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    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
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2011-001526-19
    A.3Full 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
    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.3.1Title 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.4.1Sponsor's protocol code numberBO27798
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorROCHE
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportF.Hoffmann-La Roche Ltd
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRoche S.p.A.
    B.5.2Functional name of contact pointClinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressViale G. B. Stucchi, 110
    B.5.3.2Town/ cityMonza
    B.5.3.3Post code20900
    B.5.4Telephone number039 2475070
    B.5.5Fax number039 2475085
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D. name Herceptin
    D. of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTRASTUZUMAB
    D.3.9.1CAS number 180288-69-1
    D.3.9.2Current sponsor codeRO0452317
    D.3.9.4EV Substance CodeSUB12612MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D. medicinal product typehumanised IgG1 monoclonal antibody
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical 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.1.1.1Medical 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.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level PT
    E.1.2Classification code 10063916
    E.1.2Term Metastatic gastric cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.2.2Secondary 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 &lt; 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 &lt; 12 µg/ml al Giorno 21 del Ciclo 1 di trattamento.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Vers:PK/ A
    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.

    Vers:PK/ A
    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.3Principal 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 &gt;= 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 &gt;= 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) &gt;= 45 ml/min. 6. Performance status ECOG pari a 2.
    E.4Principal 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 &gt;= 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] &gt; 180 mmHg o diastolica &gt; 100 mmHg); valvulopatia cardiaca significativa; aritmie ad alto rischio non controllabili. 6. LVEF basale &lt; 50% (documentato da ecocardiogramma, scansione MUGA o RM cardiaca).
    E.5 End points
    E.5.1Primary end point(s)
    The study primary endpoint will be OS duration in all randomized patients.
    Sopravvivenza globale (OS) in tutti i pazienti randomizzati.
    E.5.1.1Timepoint(s) of evaluation of this end point
    This is event driven, when 379 deaths have occurred.
    Quando si sono verificati 379 decessi.
    E.5.2Secondary 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.5.2.1Timepoint(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.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other 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.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E. 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.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA32
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Bosnia and Herzegovina
    Korea, Democratic People's Republic of
    Korea, Republic of
    New Zealand
    Russian Federation
    South Africa
    United States
    E.8.7Trial 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.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months98
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months98
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 263
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 142
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state32
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 130
    F.4.2.2In 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
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-11-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-11-10
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2015-08-25
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