Clinical Trials Register

Summary
EudraCT Number:	2011-001526-19
Sponsor's Protocol Code Number:	BO27798
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2011-11-18
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

2011-001526-19

A.3

Full title of the trial

A randomized, open-label, multicenter Phase IIIb study comparing two
trastuzumab dosing regimens, each in combination with cisplatin/
capecitabine chemotherapy, as first-line therapy in patients with HER2-
positive metastatic gastric or gastro-esophageal junction
adenocarcinoma who have not received prior treatment for metastatic
disease.

Studio di fase IIIb randomizzato, multicentrico, in aperto, volto a confrontare due diversi dosaggi di trastuzumab, ciascuno associato a chemioterapia con cisplatino e capecitabina, per il trattamento di prima linea di pazienti affetti da adenocarcinoma metastatico HER-2-positivo dello stomaco o della giunzione gastroesofagea, non precedentemente trattato per la malattia metastatica.

A.3.1

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

A global and multicenter Phase IIIb study comparing two trastuzumab
dosing regimens, each in combination with chemotherapy
(cisplatin/capecitabine), as therapy in patients with HER2-positive
metastatic gastric or gastro-esophageal junction adenocarcinoma who
have not received prior treatment for metastatic disease.

Studio internazionale e multicentrico di Fase IIIB volto a confrontare due diversi dosaggi di trastuzumab ciascuno associato a chemioterapia (cisplatino/capecitabina), come terapia per i pazienti affetti da adenocarcinoma metastatico HER-2-positivo dello stomaco o della giunzione gastroesofagea, che non hanno ricevuto precedentemente un trattamento per la malattia metastatica.

A.4.1

Sponsor's protocol code number

BO27798

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	ROCHE
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	F.Hoffmann-La Roche Ltd
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Roche S.p.A.
B.5.2	Functional name of contact point	Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	Viale G. B. Stucchi, 110
B.5.3.2	Town/ city	Monza
B.5.3.3	Post code	20900
B.5.3.4	Country	Italy
B.5.4	Telephone number	039 2475070
B.5.5	Fax number	039 2475085
B.5.6	E-mail	sergio.scaccabarozzi@roche.com

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	Herceptin
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	TRASTUZUMAB
D.3.9.1	CAS number	180288-69-1
D.3.9.2	Current sponsor code	RO0452317
D.3.9.4	EV Substance Code	SUB12612MIG
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	150
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	Yes
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	humanised IgG1 monoclonal antibody

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 HER2-positive adenocarcinoma of the stomach or gastroesophageal junction

Adenocarcinoma metastatico HER-2-positivo dello stomaco o della giunzione gastroesofagea

E.1.1.1

Medical condition in easily understood language

Metastatic HER2-positive adenocarcinoma of the stomach or gastroesophageal junction

Adenocarcinoma metastatico HER-2-positivo dello stomaco o della giunzione gastroesofagea

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	14.0
E.1.2	Level	PT
E.1.2	Classification code	10063916
E.1.2	Term	Metastatic 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

To compare the duration of overall survival in patients who are randomized at enrollment to treatment with one of two trastuzumab dosing regimens (loading dose of 8mg/kg) followed by either 6mg/kg or 10mg/kg maintenance doses given every 3 weeks, plus cisplatin and capecitabine.

Confrontare la durata della sopravvivenza globale (OS) in pazienti randomizzati all'arruolamento a ricevere il trattamento con uno dei due dosaggi di trastuzumab (dose di carico di 8 mg/kg seguita da dosi di mantenimento di 6 mg/kg o di 10 mg/kg ogni 3 settimane), più cisplatino e capecitabina.

E.2.2

Secondary objectives of the trial

• To compare the duration of overall survival (OS) in patients on the two trastuzumab treatment arms who are found to have trastuzumab Cmin values < 12 μg/mL on Cycle 1 Day 21. • To assess trastuzumab concentrations during treatment Cycle 1 and trastuzumab Cmin(Day 21) values in additional treatment cycles through Cycle 11 (ie, pre-dose concentration before Cycle 12) or until disease progression (whatever occurs first) for the two dosing regimens. • To evaluate the safety and tolerability of trastuzumab for the two dosing regimens. • To compare the duration of progression-free survival (PFS) and the overall objective response rate (ORR) in patients on the two trastuzumab treatment arms who are found to have trastuzumab Cmin values < 12 μg/mL on treatment Cycle 1 Day 21.

• Confrontare la durata della OS nei due bracci di trattamento per i pazienti che risulteranno avere un valore di Cmin di trastuzumab < 12 µg/ml al Giorno 21 del Ciclo 1. • Valutare le concentrazioni di trastuzumab durante il Ciclo 1 di trattamento e i valori di Cmin di trastuzumab (Giorno 21) nei successivi cicli di trattamento fino al Ciclo 11 (concentrazioni pre dose prima del Ciclo 12) o fino a progressione della malattia (a seconda di quale dei due eventi si verifichi per primo) nei due diversi dosaggi. • Valutare la sicurezza e la tollerabilità di trastuzumab nei due dosaggi. • Confrontare la durata della sopravvivenza libera da progressione (PFS) e il tasso di risposta obiettiva globale (ORR) nei pazienti dei due bracci di trattamento con trastuzumab che presentano valori di Cmin di trastuzumab < 12 µg/ml al Giorno 21 del Ciclo 1 di trattamento.

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

PHARMACOKINETIC/PHARMACODYNAMIC:
Vers:PK/ A
Date:2011/06/23
Title:Evaluation of the pharmacokinetics of trastuzumab administered every three weeks at two different maintenance dose levels to patients with metastatic HER2-positive gastric or gastro-esophageal junction adenocarcinoma.
Objectives:To characterize the serum trastuzumab concentration-vs-time (C-vs-T) profiles in the study population following the initial loading dose (8 mg/kg) at Cycle 1, and the maintenance doses (6 mg/kg or 10 mg/kg q3W) at Cycles 2 and 4. • To evaluate the accumulation of peak and trough serum trastuzumab concentrations following selected sequential doses given every three weeks, up to the projected steady-state (Cycles 1, 2, 3, 4, 5, 7, 9, and 11). • To describe the pharmacokinetic (PK) of trastuzumab in patients with metastatic gastric/GEJ cancer and compare to previous observations in patients with metastatic breast cancer and gastric cancer. • To support development and refinement of an integrated populationbased model for the PK disposition of trastuzumab in cancer patients, using data from multiple dosing regimens and disease types.

FARMACOCINETICA/FARMACODINAMICA:
Vers:PK/ A
Data:2011/06/23
Titolo:Valutazione della farmacocinetica di trastuzumab somministrato ogni tre settimane a due diversi dosaggi di mantenimento a pazienti con adenocarcinoma metastatico HER-2-positivo dello stomaco o della giunzione gastroesofagea.
Obiettivi:• Caratterizzare i profili della concentrazione sierica di trastuzumab-versus-tempo (C-vs-T) nella popolazione in studio dopo la dose di carico iniziale (8 mg/kg) al Ciclo 1, e le dosi di mantenimento (6 mg/kg o 10 mg/kg q3W) ai cicli 2 e 4.
• Valutare l’accumulo di picco e concentrazioni sieriche di trastuzumab a seguito di selezionate dosi sequenziali somministrate ogni tre settimane, fino allo stato stazionario atteso (Cicli 1, 2, 3, 4, 5, 7, 9 e 11).
• Descrivere la farmacocinetica (PK) di trastuzumab in pazienti con carcinoma gastrico/giunzione gastroesofagea metastatico e confrontare le precedenti osservazioni in pazienti con carcinoma mammario metastatico e carcinoma gastrico.
• Sostenere lo sviluppo ed il perfezionamento di un modello integrato basato sulla popolazione per la predisposizione della PK di trastuzumab in pazienti affetti da tumore, utilizzando dati provenienti da molteplici regimi di dosaggio e tipi di malattie.

E.3

Principal inclusion criteria

1. Male or female. Age ≥ 18 years. 2. Histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction with metastatic disease documented to involve at least two organs (at least lung or liver or both) 3. Measurable disease according to RECIST 1.1. 4. HER2 positive (defined as either IHC3+ or IHC2+/ISH+, with ISH positivity defined as a ratio of >=2.0 of HER2 gene copy number/number of signals for CEP 17) primary or metastatic tumor, as assessed by central laboratory 5. CCR >=45 ml/min 6. ECOG PS _2

1. Pazienti di ambo i sessi. Età >= 18 anni. 2. Adenocarcinoma dello stomaco o della giunzione gastro esofagea istologicamente confermato, con documentato coinvolgimento metastatico di almeno due organi (almeno fegato o polmone, o entrambi). 3. Malattia misurabile in base ai criteri di valutazione della risposta nei tumori solidi (RECIST 1.1), valutata mediante tecniche di diagnostica per immagini (tomografia computerizzata [TC] o risonanza magnetica [RM]), oppure malattia non misurabile ma valutabile. 4. Tumore primario o metastatico HER-2-positivo (definito da un punteggio IHC 3+ o IHC 2+/ISH+; con positività ISH definita come un rapporto >= 2,0 tra numero di copie del gene HER-2/numero di segnali per CEP17), secondo la valutazione del laboratorio centralizzato. 5. Clearance della creatinina (CrCl) >= 45 ml/min. 6. Performance status ECOG pari a 2.

E.4

Principal exclusion criteria

1. Previous chemotherapy for locally advanced or metastatic disease 2. Prior gastrectomy 3. Prior therapy with an anti-HER2 agent and/or platinum-based chemotherapeutic agent 4. Residual relevant toxicity resulting from previous therapy 5. History of documented congestive heart failure; angina pectoris requiring medication; electrocardiogram (ECG) evidence of trans-mural myocardial infarction; poorly controlled hypertension (systolic blood pressure (BP) > 180 mmHg or diastolic BP>100 mm Hg); clinically significant valvular heart disease; or high risk uncontrollable arrhythmias 6. Baseline LVEF< 50%, documented by echocardiography, MUGA scan, or cardiac MRI.

1. Precedente chemioterapia per malattia localmente avanzata o metastatica (è consentita una precedente chemioterapia a condizione che siano trascorsi almeno 6 mesi tra il completamento della terapia e l'arruolamento nello studio, purché essa non sia stata somministrata per la malattia avanzata). 2. Precedente gastrectomia (parziale o totale) per la neoplasia maligna in studio. 3. Precedente terapia con un agente anti-HER-2 e/o con un agente chemioterapico a base di platino. 4. Residua tossicità rilevante (ad eccezione di alopecia) derivante da una precedente terapia, ad esempio tossicità ematologica o neurologica di grado >= 2 (NCI CTCAE), tranne deficit neurologico stabile dovuto a un trattamento somministrato più di 5 anni prima. 5. Anamnesi di insufficienza cardiaca congestizia documentata; angina pectoris con necessità di terapia; evidenza all'elettrocardiogramma (ECG) di infarto miocardico trans murale; ipertensione non adeguatamente controllata (pressione sistolica [BP] > 180 mmHg o diastolica > 100 mmHg); valvulopatia cardiaca significativa; aritmie ad alto rischio non controllabili. 6. LVEF basale < 50% (documentato da ecocardiogramma, scansione MUGA o RM cardiaca).

E.5 End points

E.5.1

Primary end point(s)

The study primary endpoint will be OS duration in all randomized patients.

Sopravvivenza globale (OS) in tutti i pazienti randomizzati.

E.5.1.1

Timepoint(s) of evaluation of this end point

This is event driven, when 379 deaths have occurred.

Quando si sono verificati 379 decessi.

E.5.2

Secondary end point(s)

The secondary endpoints will be OS in patients with Cycle 1 Cmin <12 ug/ml, Pharmacokinetic analyses , safety and tolerability in the two dosing regimens; duration of progression-free survival (PFS) and the overall objective response rate (ORR) in patients who are found to have trastuzumab Cmin values < 12 μg/mL on treatment Cycle 1 Day 21.

Sopravvivenza globale (OS) nei pazienti con valore di Cmin < 12 µg/ml Ciclo 1, farmacocinetica, sicurezza, tasso di risposta obiettiva globale (ORR), sopravvivenza libera da progressione (PFS)in pazienti che hanno valori di trastuzumab Cmin values < 12 μg/mL al ciclo 1 Giorno 21.

E.5.2.1

Timepoint(s) of evaluation of this end point

This is event driven, when 379 deaths have occurred.

Quando si sono verificati 379 decessi.

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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

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

Yes

E.6.13.1

Other scope of the trial description

overall survival (OS); progression-free survival (PFS) and overall objective response rate (ORR)

sopravvivenza globale (OS); sopravv. libera da progressione (PFS) e tasso di risp. obiettiva globale

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

terapia standard (chemiot. cisplatino e capecitab) - Stesso farmaco ad altro dosaggio

Standard of care(cisplatin/capecitabine chemother) - 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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Bosnia and Herzegovina

Brazil

Canada

Chile

China

India

Korea, Democratic People's Republic of

Korea, Republic of

Mexico

New Zealand

Panama

Peru

Philippines

Russian Federation

South Africa

Turkey

Ukraine

United States

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

The end of the study will be when the targeted number of events for the final analysis of OS (379/400) is reached and the last patient has completed 6 months of cardiac safety follow-up thereafter, or when the study is terminated by the Sponsor. whichever occurs first.

Lo studio terminerà quando sarà stato raggiunto il n° stabilito di eventi per l'analisi finale della OS (379/400) e l'ultimo paziente avrà completato i 6 mesi di monitoraggio della sicurezza cardiaca o quando lo studio sarà interrotto dallo Sponsor.

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

Number of subjects for this age range:

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:

263

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

142

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

130

F.4.2.2

In the whole clinical trial

406

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)

Patients still receiving trastuzumab at the time of study end and who do not have PD will be allowed to continue trastuzumab until progression of disease under a separate extension protocol.

Pazienti che stanno ancora ricevendo trastuzumab al termine dello studio e che non hanno ancora avuto una progressione della malattia, potranno continuare il trattamento con trastuzumab fino a progressione della malattia, seguendo un protocollo separato di estensione.

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

2011-11-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-11-10

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2015-08-25

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