Clinical Trials Register

Summary
EudraCT Number:	2015-003572-79
Sponsor's Protocol Code Number:	SiewertIII
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-09-06
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2015-003572-79

A.3

Full title of the trial

MULTICENTRY STAGE PHASE II NOT RANDOMIZED BY NEOADJUVANT THERAPY ACCORDING TO DOX DIAGNOSIS IN ADENOCARCINOMA SIEWERT III

STUDIO SPERIMENTALE MULTICENTRICO DI FASE II NON RANDOMIZZATO DI
TERAPIA NEOADIUVANTE SECONDO SCHEMA DOCETAXEL, OXALIPLATINO E CAPECITABINA NELL'ADENOCARCINOMA SIEWERT III

A.3.1

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

NEOADJUVANT THERAPY ACCORDING TO DOCETAXEL, OXALIPLATINO AND CAPECITABINA DIAGNOSIS IN ADENOCARCINOMA SIEWERT III

TERAPIA NEOADIUVANTE SECONDO SCHEMA DOCETAXEL, OXALIPLATINO E CAPECITABINA NELL'ADENOCARCINOMA SIEWERT III

A.3.2

Name or abbreviated title of the trial where available

NEOADJUVANT THERAPY ACCORDING TO DOX DIAGNOSIS IN ADENOCARCINOMA SIEWERT III

TERAPIA NEOADIUVANTE SECONDO SCHEMA DOX NELL'ADENOCARCINOMA SIEWERT III

A.4.1

Sponsor's protocol code number

SiewertIII

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	AZIENDA OSPEDALIERA UNIVERSITARIA INTEGRATA VERONA
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	AOUI Verona
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	azienda ospedaliera integrata universitaria di verona
B.5.2	Functional name of contact point	Unità ricerca clinica
B.5.3	Address:
B.5.3.1	Street Address	piazzale stefani 1
B.5.3.2	Town/ city	verona
B.5.3.3	Post code	37126
B.5.3.4	Country	Italy
B.5.4	Telephone number	0458127043
B.5.5	Fax number	0458122814
B.5.6	E-mail	supporto.noprofit@aovr.veneto.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	TAXOTERE - 20 MG CONCENTRATO PER INFUSIONI IV + SOLVENTE
D.2.1.1.2	Name of the Marketing Authorisation holder	AVENTIS PHARMA S.A.
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	TAXOTERE
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	DOCETAXEL
D.3.9.1	CAS number	114977-28-5
D.3.9.2	Current sponsor code	DOCETAXEL
D.3.9.3	Other descriptive name	DOCETAXEL
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Yes
D.2.1.1.1	Trade name	XELODA - 500 MG 120 COMPRESSE FILMRIVESTITE IN BLISTER USO ORALE
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE REGISTRATION LIMITED
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	XELODA
D.3.2	Product code	035219017
D.3.4	Pharmaceutical form	Film-coated tablet
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	CAPECITABINA
D.3.9.1	CAS number	154361-50-9
D.3.9.2	Current sponsor code	CAPECITABINA
D.3.9.3	Other descriptive name	capecitabine
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	500
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	OXALIPLATINO ACCORD HEALTHCARE - 5MG/ML POLVERE PER SOLUZIONE PER INFUSIONE 1 FLACONCINO DI VETRO DA 100 MG
D.2.1.1.2	Name of the Marketing Authorisation holder	ACCORD HEALTHCARE LIMITED
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	Oxaliplatino Accord
D.3.2	Product code	Oxaliplatino
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.3.11 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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Adenocarcinoma of cardias siewert III

adenocarcinoma del cardias siewert III

E.1.1.1

Medical condition in easily understood language

Adenocarcinoma

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	10001187
E.1.2	Term	Adenocarcinoma of the cardia
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Overall survival (OS) after 3 years of enrollment, expressed as a percentage of patients living at 3 years

Sopravvivenza globale (OS – overall survival) a 3 anni dall’arruolamento, espressa come percentuale di pazienti vivi a 3 anni

E.2.2

Secondary objectives of the trial

Overall Survival (OS - Overall Survival) at 5 years from enrollment
DFS - disease free survival
Treatment-related toxicity
Percentage of Radical Surgery (R0)
Surgery Morbidity-Mortality

Sopravvivenza globale (OS – Overall Survival) a 5 anni dall'arruolamento
Tempo libero da malattia (DFS – disease free survival)
Tossicità correlata al trattamento
Percentuale di chirurgia radicale (R0)
Morbi-Mortalità chirurgica

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

The inclusion criteria proposed are as follows:
• Locally advanced carcinomas:> cT2N0 or any cT if cN + (TNM 7th - APPENDIX A)
• Ability to provide specific informed consent in order to be admitted to the study
• Males and Females aged 18 to 75 years (=18 and = 75 years). Female subjects of childbearing age, according to CTFG guidelines, will undergo a pregnancy test that will have to be negative in the days immediately preceding the start of treatment. In addition, all subjects must agree to use an effective contraceptive method during and for the next 6 months from the date of treatment initiation
• Good Performance Status (ECOG = 2 - APPENDIX B)
• Cardiac Siewert III endoscopic neoplasia diagnosis
• Anatomopathological diagnosis with histophyllus sec. Lauren

I criteri di inclusione proposti sono i seguenti:
• Carcinomi localmente avanzati: > cT2N0 o qualsiasi cT se cN+ (TNM 7th – APPENDICE A)
• Capacità di fornire un consenso informato specifico al fine di essere ammesso allo studio
• Maschi e Femmine di età compresa tra 18 e 75 anni (=18 e = 75 anni). I soggetti femminili in età fertile secondo linee guida CTFG eseguiranno, in regime di ricovero nei giorni immediatamente precedenti all’inizio del trattamento, un test di gravidanza che dovrà risultare negativo. Inoltre tutti i soggetti dovranno essere d’accordo nell’utilizzare un efficace metodo contraccettivo durante e per i 6 mesi successivi dalla data dell’inizio del trattamento
• Buon Performance Status (ECOG = 2 – APPENDICE B)
• Diagnosi endoscopica di neoplasia del cardias Siewert III
• Diagnosi anatomopatologica con istotipo sec. Lauren

E.4

Principal exclusion criteria

The exclusion criteria proposed are as follows:
• Non-advanced carcinoma cT1-T2N0 (TNM 7th - APPENDIX A)
• Presence of remote metastases
• Chemio-radiotherapy treatments over the past 5 years
• Altered renal function (creatinine = 1.5 UNL, or in case of borderline clearance of creatinine calculated = 60 mL / min),
• Altered liver function (total bilirubin = 1.25 UNL, AST (SGOT) and ALT (SGPT) = 2.5 UNL, alkaline phosphatase <2.5 UNL,
• Alteration of haemopoietic function (neutrophils = 1.5 x 109 / L, platelets = 100 x 109 / L, hemoglobin = 10g / dL),
• Women and men of childbearing age who do not use appropriate contraceptives,
• Pregnant women,
• Women during breastfeeding,
• Patients in an emergency,
• Patients who take: compounds that induce or inhibit cytochrome P450-3A or which come from this metabolised such as cyclosporine, terfenadine, ketoconazole, erythromycin and troleandomycin; carboplatin; prednisone; Active medicines on cytochrome P-450 2C9 substrates such as phenytoin; Anti-inflammatory coumarin derivatives (for example warfarin and phenprocoumone); Folinic acid / folic acid; Sorivudine and Similar (5-FU); antacids; allopurinol; Interferon alfa

I criteri di esclusione proposti sono i seguenti:
• Carcinomi non avanzati cT1-T2N0 (TNM 7th – APPENDICE A)
• Presenza di metastasi a distanza
• Trattamenti chemio-radioterapici negli ultimi 5 anni
• Alterata funzione renale (creatinina = 1.5 UNL, oppure in casi border-line clearance della creatinina calcolata = 60 mL/min),
• Alterata funzionalità epatica (bilirubina totale = 1.25 UNL, AST (SGOT) e ALT (SGPT) = 2.5 UNL, fosfatasi alcalina < 2.5 UNL,
• Alterata funzione emopoietica (neutrofili = 1.5 x 109 /L, piastrine = 100 x 109 /L, emoglobina = 10g/dL),
• Donne e uomini in età fertile che non fanno uso di contraccettivi adeguati,
• Donne in gravidanza,
• Donne durante l’allattamento,
• Pazienti in situazione di emergenza,
• Pazienti che assumono: composti inducenti o inibenti il citocromo P450-3A o che vengano da questo metabolizzati quali ciclosporine, terfenadina, ketoconazolo, eritromicina e troleandomicina; carboplatin; prednisone; medicinali attivi su substrati del citocromo P-450 2C9 come fenitoina; anticoaugulanti cumarino-derivati (ad esempio warfarin e fenprocumone); Acido folinico/acido folico; Sorivudina e analoghi (5-FU); antiacidi; allopurinolo; interferone alfa

E.5 End points

E.5.1

Primary end point(s)

Overall survival (OS) over 3 years from enrollment

Sopravvivenza globale (OS – overall survival) a 3 anni dall’arruolamento

E.5.1.1

Timepoint(s) of evaluation of this end point

3 years

3 anni

E.5.2

Secondary end point(s)

global survival after 5 years from enrollment; disease free survival; Treatment-related toxicity, which will be evaluated as absolute frequency and percentage of patients with one or more adverse events during treatment; Percentage of Radical Surgery (R0), which indicates a resection with free margins of neoplastic infiltration resection to the macroscopic (R1) and to the microscopic (R0) examination; Surgery Morbidity-Mortality. Surgical morbidity will be related to surgical complications (abscesses, fistulas, suture deities). Surgical mortality will be evaluated within 30 days from surgery or mortality during hospitalization

sopravvivenza globale a 5 anni dall'arruolamento; tempo libero da malattia; Tossicità correlata al trattamento, che verrà valutata come frequenza assoluta e percentuale di pazienti con uno o più eventi avversi durante il trattamento; Percentuale di chirurgia radicale (R0), che indica una resezione con i margini di resezioni liberi da infiltrazione neoplastica non solo all'esame macroscopico (R1) ma anche a quello microscopico (R0); Morbi-Mortalità chirurgica. La morbosità chirurgica riguarderà le complicanze chirurgiche (ascessi, fistole, deiescenza delle suture). La mortalità chirurgica sarà la mortalità entro 30 giorni o la mortalità in ospedale

E.5.2.1

Timepoint(s) of evaluation of this end point

5 years; during 5 years; during treatment; post surgery; 30 days after surgery

5 anni ; durante 5 anni ; durante il trattamento; post intervento; 30 giorni dopo l'intervento chirurgico

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

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

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

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.8.5.1

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

Information not present in EudraCT

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

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.1.1.1

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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 conclusion of the study, the participant will access to appropriate medical care; the physician will provide the best care.

A conclusione dello studio, il partecipante potrà accedere ad adeguate cure mediche da parte del medico il quale fornirà la migliore assistenza di supporto.

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

2018-01-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-06-06

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

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