Clinical Trials Register

Summary
EudraCT Number:	2006-001949-34
Sponsor's Protocol Code Number:	E7389-G000-305
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:	2007-06-04
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

2006-001949-34

A.3

Full title of the trial

A Phase III Open Label, Randomized Parallel Two-Arm Multi Center Study of E7389 versus ‘Treatment of Physician's Choice' in Patients with Locally Recurrent or Metastatic Breast Cancer, Previously Treated with At Least Two and a Maximum of Five Prior Chemotherapy Regimens, Including an Anthracycline and a Taxane.

A phase III Open Label, Randomised Parallel Two-Arm Multi Center Study of E7389 versus ``Treatment of Physician Choice`` in Patients with Locally Recurrent or Metastatic Breast Cancer, Previously Treated with at least Two and a Maximum of Five Prior Chemotherapy Regimens, Including an Anthracycline and a Taxane.

A.4.1

Sponsor's protocol code number

E7389-G000-305

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	EISAI LIMITED
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
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	No
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.3.1	Product name	BOLD
D.3.2	Product code	E7389
D.3.4	Pharmaceutical form	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	BOLD
D.3.9.1	CAS number	441045-17-6
D.3.9.2	Current sponsor code	E7389
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	1
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	Non Applicabile

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

Patients with locally recurrent or metastatic breast cancer

Pazienti con carcinoma mammario recidivato localmente o metastatico

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	10021977
E.1.2	Term	Inflammatory carcinoma of breast recurrent
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 of this study is to compare Overall Survival (OS) in patients treated with E7389 versus the Treatment of Physician's Choice (TPC, see ‘Treatments' section for definition) in patients with locally recurrent or metastatic breast cancer.

L'obiettivo principale di questo studio e' mettere a confronto la sopravvivenza globale (OS) nelle pazienti trattate con E7389 rispetto al trattamento di scelta del medico (TSM, vedere la sezione ‘Trattamenti' per la definizione) in pazienti con carcinoma mammario recidivato localmente o metastatico.

E.2.2

Secondary objectives of the trial

Secondary objectives are to assess:
• Progression Free Survival (PFS)
• Objective Tumor Response Rate as measured using RECIST
criteria
• Duration of Response
• Safety Parameters (adverse events, laboratory parameters,
concomitant medication, and study drug exposure)

Gli obiettivi secondari consistono nella valutazione:
• della sopravvivenza libera da progressione (PFS)
• del tasso di risposta tumorale obiettiva misurata in base ai Criteri RECIST
• della durata della risposta
• dei parametri di sicurezza (eventi avversi,parametri di laboratorio,trattamenti concomitanti ed esposizione al farmaco in studio).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Female patients with locally recurrent or metastatic breast cancer
who have received two to five prior chemotherapy regimens, which
must have contained an anthracycline and a taxane component, at
least 2 of which must have been given for locally recurrent or
metastatic disease. Patients must have proved refractory to the most
recent chemotherapy, documented by progression on or within six
(6) months of therapy
Patients with a known HER-2/neu over-expressing status may also
have been treated with trastuzumab. Patients with estrogen receptor
positive tumors may have been treated with anti-hormonals.
Previous chemotherapy, radiation, trastuzumab or hormonal therapy
must be discontinued three weeks before administration of E7389 or
TPC.

Pazienti di sesso femminile con carcinoma mammario recidivato localmente o metastatico che siano state sottoposte ad almeno due ma a non piu' di cinque regimi chemioterapici, comprensivi di un'antraciclina e di un taxano, almeno 2 dei quali somministrati per la malattia recidivata localmente o metastatica. Deve essere stata dimostrata la refrattarieta' delle pazienti alle piu' recenti chemioterapie, documentata dalla progressione durante o entro sei (6) mesi dalla terapia
Le pazienti con una condizione accertata di iperespressione dell'HER-2/neu possono essere state trattate anche con trastuzumab. Le pazienti con positivita' del tumore per i recettori per gli estrogeni possono essere state trattate con farmaci antiormonali.
La chemioterapia, la radioterapia, il trastuzumab o l'ormonoterapia somministrati in precedenza devono essere sospesi tre settimane prima della somministrazione dell'E7389 o del TSM.

E.4

Principal exclusion criteria

1. Patients who have received any of the following treatments within the specified period
before E7389 or TPC treatment start:
-chemotherapy, radiation, trastuzumab or hormonal therapy within three weeks
- any investigational drug within four weeks
2. Radiation therapy encompassing > 30% of marrow (Appendix 6)
3. Prior treatment with mitomycin C or nitrosourea
4. Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring
active treatment, including the use of oxygen
5. Patients with brain or subdural metastases are not eligible, unless they have completed
local therapy and have discontinued the use of corticosteroids for this indication for at
least 4 weeks before starting treatment in this study. Any signs (e.g. radiologic) and/or
symptoms of brain metastases must be stable for at least 4 weeks.
6. Patients with meningeal carcinomatosis7. Patients who are receiving anti-coagulant therapy with warfarin or related compounds,
other than for line patency, and cannot be changed to heparin-based therapy, are not
eligible. If a patient is to continue on mini-dose warfarin, then the prothrombin time (PT)
or international normalized ratio (INR) must be closely monitored.
8. Women who are pregnant or breast-feeding; women of childbearing potential with either
a positive pregnancy test at screening or no pregnancy test; women of childbearing
potential unless (1) surgically sterile or (2) using adequate measures of contraception in
the opinion of the Investigator. Perimenopausal women must be amenorrheic for at least
12 months to be considered of non-childbearing potential.
9. Severe/uncontrolled intercurrent illness/infection
10. Significant cardiovascular impairment (history of congestive heart failure > NYHA
grade II, unstable angina or myocardial infarction within the past six months, or serious
cardiac arrhythmia) (Appendix 7)
11. Patients with organ allografts requiring immunosuppression
12. Patients with known positive HIV status
13. Patients who have had a prior malignancy, other than carcinoma in situ of the cervix, or
non-melanoma skin cancer, unless the prior malignancy was diagnosed and definitively
treated ≥ 5 years previously with no subsequent evidence of recurrence
14. Patients with pre-existing neuropathy > Grade 2
15. Patients with a hypersensitivity to halichondrin B and/or halichondrin B chemical
derivative
16. Patients who participated in a prior E7389 clinical trial
17. Patients with other significant diseaseor disorders that, in the Investigator's opinion,
would exclude the patient from the study

1. Pazienti che, prima del periodo specificato di somministrazione di E7389 o TPC, abbiano ricevuto uno dei seguenti trattamenti:
- chemioterapia, trattamento radiante, trastuzumeb od ormonoterapia tre settimane prima dell'arruolamento;
- farmaci sperimentali nelle quattro settimane precedenrti l'arruolamento.

2. Radioterapia midollare >30%.

3. Precedente terapia con mitomicina C o nitrosurea.

4. Linfangite polmonare che comporti non adeguata funzionalita' polmonare e richieda trattamento farmacologico, compresa la somministrazione di ossigeno.

5. Pazienti con metastasi cerebrali o subdurali, ad esclusione dei soggetti che abbiano completato la terapia locale o interrotto l'uso di corticosteroidi per questa indicazione per almeno 4 settimane prima dell'inizio dello studio. Qualsiasi evidenza (e.g. radiologica) e/o sintomi di metastasi cerebrali stabile per almeno 4 settimane.

6. Pazienti con carcinomatosi meningea.

7. Pazienti in terapia anticoagulante con warfarina o composti analoghi e che non possano passare a trattamento con eparina. Nel caso di soggetti che debbano proseguire warfarina a basso dosaggio e' necessario il monitoraggio stretto del tempo di protrombina (TP) e di INR.

8. Donne in gravidanza o allattamento; donne in eta' fertile con positivita' al test di gravidanza o in assenza di test; donne in eta' fertile non sterilizzate chirurgicamente o che non usino adeguati metodi contraccettivi a giudizio dell'Investigatore.

9. Grave/non controllata malattia/infezione ricorrente.

10. Significativa patologia cardiovascolare (storia di scompenso cardiaco congestizio > grado II NYHA, angina insatbile o infarto del miocardio nei 6 mesi precedenti l'arruolamento, o severa aritmia cardiaca) (Appendice 7).

11. Pazienti con trapioanto d'organo che necessitino di terapia immunosoppressiva.

12. Pazienti HIV positivi.

13. Pazienti con precedente diagnosi di neoplasia, diversa da carcinoma della cervice in situ, o carcinoma della pelle non-melanoma, esclusa una precedente neoplasia diagnosticata e trattata in via defin itiva >5 anni prima dell'arruolamento.

14. Pazienti con pregressa neuropatia > grado 2.

15. Pazienti con ipersensitivita' ad alicondrina B e/o a derivati di alicondrina B.

16. Pazienti che hanno precedentemente preso parte ad uno studio con E7389.

17. Pazienti con altre patologie significative che, a giudizio dell'Investigatore, ne rendano necessaria l'esclusione.

E.5 End points

E.5.1

Primary end point(s)

Overall survival is the primary endpoint. The study will be declared
positive, if at the final analysis, overall survival in the E7389 arm is
statistically significantly better compared to the TPC arm (p<0.05).
The p-value will be based on a two-sided, stratified log-rank test for
the ITT population.

La sopravvivenza globale e' l'endpoint principale. Lo studio sara' dichiarato positivo se all'analisi conclusiva la sopravvivenza globale nel braccio dell'E7389 sara' migliore in modo statisticamente significativo rispetto al braccio del TSM (p<0,05). Il valore p sara' riferito a un test log-rank stratificato, a due code, per la popolazione ITT.

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

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)

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

trattamento di scelta del medico

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

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

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	No
F.1.1	Number of subjects for this age range:	0
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)	Yes
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	Yes
F.3.3.1	Women of childbearing potential not using contraception	Yes
F.3.3.2	Women of child-bearing potential using contraception	No
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	40
F.4.2	For a multinational trial
F.4.2.1	In the EEA	350
F.4.2.2	In the whole clinical trial	630

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

2007-07-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2006-12-14

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-05-31

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