Clinical Trials Register

Summary
EudraCT Number:	2010-020189-37
Sponsor's Protocol Code Number:	IRST151.01
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:	2012-03-14
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

2010-020189-37

A.3

Full title of the trial

A randomised phase II study of pre-operative or peri-operative docetaxel, oxaliplatin, capecitabine (DOX) regimen in patients with locally advanced resectable gastric cancer

STUDIO DI FASE II RANDOMIZZATO CON DOCETAXEL, OXALIPLATINO, CAPECITABINA (DOX) COME TRATTAMENTO PREOPERATORIO O PERIOPERATORIO (PRIMA E DOPO LA GASTRECTOMIA) IN PAZIENTI CON CARCINOMA GASTRICO LOCALMENTE AVANZATO RESECABILE.

A.3.2

Name or abbreviated title of the trial where available

IRST 151.01

A.4.1

Sponsor's protocol code number

IRST151.01

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	ISTITUTO SCIENTIFICO ROMAGNOLO PER LO STUDIO E LA CURA 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
B.4.2	Country
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.2.1.2	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.3.4	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	PLANT ALKALOIDS AND OTHER NATURAL PRODUCTS
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.3	Concentration number	35
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	Yes
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.3.4	Pharmaceutical form	Powder 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	OTHER ANTINEOPLASTIC AGENTS
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.3	Concentration number	80
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: 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	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.3.4	Pharmaceutical form	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	ANTIMETABOLITES
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.3	Concentration number	750
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.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

Patient with potentially resectable adenocarcinoma of the stomach

Pazienti con carcinoma dello stomaco potenzialmente resecabile

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10017758
E.1.2	Term	Gastric cancer
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

The percentage of patients receiving all the planned chemotherapeutic cycles.

La percentuale dei pazienti che hanno ricevuto tutti i cicli di chemioterapia programmati.

E.2.2

Secondary objectives of the trial

• Downstaging according to Recist criteria • pT1-3 vs pT0. • Safety: number of patients with grade 3-4 toxicity • The role of PET Scan as predictor of response • Curative vs palliative surgery • TTP • OS • Diagnostic correlation between the various staging methods • Possible correlations between CT scan, CT/PET, laparoscopy; • Molecualr marker related to toxicity: DPYD, MTHFR, TS, XPD, ERCC1, XRCC1; • Molecular marker related to prognosis: TYMS, GSTP1, COX-2, RUNX3, methylation profile (Cox2, hMLH1, MGMT); • Molecular marker related to therapy response: TYMS, DPYD, MTHFR, OPRT, ERCC1, XRCC1/2/3, GSTP1, GSTM1, GSTT1, ABCB1, methylation profile (Cox2, hMLH1, MGMT), whole genome arrayCGH

• Downstaging secondo i criteri RECIST • pT1-3 vs pT0. • Sicurezza: numero di pazienti con grado 3-4 di tossicita' • Ruolo della PET come predittore di risposta • Chirurgia curativa vs chirurgia palliativa • TTP • OS • Correlazione diagnostica fra i vari metodi di staging • Possibile correlazione fra TAC, TAC/PET, laparoscopia; • Markers molecolari relativi alla tossicita': DPYD, MTHFR, TS, XPD, ERCC1, XRCC1; • Markers molecolari relativi alla prognosi: TYMS, GSTP1, COX-2, RUNX3, profilo di metilazione (Cox2, hMLH1, MGMT); • Markers molecolari relativi alla risposta alla terapia: TYMS, DPYD, MTHFR, OPRT, ERCC1, XRCC1/2/3, GSTP1, GSTM1, GSTT1, ABCB1, profilo di metilazione (Cox2, hMLH1, MGMT), whole genome arrayCGH.

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

PHARMACOGENETIC:
Vers:1.0
Date:2010/06/01
Title:
Objectives:

FARMACOGENETICA:
Vers:1.0
Data:2010/06/01
Titolo:STUDIO DI FASE II RANDOMIZZATO CON DOCETAXEL, OXALIPLATINO, CAPECITABINA (DOX) COME TRATTAMENTO PREOPERATORIO O PERIOPERATORIO (PRIMA E DOPO LA
GASTRECTOMIA) IN PAZIENTI CON CARCINOMA GASTRICO LOCALMENTE AVANZATO RESECABILE.
Gastric neoadjuvant, biological study
Obiettivi:• Markers molecolari relativi alla tossicita': DPYD, MTHFR, TS, XPD, ERCC1, XRCC1;
• Markers molecolari relativi alla prognosi: TYMS, GSTP1, COX-2, RUNX3, profilo di metilazione (Cox2, hMLH1, MGMT);
• Markers molecolari relativi alla risposta alla terapia: TYMS, DPYD, MTHFR, OPRT, ERCC1, XRCC1/2/3, GSTP1, GSTM1, GSTT1, ABCB1, profilo di metilazione (Cox2, hMLH1, MGMT), whole genome arrayCGH.

E.3

Principal inclusion criteria

• Male or female 18-75 years of age
• Diagnosis of histologically confirmed, potentially resectable adenocarcinoma of the stomach
• cT3 subserosal - cT4a – cT4b (7th edition UICC TNM) or bulky lymph node metastases independently of T
• ECOG performance status 0-1 at study entry
• Laboratory requirements (up to 8 days prior to randomization):
a) Haematology:
I) Neutrophils > 1.5 x 109 /L
II) Platelets > 100 x 109 /L
III) Hemoglobin > 10g/dL
b) Hepatic function
I) Total bilirubin < 1.25 UNL
II) AST (SGOT) and ALT (SGPT)<2.5xUNL
II) Alkaline phosphatase < 2.5xUNL c) Renal function
I) Creatinine <1.5 UNL
In the presence of border-line values, the calculated creatinine clearance should be >= 60 mL/min;
• Written informed consent signed and dated before randomization procedures, must be obtained and documented according to the local regulatory requirement.
• Effective contraception for both male and female patients if the risk of conception exists.

. Maschi o femmine 18-75 anni di eta'
. Diagnosi istologicamente confermata di adenocarcinoma dello stomaco
potenzialmente resecabile
. cT3 sottosierosa - cT4a – cT4b (7th edizione UICC TNM) o metastasi
linfonodali indipendentemente da T
. ECOG performance status 0-1 all’ingresso in studio
. Requisiti di laboratorio (fino a 8 giorni prima della randomizzazione):
a) Ematologia:
I) Neutrofili > 1.5 x 109 /L
II) Piastrine > 100 x 109 /L
III) Emoglobina > 10g/dL
b) Funzionalita' epatica
I) Bilirubina totale < 1.25 UNL
II) AST (SGOT) e ALT (SGPT) < 2.5xUNL
III) Fosfatasi alcalina < 2.5xUNL
c) Funzionalita' renale
I) Creatinina <1.5 UNL
In presenza di valori border-line, la clearance della creatinina
calcolata dovrebbe essere >= 60 mL/min;
· Un consenso informato scritto firmato e datato deve essere ottenuto e
documentato secondo le esigenze locali di regolamentazione, prima delle
procedure di randomizzazione.
· Se esiste il rischio di concepimento, deve essere utilizzato un
contraccettivo efficace sia per i pazienti maschi e che per le pazienti
femmine.

E.4

Principal exclusion criteria

• Early gastric cancer (if N0)
• T2 (according to 7th edition of UICC TNM) if N0
• Linitis plastica
• Positive peritoneal cytology
• Distant metastases
• Tumor involving the gastro-esophageal junction
• Peritoneal involvement
• Concurrent chronic systemic immune therapy
• Any investigational agent(s) 4 weeks prior to study entry
• Clinically relevant coronary artery disease, a history of myocardial infarction or a history of hypertension not controlled by therapy within the last 12 months
• Known grade 3 or 4 allergic reaction to any of the components of the treatment
• Known drug abuse/alcohol abuse
• Legal incapacity or limited legal capacity
• Medical or psychological condition which, in the opinion of the investigator, would not permit the patient to complete the study or sign meaningful informed consent
• Women who are pregnant or breastfeeding
• Acute or subacute intestinal occlusion
• Any concurrent malignancy other than non-melanoma skin cancer, or carcinoma in situ of the cervix. (Patients with a previous malignancy but without evidence of disease for ≥ 5 years will be allowed to enter the trial)

. Early gastric cancer (se N0)
. T2 (secondo la 7th edizione della UICC TNM) se N0
. Linite plastica
. Citologia peritoneale positiva
. Metastasi a distanza
. Tumori che coinvolgono la giunzione gastro-esofagea
. Coinvolgimento peritoneale
. Concomitante terapia sistemica immunitaria
. Utilizzo di qualsiasi agente sperimentale nelle 4 settimane precedenti lo studio
. Malattia coronaria clinicamente significativa, storia di infarto al
miocardio o storia di ipertensione non controllata entro gli ultimi 12 mesi
. Reazione allergica nota di Grado 3 o 4 ad uno qualsiasi dei componenti
del trattamento
. Abuso noto di farmaci e alcol
. Incapacita' legale o limitata capacita' legale
. Condizione medica o psicologica che, ad opinione del medico, non
potrebbe consentire al paziente di completare lo studio o firmare il
consenso informato
. Donne che sono incinte o che allattano
. Occlusione intestinale acuta o subacuta
. Qualsiasi altra neoplasia diversa dal tumore cutaneo non melanoma o
carcinoma in situ della cervice. (Pazienti con precedente neoplasia ma
senza evidenza di malattia per un periodo ≥ 5 anni potranno entrare in
studio)

E.5 End points

E.5.1

Primary end point(s)

The percentage of patients receiving all the planned chemotherapeutic cycles.

La percentuale dei pazienti che hanno ricevuto tutti i cicli di chemioterapia programmati

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

Yes

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

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

Yes

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

- Stesso farmaco ad altro dosaggio

- same IMP used at different dosage

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

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

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	No
F.1.1	Number of subjects for this age range:	0
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	90

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

2010-08-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-07-21

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-09-15

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