Clinical Trials Register

Summary
EudraCT Number:	2022-003561-38
Sponsor's Protocol Code Number:	APHP220729
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2023-01-31
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

France - ANSM

A.2

EudraCT number

2022-003561-38

A.3

Full title of the trial

Durvalumab/Tremelimumab in neoadjuvant and adjuvant setting in patients with HCC treated by electroporation ablation in curative intent: French multicenter phase 2 therapeutic DUMELEP trial (DUMELEP)

A.3.1

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

DUMELEP

A.3.2

Name or abbreviated title of the trial where available

DUMELEP

A.4.1

Sponsor's protocol code number

APHP220729

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	Assistance publique - Hôpitaux de Paris
B.1.3.4	Country	France
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	AstraZeneca
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	Assistance publique - Hôpitaux de Paris
B.5.2	Functional name of contact point	Clinical research officer
B.5.3	Address:
B.5.3.1	Street Address	1 avenue Claude Vellefaux, Porte 23, Carré historique de l'Hôpital St Louis
B.5.3.2	Town/ city	Paris
B.5.3.3	Post code	75010
B.5.3.4	Country	France
B.5.4	Telephone number	+33144 84 17 35
B.5.5	Fax number	+33144 84 17 01
B.5.6	E-mail	thibaut.vanrietvelde@aphp.fr

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	IMFINZI®
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca
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	Durvalumab
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	Durvalumab
D.3.9.2	Current sponsor code	Durvalumab
D.3.9.4	EV Substance Code	SUB176342
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	50
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	No
D.2.1.1.1	Trade name	TREMELIMUMAB
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca
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	Tremelimumab
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	Tremelimumab
D.3.9.1	CAS number	745013-59-6
D.3.9.4	EV Substance Code	SUB37101
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	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.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 (HCC)

E.1.1.1

Medical condition in easily understood language

Hepatocellular carcinoma (HCC)

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	PT
E.1.2	Classification code	10073071
E.1.2	Term	Hepatocellular carcinoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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 assess local recurrence-free survival at 1-year following neoadjuvant/adjuvant Durvalumab/Tremelimumab and adjuvant Durvalumab therapy associated with IRE procedure in patients with BCLC A HCC

E.2.2

Secondary objectives of the trial

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Male or female patients ≥ 18 years of age
- Histological or radilogical diagnosis of HCC
- Patients with newly diagnosed or recurrent HCC (following a previous curative procedure performed at least 6 months before inclusion) eligible for IRE as assessed by multidisciplinary board corresponding to BCLC A stage:

x Uninodular HCC ≥ 2 cm and ≤ 5 cm, no macroscopic vascular invasion
x Multinodular maximum 3 nodules ≤ 3 cm, Body weight >30 kg
x At least one uni-dimensional measurable lesion by computed tomography (CT) scan or magnetic resonance imaging (MRI) according to modified RECIST for HCC
x Liver function status Child-Pugh Class A
x <<Eastern Cooperative Oncology Group (ECOG)>><<World Health Organisation (WHO) performance status of 0 or 1

- Adequate bone marrow, liver and renal function as assessed by the following laboratory tests:

x Total bilirubin ≤ 2 mg/dL
x Serum creatinine ≤ 1.5 x ULN
x Lipase ≤ 2 x ULN
x Prothrombine time-international normalized ratio (PT-INR) < 2.3 and PTT < 1.5
x Glomerular Filtration Rate (GFR) ≥ 30 mL/min/1.73 m2

- Life expectancy ≥ 3 months
- Women of childbearing potential (WOCBP) need to accept one effective method of contraception until 3 months after the last infusion of durvalumab and avoid pregnancy

- Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or180 days after the last dose of durvalumab and tremelimumab combination therapy.

- Patients affiliated to a Social Security System
- Written informed consent signed
- Haemoglobin ≥9.0 g/dL
- Absolute neutrophil count (ANC ≥1.0 × 109 /L)
- Platelet count ≥75 × 109/L
- Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). (This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.)
- AST (SGOT) and ALT (SGPT) ≤5x ULN
- Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine clearance CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:

Males:
Creatinine CL (mL/min) = Weight (kg) x (140 – Age)
72 x serum creatinine (mg/dL)

Females:
Creatinine CL (mL/min) = Weight (kg) x (140 – Age) x 0.85
72 x serum creatinine (mg/dL)
- Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
- At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion (TL) at baseline. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to inclusion

E.4

Principal exclusion criteria

Not enough room: see protocol

E.5 End points

E.5.1

Primary end point(s)

Local recurrence-free survival at 1-year following neoadjuvant Durvalumab/Tremelimumab and adjuvant Durvalumab therapy associated with IRE procedure in patients with BCLC A HCC

E.5.1.1

Timepoint(s) of evaluation of this end point

1-year following neoadjuvant Durvalumab/Tremelimumab and adjuvant Durvalumab therapy associated with IRE procedure in patients with BCLC A HCC

E.5.2

Secondary end point(s)

- To assess the changes of tumorous and non-tumorous perfusion parameters observed with MRI after one months of neoadjuvant treatments
- To assess the Per nodule rates of early response (one month) after a single procedure of IRE
- To assess the incidences of intra segmental/ extra segmental distant recurrence
- To assess the overall survival at 1-yr following IRE procedure
- To assess the respect of scheduled IRE procedure as a function of neoadjuvant phase potential SAEs
- To assess the compliance to neoadjuvant and adjuvant treatments
- To assess the tolerance of Durvalumab/Tremelimumab in the setting of neo- and adjuvant therapy to IRE

For biomarker studies:
- To assess histopathological and molecular features of non-tumoral and tumor tissue after neoadjuvant phase on sequential biopsies before IRE procedure
- To assess early effects of neoadjuvant Durvalumab/Tremelimumab on the tumor before IRE, judged by histology, radiology and sequential serum markers performed before AP. In particular, peripheral and histological samples will be evaluated for immunophenotyping of lymphocyte populations, circulating cytokine and chemokine assays, changes in inflammatory infiltrates and expression of immunity modulating genes.
- To study changes in cytokine/chemokines profiling on sequential serum samples of patients before and after treatment as well as evaluation of sequential liquid biopsy on plasma samples

E.5.2.1

Timepoint(s) of evaluation of this end point

1 year

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

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

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

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

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.8.3

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

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)

Information not present in EudraCT

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

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)

Standard of care

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

2023-05-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-08-23

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

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