to impact on informed consent
15. Known history of HIV
16. Patient is unable and/or unwilling to comply with treatment and trial
instructions
17. Patients with active auto-immune disorder
18. Hypersensitivity to cyclophosphamide or to any of its metabolites
19. Current cystitis infection
20. Urinary outflow obstruction

E.5 End points

E.5.1

Primary end point(s)

Progression free survival (PFS) is defined as the time from date of randomisation to the date where progressive disease is first recorded, or date of death without previously recorded progression. Progression will be determined according to RECIST 1.1. In the absence of radiological disease, patients may be considered to have clinically progressed based on clinical evidence. Whether progression is classed as radiological or clinical will be documented. Patients who are alive with no recorded progression at the time of analysis will be censored at the last date of recorded assessment.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months

E.5.2

Secondary end point(s)

Secondary:
Radiological response over time will be reported. Patients will be categorised according to their ‘best’ response and proportions reported by treatment group.

Mean change in serum AFP from baseline, with confidence intervals, will be reported descriptively by treatment group.

Toxicity: the proportions of patients with specific grade 3/4 toxicities will be reported descriptively across treatments.

Overall survival estimates will be calculated using the method of Kaplan and Meier. Median and 12 months overall survival rates with confidence intervals will be presented by treatment group.

Immune response will be based on CD4 and CD8 T cell analyses based on change in counts over time.

mRECIST assessed radiological response over time will be reported. Patients will be categorised according to their ‘best’ response and proportions reported by treatment group.

mRECIST assessed progression free survival estimates will be calculated using the method of Kaplan and Meier. Median and 12-month survival rates, with confidence intervals, will be presented by treatment group.

E.5.2.1

Timepoint(s) of evaluation of this end point

See above

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

Yes

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

Immune responses

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)

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

Yes

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

Yes

E.8.2.3.1

Comparator description

Dendritic vaccine vs No vaccine

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

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

The trial will end when the final participant has completed their final follow up at 14 months

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