Clinical Trials Register

Summary
EudraCT Number:	2007-005021-30
Sponsor's Protocol Code Number:	FARM5P8YFC
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:	2007-11-15
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

2007-005021-30

A.3

Full title of the trial

TOP TRIAL. A RANDOMISED PHASE III CLINICAL TRIAL OF TRASTUZUMAB (HERCEPTIN) OPTIMIZATION IN PATIENTS WITH LOCALLY ADVANCED AND/OR METASTATIC BREAST CANCER OVEREXPRESSING HER2 AFTER A FIRST LINE CHEMOTHERAPY PLUS TRASTUZUMAB

A.3.2

Name or abbreviated title of the trial where available

TOP TRIAL

A.4.1

Sponsor's protocol code number

FARM5P8YFC

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	REGIONE LOMBARDIA - DIREZIONE GENERALE SANITA'
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	HERCEPTIN
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE 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	Powder for infusion*
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	21
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.8	Extractive medicinal product	Information not present in EudraCT
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Women with locally advanced or metastatic breast cancer over expressing HER2 who have been previously treated with a first line chemotherapy plus trastuzumab.

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10006279
E.1.2	Term	Breast neoplasm

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 whether a maintenance therapy with trastuzumab is superior in terms of PFS to no further trastuzumab treatment in patients with locally advanced and/or metastatic breast cancer over expressing HER2 and not progressed to a first line chemotherapy containing trastuzumab (maintenance study)  To assess whether a second line chemotherapy with trastuzumab after failure of a first line regimen of chemotherapy plus trastuzumab is superior in terms of OS to chemotherapy alone in patients with locally advanced and/or metastatic breast cancer over expressing HER2 (2nd line study)

E.2.2

Secondary objectives of the trial

 To assess whether a maintenance therapy with trastuzumab is superior in terms of OS to no further trastuzumab treatment in patients with locally advanced and/or metastatic breast cancer over expressing HER2 and not progressed to a first line chemotherapy containing trastuzumab (maintenance study) To assess whether a second line chemotherapy with trastuzumab after failure of a first line regimen of chemotherapy plus trastuzumab is superior in terms of PFS to chemotherapy alone in patients with locally advanced and/or metastatic breast cancer over expressing HER2 (2nd line study) To evaluate the safety profiles of the treatments

E.2.3

Trial contains a sub-study

Information not present in EudraCT

E.3

Principal inclusion criteria

 >18 years of age. Patients older of 70 years of age are eligible on the basis of an individual risk-benefit assessment by the investigator  Histologically confirmed breast cancer with locally advanced and/or metastatic disease  Over expression of HER2 (3+) as determined by IHC or amplification of HER2/c-erbB2 by FISH/CISH of the primary tumour or of a metastasis  Assessable disease. The presence of measurable disease is not needed for enrolment. Patients with bone lesions, ascites and pleural effusion as only sites of disease are considered eligible  Completion of a first line chemotherapy in association with trastuzumab given for at least 6 months for advanced disease. The last dose of trastuzumab should have to be given within 6 weeks prior to randomisation for treatments given with a 3 weekly schedule or within 3 weeks if a weekly schedule was used (only for maintenance study)  Progressive disease during or within 6 months from the completion of a first line chemotherapy plus trastuzumab for advanced disease or within 6 months from the completion of an adjuvant treatment for early disease (only for 2nd line study). Patients progressing more than 6 months after the completion of a first line trastuzumab-containing regimen should be re-treated with the previous regimen and included in 2nd line study after evidence of progression.  Signed written informed consent obtained prior to any study specific study procedures

E.4

Principal exclusion criteria

Women with locally advanced or metastatic breast cancer over expressing HER2 who have been previously treated with a first line chemotherapy plus trastuzumab.  >18 years of age. Patients older of 70 years of age are eligible on the basis of an individual risk-benefit assessment by the investigator  Histologically confirmed breast cancer with locally advanced and/or metastatic disease  Over expression of HER2 (3+) as determined by IHC or amplification of HER2/c-erbB2 by FISH/CISH of the primary tumour or of a metastasis  Assessable disease. The presence of measurable disease is not needed for enrolment. Patients with bone lesions, ascites and pleural effusion as only sites of disease are considered eligible  Completion of a first line chemotherapy in association with trastuzumab given for at least 6 months for advanced disease. The last dose of trastuzumab should have to be given within 6 weeks prior to randomisation for treatments given with a 3 weekly schedule or within 3 weeks if a weekly schedule was used (only for maintenance study)  Progressive disease during or within 6 months from the completion of a first line chemotherapy plus trastuzumab for advanced disease or within 6 months from the completion of an adjuvant treatment for early disease (only for 2nd line study). Patients progressing more than 6 months after the completion of a first line trastuzumab-containing regimen should be re-treated with the previous regimen and included in 2nd line study after evidence of progression.  Signed written informed consent obtained prior to any study specific study procedures  ECOG-PS >2  Pregnant or lactating women. Women of childbearing potential must implement adequate contraceptive measures  Previous or current malignancies at other sites, with the exception of adequately treated in situ carcinoma of the cervix uteri, basal or squamous cell carcinoma of the skin, or other cancer curatively treated by surgery and with no evidence of disease for at least 5 years.  Baseline LVEF <50% (measured by echocardiography or MUGA) performed within 4 weeks prior to randomisation. History of documented congestive heart failure, angina pectoris requiring antianginal medication, evidence of transmural infarction ECG, poorly controlled hypertension (systolic > 180 mmHg or diastolic > 100 mmHg); clinically significant valvular heart disease; high-risk uncontrolled arrhythmias  Presence of CNS metastases, not amenable to curative therapy. Patients with previously treated CNS metastases must be asymptomatic and stable at radiological imaging from at least 3 months  Patients with dyspnoea at rest due to malignant or other disease, or who require supportive oxygen therapy. Patients with pre-existing lung disease or advanced pulmonary involvement may be at increased risk of serious toxicities with trastuzumab and should be evaluated carefully before entry into the study  Concomitant chemotherapy with anthracyclines, including liposomial drugs (only for 2nd line study)  Treatment with any investigational drug within 30 days before beginning of enrolment in the trial  History or presence of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of trastuzumab

E.5 End points

E.5.1

Primary end point(s)

 PFS is defined as the time from the date of randomisation up to the date of first progression, second primary malignancy or death from any cause, whichever comes first. Subjects who have not progressed or died while on study will be censored at the last disease assessment date.  OS is defined as the time from the date of randomisation to the date of death from any cause. Subjects who were not reported as having died at the time of the analysis will be censored at the date they were last known to be alive.  Toxicity, graded according to the NCI-CTAE version 3.0  Frequency and nature of serious adverse reactions  Premature withdrawals During the course of the trial, an independent Data and Safety Monitoring Committee (DSMC) will advise the Steering Committee on efficacy and safety aspects of the study.

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

Information not present in EudraCT

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Information not present in EudraCT

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

assunzione del farmaco - interruzione assunzione

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.8.5

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

Information not present in EudraCT

E.8.7

Trial has a data monitoring committee

Information not present in EudraCT

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	No
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	No
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Information not present in EudraCT
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 2007-11-15.	Yes
F.3.3.2	Women of child-bearing potential using contraception	Information not present in EudraCT
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	600

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

2007-10-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2007-09-25

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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