Clinical Trials Register

Summary
EudraCT Number:	2016-000935-42
Sponsor's Protocol Code Number:	IJB-GASTON-002-ARTEMIS-Eso
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-03-17
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2016-000935-42

A.3

Full title of the trial

Assessment of Metabolic and pathological Response to Treatment with Radio-chemotherapy (RCT) and Immunotherapy (ImT) before Surgery in locally advanced Esophageal and gastro-esophageal junction cancer: ARTemIS-Eso, a three-level, open-label, phase I-II study

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

ARTEMIS-Eso

A.4.1

Sponsor's protocol code number

IJB-GASTON-002-ARTEMIS-Eso

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	Institut Jules Bordet
B.1.3.4	Country	Belgium
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	Innate Pharma
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	Institut Jules Bordet
B.5.2	Functional name of contact point	CTSU
B.5.3	Address:
B.5.3.1	Street Address	Boulevard de Waterloo121
B.5.3.2	Town/ city	Bruxelles
B.5.3.3	Post code	1000
B.5.3.4	Country	Belgium
B.5.6	E-mail	artemis.eso.trial@bordet.be

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	Monalizumab_IJB
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	Monalizumab
D.3.9.1	CAS number	1228763-95-8
D.3.9.2	Current sponsor code	Monalizumab_IJB
D.3.9.3	Other descriptive name	MONALIZUMAB
D.3.9.4	EV Substance Code	SUB180109
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	100
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)	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	Yes
D.3.11.13.1	Other medicinal product type	Humanized IgG4 monoclonal antibody
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	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	Fluorouracil_IJB
D.3.4	Pharmaceutical form	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	Fluorouracil
D.3.9.1	CAS number	51-21-8
D.3.9.2	Current sponsor code	Fluorouracil_IJB
D.3.9.3	Other descriptive name	FLUOROURACIL
D.3.9.4	EV Substance Code	SUB07721MIG
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	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	Yes
D.3.11.13.1	Other medicinal product type	Pyrimidin analog
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.2.1.2	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	Oxaliplatin_IJB
D.3.2	Product code	PRD4523518
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	OXALIPLATIN
D.3.9.1	CAS number	61825-94-3
D.3.9.2	Current sponsor code	Oxaliplatin_IJB
D.3.9.4	EV Substance Code	SUB09490MIG
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	5
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	Yes
D.3.11.13.1	Other medicinal product type	other antineoplastic agents, platinum compounds

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

Adenocarcinomas of the esophagus or gastro-esophageal junction and squamous cell carcinoma of the esophagus.

E.1.1.1

Medical condition in easily understood language

gatrointestinal 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	PT
E.1.2	Classification code	10061534
E.1.2	Term	Oesophageal squamous cell carcinoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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	10030137
E.1.2	Term	Oesophageal adenocarcinoma
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 establish the recommended schedule of immunotherapy (monalizumab) that can be safely administered in combination with RCT in patients with esophageal SCC or ADC including gastro-esophageal junction ADC.

E.2.2

Secondary objectives of the trial

1) To evaluate the pathological response on the surgical specimen.
2) To evaluate the recurrence pattern and survival at 2 years after surgery.
3) To monitor the immunogenicity of monalizumab given with RCT

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

A sub-study will also be conducted in some pre-selected centers. If the patient agrees to do so, some additional tumor biopsy cores will be collected at baseline, after one course of FOLFOX and at surgery for fresh tissue analysis. Sponsor Protocol Number: IJB-GASTON-002-ARTEMIS-Eso version 1, dated 13/12/2016

E.3

Principal inclusion criteria

1. Age ≥ 18 years old
2. ECOG performance status ≤ 1
3. Female and Male
4. Must have histologically confirmed esophageal ADC or SCC or gastro-esophageal junction ADC (Siewert I and II) eligible for a curative intent resection (recommended exploration by EUS and diagnostic laparoscopy in gastro-esophageal junctions) without restriction in age and sex and candidate for neoadjuvant RCT.
5. At least classified clinical T3Nx or any T, N+ according to cTNM version 7.
6. Negative serum pregnancy test (for women of childbearing potential) within 7 (+/-1) days prior to the beginning of treatment.
7. Women of childbearing potential must agree to use one highly effective method of contraception at study entry (if this is not already the case, put in place within 1 week after ICF signature, and at the very latest before 1st administration of study treatment), during the study treatment administration and at least 6 months after the last administration of study treatment.
8. Men must agree to use condom during the course of this study and for at least 6 months after the last administration of the study treatment.
9. Adequate bone marrow function as defined below:
• Absolute neutrophil count ≥1500/µL or 1.5x109/L
• Hemoglobin ≥ 9 g/dL
• Platelets ≥100000/µL or 100x109/L
10. Adequate liver function as defined below:
• Serum total bilirubin ≤ 1.5 x ULN. In case of known Gilbert’s syndrome < 3xUNL is allowed
• AST (SGOT)/ALT (SGPT) ≤ 2.5 x ULN
• Alkaline phosphatase ≤ 2.5 x ULN
11. Adequate renal function as defined:
• Creatinine ≤ 1.5 x UNL or creatinine clearance >60 mL/min
12. Participants must have normal cardiac and pulmonary functions defined with ultrasonography (LVEF>50%) and pulmonary function tests (including DLCO (diffusing capacity factor of the lung for carbon monoxide)).
13. Completion of all necessary screening procedures within 28 days prior to enrolment.
14. Accessible tumour for biopsies through upper gastro-intestinal endoscopy (for translational research activities).
15. Signed Informed Consent form (ICF) obtained prior to any study related procedure and study treatment.
16. For the phase II expansion cohort only, significant FDG uptake at the primary tumour on baseline PET/CT, performed not more than 7 days before the beginning of the first course of CT, defined as SUVmax > 2x the mean liver uptake.

E.4

Principal exclusion criteria

1. Patient ineligible for curative intent surgery:
• T4 with involvement of mediastinal structures as tracheobronchial, recurrent nerve, aorta over 90° of its circumference, vertebral body
• Tumour ≥ 4cm in diameter developed above the carina
• Visceral metastasis
• Metastatic lymph nodes: supraclavicular and/or lombo-aortic
• Cervical esophageal cancer defined as a tumor involving the lower border of the cricoid cartilage (at the level of the sixth cervical vertebra) to the thoracic inlet 5cm down under, generally between 18 and 20 cm from the dental arcade
2. Uncontrolled concurrent illness or any significant disease that, in the investigator’s opinion, would exclude the patient from the study.
3. Absolute contraindication for surgery: respiratory failure (VEMS < 1000mL), weight loss> 20%, renal failure: creatinine > 1.5 ULN, myocardial infarct < 6 months, evolutive cardiopathy, ECOG 3 and 4, non-compensated cirrhosis.
4. Pregnant and/or lactating women.
5. Uncontrolled diabetes.
6. Individuals with a history of a different malignancy within the last 5 years are ineligible except cervical cancer in situ, and early stage basal cell or squamous cell carcinoma of the skin.
7. Patients with active, known or suspected autoimmune disease or condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive systemic treatment.
• (Exception: patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring immunosuppressive systemic treatment, or conditions not expected to recur in the absence of an external trigger, are permitted to be enrolled.
• Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active/autoimmune disease.
8. Patients with diseases known for hypersensitivity to radiotherapy.
9. Prior treatment for esophageal cancer: surgery, radiotherapy, chemotherapy or immunotherapy (in particular but not limited to anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, including prior therapy with anti-tumour vaccines or other immuno-stimulatory anti-tumour agents.
10. Positive test for hepatitis B virus surface antigen (HBsAg) or hepatitis C virus (ribonucleic acid or HCV antibody) indicating acute or chronic infection.
11. Positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
12. History of allergy to study drug components or excipients.
13. Subject with a significant medical, neuro-psychiatric, or surgical condition, currently uncontrolled by treatment, which, in the principal investigator’s opinion, may interfere with completion of the study.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the pCR defined by the absence of any tumoural cells on the surgical specimen post esophagectomy.

E.5.1.1

Timepoint(s) of evaluation of this end point

End of the study

E.5.2

Secondary end point(s)

1) Toxicity profile according to CTCAE v.4.03
2) Metabolic response after 1 course of CT and before surgery
3) Number of the tumour-infiltrating lymphocytes (TILs) at baseline, after 1 course of CT and after surgery
4) Two year-disease free survival (DFS) and two year-overall survival (OS)

Exploratory endpoints
1. Genomic/Transcriptomic and immune changes between pre-treatment and post-treatment tumour samples;
2. Baseline Genomic/Transcriptomic/Microbiologic and immune profiles of sensitivity/resistance to CT alone and to RCT combined with monalizumab
3. Baseline Genomic/Transcriptomic/Microbiologic and immune profiles of sensitivity/resistance to CT alone and to RCT combined with monalizumab with DFS and OS;
4. Plasma ctDNA genomic changes before, during and after treatment to monitor response/resistance to RCT combined with monalizumab

E.5.2.1

Timepoint(s) of evaluation of this end point

end 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

Yes

E.6.4

Safety

Yes

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

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)

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

a [3+3] scheme to determine the best schedule to give immunotherapy with radiochemotherapy

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

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

Yes

E.8.1.7.1

Other trial design description

[3+3] scheme

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

Both the schedule of immunotherapy and the total dose are differents for the Phase I.

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

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

A scientific committee will be constituted to monitor data and overall safety.
In Phase II, the same scientific committee is planned to review safety and events (relapse, deaths).
No Independent Data Monitoring Committee is foreseen in phase I/II because centres selected to participate are restricted to few centres used to phase I/II management and practices.

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

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)

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

100

F.4.2.2

In the whole clinical trial

100

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)

At the physician's dscretion according to the local 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

2017-03-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-04-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-12-11

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