Clinical Trials Register

Summary
EudraCT Number:	2014-000334-30
Sponsor's Protocol Code Number:	INT27/14
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-03-27
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2014-000334-30

A.3

Full title of the trial

Immunomodulatory effect of esomeprazole antitumoral and high-dose under neoadjuvant and adjuvant in patients with melanoma in stage III. Randomized pilot study treatment vs control

EFFETTO IMMUNOMODULATORIO E ANTITUMORALE DELL'ESOMEPRAZOLO AD ALTE DOSI IN REGIME NEOADIUVANTE E ADIUVANTE IN PAZIENTI CON MELANOMA IN STADIO III. STUDIO PILOTA RANDOMIZZATO TRATTAMENTO VS CONTROLLO

A.3.1

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

Immunomodulatory and anti-tumor effect of high doses of esomeprazole treatment before and after surgery in patients with stage III melanoma. Randomized pilot study treatment vs. control

effetto immunomodulatorio e antitumorale dell'esomeprazolo ad alte dosi in trattamento prima e dopo chirurgia in pazienti con melanoma in stadio III. Studio pilota randomizzato trattamento vs controllo

A.3.2

Name or abbreviated title of the trial where available

AdESOM Study

Studio Adesom

A.4.1

Sponsor's protocol code number

INT27/14

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	Fondazione IRCCS ''IStituto Nazionale dei Tumori''
B.1.3.4	Country	Italy
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	AIRC
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fondazione IRCCS ''IStituto Nazionale dei Tumori''
B.5.2	Functional name of contact point	Segreteria Tecnico Scientifica
B.5.3	Address:
B.5.3.1	Street Address	via G. Venezian 1
B.5.3.2	Town/ city	Milan
B.5.3.3	Post code	20133
B.5.3.4	Country	Italy
B.5.6	E-mail	etico@istitutotumori.mi.it

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	Nexium
D.2.1.1.2	Name of the Marketing Authorisation holder	Astra Zeneca
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Esomeprazole
D.3.2	Product code	034972416/M(40mg)
D.3.4	Pharmaceutical form	Pastille
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	Esomeprazole
D.3.9.1	CAS number	217087-09-7
D.3.9.3	Other descriptive name	ESOMEPRAZOLE MAGNESIUM TRIHYDRATE
D.3.9.4	EV Substance Code	SUB126849
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	40
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	Proton Pump Inhibitor (PPI)
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	Nexium
D.2.1.1.2	Name of the Marketing Authorisation holder	Astra Zeneca
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Esomeprazole
D.3.2	Product code	034972265/M(20mg)
D.3.4	Pharmaceutical form	Pastille
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	Esomeprazole
D.3.9.1	CAS number	217087-09-7
D.3.9.3	Other descriptive name	ESOMEPRAZOLE MAGNESIUM TRIHYDRATE
D.3.9.4	EV Substance Code	SUB126849
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	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	Yes
D.3.11.13.1	Other medicinal product type	Proton Pump Inhibitor (PPI)

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

metastatic melanoma BLS+ and BRAF wt

melanoma metastatico per BLS+ e BRAF wt

E.1.1.1

Medical condition in easily understood language

progressed to melanoma metastasis to the sentinel lymph node biopsy positivity (bls+) and negativity for BRAF mutation (BRAFwt)

melanoma progredito a metastasi per positivitá alla biopsia del linfonodo sentinella (bls+) e negativitá per mutazione BRAF (BRAFwt)

E.1.1.2

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	PT
E.1.2	Classification code	10025670
E.1.2	Term	Malignant melanoma stage III
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 evaluate the effect of immunomodulatory and anti-tumor effect of treatment with high doses of esomeprazole in patients with metastatic melanoma

valutare l'effetto immunomodulatorio e anti-tumorale del trattamento con alte dosi di Esomeprazolo in pazienti con melanoma metastatico

E.2.2

Secondary objectives of the trial

not applicable

non applicabile

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Age > 18 years; diagnosis of cutaneous melanoma and sentinel node biopsy (SNB) positive for melanoma metastasis; lack of BRAF mutation in melanoma lesions (primary melanoma or SNB); lack of valid adjuvant therapy; performance status of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG); obtainment of a written informed consent prior to any protocol-specific procedure

Età > 18; Pazienti con melanoma cutaneo in stadio III con biopsia del linfonodo sentinella (SNB) positiva e in attesa di svuotamento linfonodale regionale; Assenza di mutazione BRAF in biopsie tumorali (melanoma primitivo o SNB) disponibili al momento dell’arruolamento; Assenza di valide terapie adiuvanti proponibili; Performance Status secondo l’Eastern Cooperative Oncology Group (ECOG) pari a 0 o 1; Ottenimento del consenso informato scritto per lo studio prima di effettuare qualsiasi procedura protocollo specifica

E.4

Principal exclusion criteria

Diagnosis of any other tumor within the last 2 years with the exception of basocellular and adequately treated in situ cervical carcinoma; major surgery within 28 days before enrolment in the study; Pregnancy or breast feeding for female patients; severe and documented liver, renal and lung dysfunctions; Evidence of hemorrhagic diatheses and coagulopathy; uncontrolled blood hypertension; Diagnosed epileptic, neurologic or psychiatric disease that might compromised the ability of patients to provide the written informed consent; Severe infection requiring e.v. therapy with antibiotics or under treatment tybercolosis; uncontrolled diabetes or other chronic diseases that might affect patient compliance; known history of immunodeficiencies treatment with drugs whose metabolism is known to be affected by PPI therapy, such as diazepam (Valium, Diastat), ketoconazolo (Nizoral), digossina (Lanoxin), cilostazolo (Pletal), clopidogrel (Plavix) and anti-viral therapy such as saquinar (Invirase, Fortovase), nelfinavir (Viracept) and atazanavir (Reyataz).

Presenza di altri tumori diagnosticati entro gli ultimi 2 anni, con l’eccezione di carcinomi basocellulari curati o carcinomi in situ della cervice adeguatamente trattati;Recenti interventi di chirurgia maggiore (entro 28 giorni prima dell’inizio del trattamento in studio); Per soggetti di sesso femminile: gravidanza ed allattamento. Malattie gravi del fegato o del polmone documentate; Evidenza di diatesi emorragica o coagulopatia; Ipertensione arteriosa non controllata; Pazienti che presentano epilessia o storia di significative malattie neurologiche o psichiatriche che possono compromettere la capacità di fornire il consenso informato;Infezione che richiede una terapia antibiotica per via endovenosa e tubercolosi in trattamento; diabete mellito instabile ed altre malattie significative documentate e non controllate a giudizio del ricercatore; Pazienti con storia positiva al virus dell’immunodeficienza; Pazienti in trattamento con farmaci a nota interferenza a livello metabolico con l’esomeprazolo, ovvero: diazepam (Valium, Diastat) ketoconazolo (Nizoral), digossina (Lanoxin), cilostazolo (Pletal), clopidogrel (Plavix) e antivirali quali saquinar (Invirase, Fortovase), nelfinavir (Viracept) e atazanavir (Reyataz).

E.5 End points

E.5.1

Primary end point(s)

1. Study of changes in the immune profile induced by treatment with PPI
in the tumor-draining LN
2. Analysis of the effect of treatment with PPI systemic immunity
3. Analysis of the antitumor activity of PPI in metastatic LN

1. Studio delle modificazioni del profilo immunitario indotte dal
trattamento con PPI nei LN drenanti il tumore
2. Analisi dell'effetto del trattamento con PPI sull'immunità sistemica
3. Analisi dell'attività antitumorale dei PPI nei LN metastatici

E.5.1.1

Timepoint(s) of evaluation of this end point

1. 1 month
2. 1,2 visit
3. 1 month

1. 1 mese
2. 1,2 (visite)
3. 1 mese

E.5.2

Secondary end point(s)

1. Assessment of disease-free survival.
2. Anlisi out expression profiling of gene expression in LN obtained from patients treated with PPI vs control

1. Valutazione della sopravvivenza libera da malattia.
2. Anlisi dei profili di espresione genica nei LN ottenuti da pazienti trattati con PPI vs controlli

E.5.2.1

Timepoint(s) of evaluation of this end point

1. every month
2. 1 month

1. Ogni 3 mesi
2. 1 mese

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

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

Yes

E.6.13.1

Other scope of the trial description

immunomodulation

immunomodulazione

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

nessun trattamento

no treatment

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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)

continuation of follow-up required for the pathology according to the guidelines

proseguimento del follow up richiesto dalla patologia secondo le linee guida

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

2014-09-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-02-25

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

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