Clinical Trials Register

Summary
EudraCT Number:	2011-000155-16
Sponsor's Protocol Code Number:	CROLT/02
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:	2012-03-20
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

2011-000155-16

A.3

Full title of the trial

Modulation of response to hormonal therapy with lapatinib and/or metformin in patients with HER2-negative, ER and/or PgR positive metastatic breast cancer with progressive disease after first-line hormonal therapy

Modulazione della risposta alla terapia ormonale con lapatinib, e/o metformina in pazienti con carcinoma mammario metastatico recettori ormonali positivi HER2 negativo, in progressione dopo prima linea di ormonoterapia

A.3.1

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

A.4.1

Sponsor's protocol code number

CROLT/02

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	FONDAZIONE MICHELANGELO - AVANZAMENTO DELLO STUDIO E 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	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	Fondazione Michelangelo
B.5.2	Functional name of contact point	Operations Office
B.5.3	Address:
B.5.3.1	Street Address	Via Venezian, 1
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20133
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39-02-2390 3068
B.5.5	Fax number	+39-02-2390 2678
B.5.6	E-mail	michelangelo.monitor@yahoo.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*70CPR RIV 250MG
D.2.1.1.2	Name of the Marketing Authorisation holder	GLAXOSMITHKLINE SpA
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	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
D.3.9.1	CAS number	231277-92-2
D.3.9.4	EV Substance Code	NA
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	Yes
D.3.11.13.1	Other medicinal product type	antineoplastico
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	METFORMINA TEVA*50CPR 500MG OP
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA ITALIA Srl
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	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	METFORMIN HYDROCHLORIDE
D.3.9.1	CAS number	1115-70-4
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	500
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	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	antidiabetici

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

Female patients with HER2-negative, ER and/or PgR positive breast cancer in progression after first-line hormonal therapy

Pazienti con carcinoma mammario metastatico in progressione dopo trattamento ormonale di prima linea, recettori ormonali positivi e stato di HER2 negativo

E.1.1.1

Medical condition in easily understood language

Female patients with hormonal sensitive metastatic breast cancer in progression after hormonal therapy

Pazienti con carcinoma mammario ormonosensibile in progressione dopo trattamento ormonale

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	SOC
E.1.2	Classification code	10038604
E.1.2	Term	Reproductive system and breast disorders
E.1.2	System Organ Class	10038604 - Reproductive system and breast disorders

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 assess the rate of patients free from disease progression at 3 months from randomization

Valutare la percentuale di pazienti senza progressione di malattia a 3 mesi

E.2.2

Secondary objectives of the trial

To assess the overall response rate To assess the duration of response To assess 3-years overall survival rate To assess tolerability of each proposed treatment

Valutare la percentuale di risposta clinica Valutare la durata mediana della risposta Valutare la sopravvivenza a 3 anni Valutare la tollerabilità ai trattamenti

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Female patients with a histologically or cytologically confirmed adenocarcinoma of the breast progressing from prior hormonal therapy 2. Receptor positive disease (ER+ and/or PgR+) 3. HER2 negative 4. Pre- and post-menopausal status 5. Documented disease progression after first-line hormone therapy 6. Age >= 18 years 7. Measurable or evaluable metastatic disease according to RECIST Criteria 1.1 8. Life expectancy > 3 months 9. ECOG Performance Status < 1 10. Adequate bone marrow, liver, and renal function as assessed by the following parameters: Hemoglobin > 9.0 g/dl Leucocytes count >= 3,000/mm3 Absolute neutrophil count (ANC)>= 1,500/mm3 Platelet count >= 100,000/mm3 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=2.5 x ULN <= 5 x ULN for patients with liver involvement) Albumine and total bilirubin <= 1.5 x ULN Prothrombin Time (PT) < 70 % Serum creatinine <= 1.4 mg/ml, creatinine clearance > 70 ml/min 11. Normal Respiratory Function and Saturation level > 90% 12. New York Hearth Association (NYHA) Classification <= 2 and baseline left ventricular ejection fraction (LVEF) >= 50% 13. Patients must be willing and able to sign a written informed consent

1. Pazienti di sesso femminile con diagnosi istologica/citologica di carcinoma mammario metastatico 2. Positività per recettori ormonali (ER+ e/o PgR+) 3. Negatività di HER2 4. Pazienti in pre o postmenopausa 5. Documentata progressione con ormonoterapia di prima linea 6. Età >= 18 anni 7. Estensione di malattia misurabile o valutabile 8. Aspettativa di vita di almeno 3 mesi 9. ECOG performance status (PS) < 1 10. Adeguati valori ematologici ed adeguata funzionalità d’organo, definiti sulla base dei seguenti valori di laboratorio: Emoglobina > 9,0 g/dl Leucociti >= 3.000/μL Conteggio assoluto dei neutrofili >=1.500/μL Piastrine >= 100.000/μL AST (SGOT) e ALT (SGPT) <= 2,5 volte il limite superiore normale (ULN) con l’eccezione delle pazienti con documentate metastasi epatiche (AST e/o ALT <= 5 volte ULN) Albumina e bilirubina totale <= 1,5 volte il limite superiore normale Tempo di protrombina (PT) < 70% Creatinina < 1,4 mg/ml, creatinina clearance > 70 ml/min 11. Normale funzionalità respiratoria e saturazione in aria > 90% 12. Compenso cardiocircolatorio (Classificazione NYHA <= 2) e frazione di eiezione del ventricolo sinistro (FEVS) entro limiti di norma (>= 50%) 13. Capacità di intendere la finalità del protocollo, sottoscrivere il consenso informato e aderire alle procedure

E.4

Principal exclusion criteria

1. Previous or concomitant treatment with lapatinib and/or metformin 2. More than one line of prior hormone therapy for metastatic breast cancer 3. More than two lines of prior chemotherapy for metastatic breast cancer 4. Unique location of disease local-regionally treated (surgery, radiotherapy, other) 5. Disease progression not documented or less than 30% 6. Metastatic disease defined as aggressive at investigator’s judgement (e.g.. visceral disease more than >1/3 of involved parenchima, symptomatic disease requiring intensive supportive measures or therapies not allowed by protocol) 7. Patients with brain metastasis 8. Osteosclerotic bone metastasis as unique disease site 9. Pathological tumor markers as unique sign of progressive disease 10. Concomitant treatment with any other anticancer drugs (biphosphonates are permitted) 11. Serious, not solved or unstable toxicity from previous treatment 12. Diabetes mellitus Type I and Type II 13. Renal insufficiency (creatinine > 1.4 mg/ml) 14. Malabsorption syndrome or diseases that significantly may alter gastroenteric functions 15. Other serious illness or medical conditions judged by the investigator to be clinically significant that may adversely affect patient’s participation in the trial or interfere with safety profile 16. Active clinically significant or uncontrolled infections (bacterial or viral) 17. Known history of unstable angina (angina symptoms at rest), cardiac ventricular arrhythmias clinically significant, myocardial infarction, stroke or congestive heart failure within 12 months prior to randomization 18. History of lactic acidosis 19. Evidence or symptoms of hepatic insufficiency 20. Chronic alcoholism 21. Concomitant treatment with amiodarone or any other agent that could interfere with study drugs 22. Known or suspected hypersensitivity or allergy to lapatinib, metformin or used eccipients 23. Women who are pregnant or lactating 24. History of previous cancer, unless at low risk of relapse per investigator’s judgement

1. Precedente o concomitante terapia con metformina e/o lapatinib 2. Più di una linea di ormonoterapia per malattia metastatica 3. Più di due linee di chemioterapia per malattia metastatica 4. Unica sede di malattia sottoposta a trattamento loco-regionale (chirurgia, radioterapia o altro) 5. Progressione di malattia non documentata o inferiore al 30% 6. Malattia metastatica considerata aggressiva a giudizio del clinico (es. malattia viscerale estesa a >1/3 del parenchima interessato, malattia sintomatica che richiede terapie di supporto maggiori o non consentite dal protocollo di studio) 7. Metastasi a livello del sistema nervoso centrale 8. Metastasi ossee addensanti come unica sede di malattia 9. Alterazioni del marcatore tumorale come unico parametro di malattia 10. Concomitante assunzione di altre terapie antitumorali (il trattamento con i bifosfonati è consentito) 11. Grave tossicità irrisolta o instabile da precedente trattamento 12. Diabete mellito di tipo 1 e di tipo 2 13. Insufficienza renale (creatinina >=1,4 mg/ml) 14. Sindrome da malassorbimento, malattie con rilevanti alterazioni della funzionalità gastrointestinale 15. Concomitanti malattie o condizioni che rendano inappropriata l’inclusione in studi clinici o possano interferire con la sicurezza della paziente. 16. Infezioni attive o incontrollate (batteriche o virali) 17. Anamnesi di angina incontrollata o sintomatica, aritmie clinicamente rilevanti, ischemia miocardica, ictus o scompenso cardiaco congestizio nei 12 mesi precedenti 18. Anamnesi di acidosi lattica 19. Segni e sintomi di scompenso epatico 20. Etilismo cronico 21. Trattamento concomitante con amiodarone o con altri farmaci potenzialmente in grado di interferire con i farmaci in studio 22. Nota ipersensibilità o intolleranza a lapatinib, metformina o eccipienti. 23. Gravidanza o allattamento 24. Presenza di altri tumori maligni, tranne quelli considerati dallo sperimentatore a basso rischio di recidiva

E.5 End points

E.5.1

Primary end point(s)

To assess how many patients, after 3 months of therapy, are free of progressive disease

Valutare quante pazienti non hanno presentato progressione di malattia dopo 3 mesi di trattamento

E.5.1.1

Timepoint(s) of evaluation of this end point

After three months of treatment

Dopo tre mesi di trattamento

E.5.2

Secondary end point(s)

To assess the overall response rate To assess the duration of response in patients who achieved e partial or complete remission To assess 3-years overall survival rate To assess tolerability of each proposed treatment

Valutare la percentuale di risposta clinica Valutare la durata mediana della risposta nelle pazienti che hanno ottenuto una remissione parziale o completa Valutare la sopravvivenza a 3 anni Valutare la tollerabilità ai trattamenti

E.5.2.1

Timepoint(s) of evaluation of this end point

After 3 years from the start of treatment

Dopo 3 anni dall'inizio del trattamento

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

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

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

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

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:

144

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2012-03-20.

Yes

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

168

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)

According to optimal conventional treatment for patients with progressive metastatic breast cancer

Secondo il miglior trattamento convenzionale per pazienti con carcinoma mammario metastatico in progressione di malattia

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

2011-10-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-06-09

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2014-01-31

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