Clinical Trials Register

Summary
EudraCT Number:	2010-019577-16
Sponsor's Protocol Code Number:	EGF114299
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:	2012-03-08
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

2010-019577-16

A.3

Full title of the trial

A Phase III trial to compare the safety and efficacy of lapatinib plus trastuzumab plus an aromatase inhibitor (AI) versus trastuzumab plus an AI versus lapatinib plus an AI as first-line therapy in postmenopausal subjects with hormone receptor positive, HER2-positive metastatic breast cancer (MBC) who have received trastuzumab and endocrine therapy in the neoadjuvant and/or adjuvant setting.

Studio di fase III per confrontare la sicurezza e l'efficacia di lapatinib piu' trastuzumab piu' un inibitore dell'aromatasi (IA) rispetto a trastuzumab piu' un IA rispetto a lapatinib piu' un IA come terapia di prima linea in pazienti in post-menopausa affette da carcinoma mammario metastatico (CMM) positive a recettori ormonali e per l'HER2, che hanno ricevuto trastuzumab e una terapia endocrina in regime neoadiuvante e/o adiuvante.

A.3.1

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

A study to compare the safety and efficacy of an aromatase inhibitor in combination with lapatinib or trastuzumab, or both for the treatment of hormone receptor positive, HER2+ metastatic breast cancer.

Studio per valutare la sicurezza ed l'efficacia di un inibitore dell'aromatasi in combinazione con lapatinib or trastuzumab da soli o in associazione per il trattamento del carcinoma mammario metastatico positivo ai recettori ormonali HER2+.

A.4.1

Sponsor's protocol code number

EGF114299

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01160211

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	GLAXOSMITHKLINE RESEARCH & DEVELOPMENT LTD.
B.1.3.4	Country	United Kingdom
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	GlaxoSmithKline
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GlaxoSmithKline
B.5.2	Functional name of contact point	GSK Clinical Support Helpdesk
B.5.3	Address:
B.5.3.1	Street Address	GlaxoSmithKline, Iron Bridge Road, Stockley Park West
B.5.3.2	Town/ city	Uxbridge, Middlesex
B.5.3.3	Post code	UB11 1BU
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44 020 8 9904466
B.5.5	Fax number	+44 020 8 9904968
B.5.6	E-mail	GSKClinicalSupportHD@gsk.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	Tyverb
D.2.1.1.2	Name of the Marketing Authorisation holder	Glaxo Group Ltd
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	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	LAPATINIB TOSILATE
D.3.9.1	CAS number	388082-78-8
D.3.9.2	Current sponsor code	GW572016
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB27753
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	250
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	Comparator
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 Ltd
D.2.1.2	Country which granted the Marketing Authorisation	Switzerland
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	NA
D.3.9.3	Other descriptive name	NA
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	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	Anticorpo monoclonale IgG umanizzato

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

HER2-positive metastatic breast cancer who have received trastuzumab and endocrine therapy in the neoadjuvant and/or adjuvant setting.

Carcinoma mammario metastatico positive a recettori ormonali e per l'HER2, che hanno ricevuto trastuzumab e una terapia endocrina in regime neoadiuvante e/o adiuvante.

E.1.1.1

Medical condition in easily understood language

Advanced/Metastatic Breast Cancer.

Carcinoma metastatico della mammella in fase avanzata.

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	10006279
E.1.2	Term	Breast neoplasm
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 primary objective is to demonstrate superiority of lapatinib/trastuzumab/AI combination (Treatment Group A) vs. trastuzumab/AI combination (Treatment Group B) for overall survival.

Dimostrare la superiorità della combinazione di lapatinib/trastuzumab/inibitore dell'aromatasi (IA) rispetto alla combinazione di trastuzumab/IA per la sopravvivenza globale (OS).

E.2.2

Secondary objectives of the trial

• To compare OS in Treatment Group B (trastuzumab/AI) vs. Treatment Group C (lapatinib/AI) and Treatment Group A (trastuzumab/lapatinib/AI) vs. Treatment Group C (lapatinib/AI) • To compare progression free survival (PFS) in Treatment Group A (lapatinib /trastuzumab/AI) vs. Treatment Group B (trastuzumab/AI) and Treatment Group C ( lapatinib/AI) vs. Treatment Group B (trastuzumab/ AI) • To compare overall response rate (complete or partial response), time to response, and duration of response in Treatment Group A (lapatinib /trastuzumab/AI) vs. Treatment Group B (trastuzumab/AI) and Treatment Group C (lapatinib/AI) vs. Treatment Group B (trastuzumab/AI) • To compare clinical benefit (complete response, partial response, or stable disease for at least 6 months) in Treatment Group A (lapatinib /trastuzumab/AI) vs. Treatment Group B (trastuzumab/AI) and Treatment Group C (lapatati

• Confrontare la sopravvivenza globale con trastuzumab/IA rispetto a lapatinib/IA e trastuzumab/lapatinib/IA rispetto a lapatinib/IA. • Confrontare la sopravvivenza libera da progressione (PFS) con lapatinib/trastuzumab/IA rispetto a trastuzumab/IA e lapatinib/IA rispetto a trastuzumab/IA. • Confrontare il tasso di risposta globale (risposta completa o parziale), il tempo alla risposta e la durata della risposta con lapatinib/trastuzumab/IA rispetto a trastuzumab/IA e lapatinib/IA rispetto a trastuzumab/IA.3 • Confrontare il beneficio clinico (risposta completa, risposta parziale o malattia stabile per almeno 6 mesi) con lapatinib/trastuzumab/IA rispetto a trastuzumab/IA e lapatinib/IA rispetto a trastuzumab/IA. • Valutare la sicurezza e la tollerabilità di tutti e tre i gruppi di trattamento (lapatinib/trastuzumab/IA, trastuzumab/IA o lapatinib/IA). • Confrontare lapatinib/trastuz

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects eligible for enrollment in the study must meet all of the following criteria: 1. Signed written informed consent 2. Post-menopausal female subjects ≥18 years of age. Post-menopausal as defined by any of the following: • Age > 60 years • Age ≥ 45 years with amenorrhea > 12 months with an intact uterus • Having undergone a bilateral oophorectomy or radiation castration with amenorrhea for at least 6 months • FSH and estradiol levels in postmenopausal range (utilizing ranges from the local laboratory facility). In subjects who have previously been treated with an GnRH/LHRH analogue, the last injection must have been administered >4 months prior to randomization and menses must not have restarted 3. Histologically confirmed Stage IV invasive breast cancer • Subjects may have either measurable or non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) [Eisenhauer, 2009] 4. Tumors that are ER+ and/or PgR+ by local laboratory 5. Documentation of HER2 overexpression or gene amplification, in the invasive component of either the primary tumor or metastatic disease site as defined as: • 3+ by Immunohistochemistry (IHC) and/or • HER2/neu gene amplification by fluorescence, chromogenic or silver in situ hybridization [FISH, CISH or SISH; >6 HER2/neu gene copies per nucleus or a FISH, CISH or SISH test ratio (HER2 gene copies to chromosome 17 signals) of ≥2.0] 6. Subject must have received prior neoadjuvant and/or adjuvant trastuzumab 7. Subject must have received prior neoadjuvant and/or adjuvant endocrine therapy 8. Subjects who have a life expectancy of > 6 months as assessed by the treating investigator 9. Have baseline of Left Ventricular Ejection Fraction (LVEF) ≥50% measured by echocardiography (ECHO) or multi-gated acquisition scan (MUGA) 10. ECOG performance status of 0-1 (Section 12.2, Appendix 2) 11. All prior treatment related toxicities must be CTCAE (Version 4.0) ≤ Grade 1 [NCI, 2009] at the time of randomization 12. Completion of screening assessments 13. Adequate baseline organ function defined by: (Refer to page 26 of Protocol)

I soggetti idonei per l'arruolamento nello studio devono soddisfare tutti i criteri seguenti: 1. Firma del consenso informato scritto. 2. Soggetti di sesso femminile in post-menopausa di età ≥18 anni. Post-menopausa definita da uno dei criteri seguenti: • Età > 60 anni • Età ≥ 45 anni con amenorrea > 12 mesi con utero intatto • Precedente ooforectomia bilaterale o sterilizzazione mediante radiazioni con amenorrea da almeno 6 mesi • Livelli di FSH e di estradiolo nel range previsto per la post-menopausa (in base ai range del laboratorio locale). Per i soggetti precedentemente trattati con un analogo del GnRH/LHRH, deve essere stata somministrata l'ultima iniezione >4 mesi prima della randomizzazione e il ciclo mestruale non deve più essere comparso 3. Cancro mammario invasivo di stadio IV confermato istologicamente. • I soggetti possono presentare una malattia misurabile o non misurabile in base ai criteri di valutazione della risposta nei tumori solidi (RECIST 1.1) [Eisenhauer, 2009] 4. Tumori di tipo ER+ e/o PgR+ confermato dal laboratorio locale. 5. Documentazione di sovraespressione di HER2 o amplificazione genica, nel componente invasivo del tumore primario o della sede della patologia metastatica, definita come: • 3+ tramite esame immunoistochimico (IHC) e/o • Amplificazione genica HER2/neu tramite analisi di ibridazione in situ a fluorescenza, cromogenica o con argento [FISH, CISH o SISH; >6 copie di gene HER2/neu per nucleo o un rapporto di prova FISH, CISH o SISH (copie gene HER2 a segnali del cromosoma 17) ≥2,0] 6. il soggetto deve aver precedentemente assunto trastuzumab neoadiuvante e/o adiuvante. 7. il soggetto deve aver precedentemente ricevuto terapia endocrina neoadiuvante e/o adiuvante. 8. i soggetti deveno aver un’aspettativa di vita > 6 mesi secondo la valutazione dello sperimentatore responsabile del trattamento. 9. Presenza di frazione di eiezione ventricolare sinistra (LVEF) alla baseline ≥50% misurata tramite ecocardiografia (ECHO) o angioscintigrafia miocardica (MUGA). 10. Stato di performance ECOG pari a 0-1 (Sezione 12.2 del Protocollo, Appendice2). 11. Tutte le tossicità legate a trattamenti precedenti devono essere CTCAE (versione 4.0) ≤ grado 1 [NCI, 2009] al momento della randomizzazione. 12. Completamento delle valutazioni di screening. 13. Funzionalità degli organi alla baseline adeguata, definita tramite (fare riferimento alla pagina 26 del protocollo).

E.4

Principal exclusion criteria

Subjects meeting any of the following criteria must not be enrolled in the study: 1. History of another malignancy. Exception: Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. 2. Subjects with extensive symptomatic visceral disease including hepatic involvement and pulmonary lymphangitic spread of tumor, or the disease is considered by the investigator to be rapidly progressing or life threatening (subjects who are intended for chemotherapy) 3. Subjects who received prior chemotherapy, hormonal therapy, immunotherapy, biologic therapy, or anti-HER2 therapy for advanced or metastatic disease 4. Serious cardiac illness or medical condition including but not confined to: • Uncontrolled arrhythmias • Uncontrolled or symptomatic angina • History of congestive heart failure (CHF) • Documented myocardial infarction <6 months from study entry 5. Known history of, or clinical evidence of, central nervous system (CNS) metastases or leptomeningeal carcinomatosis 6. Current active hepatic or biliary disease (with exception of subjects with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment) 7. Concurrent disease or condition that may interfere with study participation, or any serious medical disorder that would interfere with the subject's safety (for example, active or uncontrolled infection or any psychiatric condition prohibiting understanding or rendering of informed consent) 8. Have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels 9. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the study agents or their excipients that, in the opinion of the Investigator or GSK medical monitor, contraindicates their participation 10. Any prohibited medication as described in Section 6.2 of the protocol. 11. Administration of an investigational drug within 30 days or 5 halflives, whichever is longer, preceding the first dose of study treatment.

1. Storia di un'altra neoplasia maligna. Eccezione: i soggetti che sono liberi dalla malattia da 5 anni o i soggetti con una storia di tumore cutaneo non-melanomatoso completamente asportato o di carcinoma in situ trattato con successo sono idonei. 2. Malattia viscerale sintomatica estesa, con coinvolgimento epatico e diffusione linfangitica polmonare del tumore, o con malattia considerata dallo sperimentatore in rapida progressione o potenzialmente mortale(soggetti destinati alla chemioterapia). 3. Precedente trattamento con chemioterapia, terapia ormonale, immunoterapia, terapia biologica o terapia anti-HER2 per patologia avanzata o metastatica. 4. Patologia cardiaca o condizione medica grave, comprese, in via non limitativa: • Aritmia incontrollata • Angina incontrollata o sintomatica • Storia di insufficienza cardiaca congestizia (CHF) • Infarto miocardico documentato <6 mesi dall'ingresso nello studio 5. Storia nota o evidenza clinica di metastasi al sistema nervoso centrale (CNS) o carcinomatosi leptomeningea. 6. Patologia epatica o biliare attualmente attiva (fatta eccezione per soggetti con sindrome di Gilbert, colelitiasi asintomatica, metastasi al fegato o patologia epatica cronica stabile secondo la valutazione dello sperimentatore). 7. Patologia o condizione concomitante che potrebbe interferire con la partecipazione allo studio oppure qualsiasi disturbo medico grave in grado di interferire con la sicurezza del soggetto (ad esempio infezione attiva o incontrollata oppure qualsiasi condizione psichiatrica tale da impedire la comprensione o il rilascio del consenso informato). 8. Anomalia gastrointestinale clinicamente significativa, in grado di alterare l'assorbimento, come la sindrome da malassorbimento oppure resezione di ampia portata di stomaco o intestino. 9. Reazione nota di ipersensibilità immediata o ritardata o idiosincrasia a farmaci chimicamente correlati a un qualsiasi agente dello studio o ai relativi eccipienti e che, secondo lo sperimentatore o il responsabile medico di GSK, è controindicata per la partecipazione. 10. Assunzione di un qualsiasi farmaco vietato, come indicato nella Sezione 6.2 del Protocollo. 11. Assunzione di un farmaco sperimentale nei 30 giorni o nelle 5 emivite, a seconda della condizione che si protrae più a lungo, precedenti la prima dose del trattamento dello studio.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint of this study is overall survival assessed for lapatinib/trastuzumab/AI combination (Treatment Group A) vs. trastuzumab/AI combination (Treatment Group B). Overall Survival is defined as the time from randomization until death due to any cause.

L'endpoint di efficacia primario di questo studio è la sopravvivenza globale valutata per la combinazione di lapatinib/trastuzumab/IA (Gruppo di trattamento A) rispetto alla combinazione di trastuzumab/IA (Gruppo di trattamento B). Per sopravvivenza globale si intende il periodo dalla randomizzazione al decesso per qualsiasi causa.

E.5.1.1

Timepoint(s) of evaluation of this end point

The time point of primary end point, overall survival will be assessed at the end of study - Q2 2018

L'obiettivo primario di questo studio è valutare la OS al termine dello studio - secondo trimestre 2018.

E.5.2

Secondary end point(s)

The secondary efficacy endpoints of this study are: • OS in Treatment Group B (trastuzumab/AI) vs. Treatment Group C (lapatinib/AI) and Treatment Group A (trastuzumab/lapatinib/AI) vs. Treatment Group C (lapatinib/AI) defined as the time from randomization until death due to any cause. • Progression free survival (PFS) in Treatment Group A (lapatinib/trastuzumab/AI) vs. Treatment Group B (trastuzumab/AI) and Treatment Group C (lapatinib/AI) vs. Treatment Group B (trastuzumab/AI) which is defined as the interval of time (in weeks) between the date of randomization and the earlier of date of disease progression or date of death due to any cause as assessed by the investigator. • Overall response rate (complete or partial response) which is defined as the percentage of subjects achieving either a CR or PR as per RECIST 1.1 criteria in Treatment Group A (lapatinib/trastuzumab/AI) vs. Treatment Group B (trastuzumab/AI) and Treatment Group C (lapatinib/AI) vs. Treatment Group B (trastuzumab/AI) as assessed by the investigator. • Time to response which is defined as the time from randomization until first documented evidence of PR or CR (whichever status is recorded first) as per RECIST 1.1 criteria in Treatment Group A (lapatinib/trastuzumab/AI) vs. Treatment Group B (trastuzumab/AI) and Treatment Group C (lapatinib/AI) vs. Treatment Group B (trastuzumab/AI) as assessed by the investigator. • Duration of response which is defined, for the subset of subjects who achieve a CR or PR, to be the time from first documented evidence of PR or CR until the first documented sign of disease progression or death due to breast cancer, if sooner as per RECIST 1.1 criteria in Treatment Group A (lapatinib/trastuzumab/AI) vs. Treatment Group B (trastuzumab/AI) and Treatment Group C (lapatinib/AI) vs. Treatment Group B (trastuzumab/AI) as assessed by the investigator. • Clinical benefit in Treatment Group A (lapatinib/trastuzumab/AI) vs. Treatment Group B (trastuzumab/AI) and Treatment Group C (lapatinib/AI) vs. Treatment Group B (trastuzumab/AI) which is defined as the percentage of subjects with evidence of CR, PR, or SD for at least 6 months as per RECIST 1.1 criteria as assessed by the investigator.

Gli endpoint di efficacia secondari di questo studio sono: • Sopravvivenza globale (OS) nel Gruppo di trattamento B (trastuzumab/IA) rispetto al Gruppo di trattamento C (lapatinib/IA) e nel Gruppo di trattamento A (trastuzumab/lapatinib/IA) rispetto al Gruppo di trattamento C (lapatinib/IA), definita come il periodo dalla randomizzazione al decesso per qualsiasi causa. • Sopravvivenza libera da progressione (PFS) nel Gruppo di trattamento A (lapatinib/trastuzumab/IA) rispetto al Gruppo di trattamento B (trastuzumab/IA) e nel Gruppo di trattamento C (lapatinib/IA) rispetto al Gruppo di trattamento B (trastuzumab/IA), definita come il periodo (in settimane) tra la data di randomizzazione e la prima data di progressione della malattia o la data del decesso per qualsiasi causa, come stabilito dallo sperimentatore. • Tasso di risposta globale (risposta completa o parziale), definito come la percentuale di soggetti che raggiungono una CR o una PR in base ai criteri RECIST 1.1 nel Gruppo di trattamento A (lapatinib/trastuzumab/IA) rispetto al Gruppo di trattamento B (trastuzumab/IA) e nel Gruppo di trattamento C (lapatinib/IA) rispetto al Gruppo di trattamento B (trastuzumab/IA) come stabilito dallo sperimentatore. • Tempo alla risposta, definito come il periodo dalla randomizzazione alla prima evidenza documentata di PR o CR (qualunque sia lo stato registrato per primo) in base ai criteri RECIST 1.1 nel Gruppo di trattamento A (lapatinib/trastuzumab/IA) rispetto al Gruppo di trattamento B (trastuzumab/IA) e nel Gruppo di trattamento C (lapatinib/IA) rispetto al Gruppo di trattamento B (trastuzumab/IA) come stabilito dallo sperimentatore. • Durata della risposta, definita, per i soggetti che ottengono una CR o una PR, come il periodo tra la prima evidenza documentata di PR o CR e il primo segno documentato di progressione della malattia o il decesso causato dal cancro mammario, se precedente, in base ai criteri RECIST 1.1 nel Gruppo di trattamento A (lapatinib/trastuzumab/IA) rispetto al Gruppo di trattamento B (trastuzumab/IA) e nel Gruppo di trattamento C (lapatinib/IA) rispetto al Gruppo di trattamento B (trastuzumab/IA) come stabilito dallo sperimentatore. • Beneficio clinico nel Gruppo di trattamento A (lapatinib/trastuzumab/IA) rispetto al Gruppo di trattamento B (trastuzumab/IA) e nel Gruppo di trattamento C (lapatinib/IA) rispetto al Gruppo di trattamento B (trastuzumab/IA), definito come percentuale di soggetti con evidenza di CR, PR o SD per almeno 6 mesi in base ai criteri RECIST 1.1 come stabilito dallo sperimentatore.

E.5.2.1

Timepoint(s) of evaluation of this end point

The time point of the secondary end points: overall survival and progression free survival will be assessed at the end of study - Q2 2018. Lesion assessments assessed by Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) will be performed every 12 weeks and at study conclusion.

Tempo di rilevazione degli obiettivi secondari: valutare la OS al termine dello studio -secondo trimestre 2018; Le valutazioni delle lesioni definite tramite i criteri di valutazione della risposta nei tumori solidi 1.1(RECIST 1.1) saranno effettuate ogni 12 settimane e alla conclusione dello studio.

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)

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

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)

Yes

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

124

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

Argentina

Brazil

Hong Kong

Korea, Republic of

Russian Federation

Taiwan

Ukraine

United States

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

Collection of all study data will continue until: at least 75% of subjects have reached an event (death) or at most 25% subjects are censored AND the last subject has discontinued study treatment. The primary endpoint is Overall survival so when the events for the analysis have been reached that will be the final analysis

I dati saranno raccolti sino a: almeno il 75 % dei soggetti ha raggiunto l'evento (morte) o al massimo il 25 % sono vivi o persi al follow up e l'ultimo soggetto ha interrotto il trattamento.

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:

340

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

185

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

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.4.2

For a multinational trial

F.4.2.1

In the EEA

263

F.4.2.2

In the whole clinical trial

525

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)

Post study treatment will not be provided by GSK as part of this protocol. Upon discontinuation from an assigned study treatment, subjects may receive additional anticancer therapy at the discretion of the treating physician. The investigator is responsible for ensuring that consideration has been given for the post-study care of the patient's medical condition.

Dopo il termine dello studio GSK non fornirà alcun trattamento ed il paziente potrà ricevere altre terapie antitumorali a discrezione del medico dello studio, il quale è responsabile delle condizioni cliniche del paziente dopo il termine dello studio.

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

2012-03-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-01-26

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

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IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
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