Clinical Trials Register

Summary
EudraCT Number:	2013-003194-10
Sponsor's Protocol Code Number:	GIM11-BERGI
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2014-04-11
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

2013-003194-10

A.3

Full title of the trial

A Phase II Single Arm Trial Evaluating the Efficacy and Safety of Eribulin in Combination With Bevacizumab for Second-Line Treatment of Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer Progressing after First-Line Therapy With Bevacizumab and Paclitaxel

Studio di fase II per la valutazione dell’Efficacia e della Sicurezza di Eribulina in combinazione con Bevacizumab come trattamento di seconda linea del carcinoma mammario metastatico con fattore di crescita epidermico umano 2-negativo in progressione dopo una terapia di prima linea con Bevacizumab e Paclitaxel

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

GIM11-BERGI

A.4.1

Sponsor's protocol code number

GIM11-BERGI

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	Consorzio Oncotech
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	Roche Spa
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Clinical Research Technology
B.5.2	Functional name of contact point	Giovanni Cucchiara
B.5.3	Address:
B.5.3.1	Street Address	Via San Leonardo trav Migliaro snc
B.5.3.2	Town/ city	Salerno
B.5.3.3	Post code	84131
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39089301545
B.5.5	Fax number	+390897724155
B.5.6	E-mail	helpdesk.gim11@oncotech.org

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	Avastin 25 mg/ml concentrate for solution for infusion.
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Ltd United kindom
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.3.1	Product name	Bevacizumab
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 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	Yes
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	Recombinant humanised monoclonal antibody
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	Halaven 0.44 mg.ml solution for injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Eisai Europe Ltd
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.3.1	Product name	Halaven 0.44 mg.ml solution for injection
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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.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

Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer

Carcinoma mammario metastatico con fattore di crescita epidermico umano 2-negativo

E.1.1.1

Medical condition in easily understood language

Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer

Carcinoma mammario metastatico con fattore di crescita epidermico umano 2-negativo

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	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10027475
E.1.2	Term	Metastatic breast cancer
E.1.2	System Organ Class	100000004864

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 efficacy and safety of Eribulin in combination with Bevacizumab for second-line treatment of human epidermal growth factor receptor 2–negative metastatic breast cancer progressing after first-line therapy with Bevacizumab and Paclitaxel

Valutare l’efficacia e la sicurezza dell’eribulina in combinazione con il bevacizumab come trattamento di seconda linea del carcinoma mammario metastatico con fattore di crescita epidermico umano 2-negativo in progressione dopo una terapia di prima linea con Bevacizumab e Paclitaxel

E.2.2

Secondary objectives of the trial

Other assessments of the efficacy and safety of Eribulin in combination with Bevacizumab

Ulteriori valutazioni dell’efficacia e sicurezza del trattamento continuo con bevacizumab in combinazione con eribulina

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed informed consent
2. Female patients ≥18 years of age.
3. Histologically confirmed HER2-negative adenocarcinoma of the breast with documented progression of disease per investigator assessment following or during first-line treatment with Bevacizumab in combination with Paclitaxel for MBC; patients can have measurable or non-measurable disease;
4. A minimum of 4 cycles of Bevacizumab 15 mg/kg or 6 cycles 10 mg/kg received in the first-line setting.
5. Patients must have received Bevacizumab in combination with Paclitaxel.
6. ECOG performance status (PS) of 0-2.
7. At least 28 days since prior radiation therapy or surgery and recovery from treatment.
8. Patients must have measurable disease which must be evaluable per RECIST v1.1.
9. Estimated life expectancy of ≥12 weeks

1. Firma consenso informato
2. Donne con età ≥18
3. Adenocarcinoma mammario HER2 negativo confermato istologicamente con progressione documentata dopo o durante prima linea con bevacizumab in combinazione con paclitaxel per MBC, i pazienti possono avere lesioni misurabili o non misurabili;
4. Un minimo di 4 cicli di bevacizumab 15 mg/kg o 6 cicli da 10 mg/kg in prima linea
5. I pazienti devono aver ricevuto bevacizumab in combinazione con paclitaxel
6. ECOG performance status 0-2
7. Almeno 28 giorni dall’ultima radioterapia o chirurgia o recupero dal trattamento
8. I pazienti devono riportare lesioni misurabili che devono potere essere valutabili secondo i criteri RECIST v1.1.
9. Una stima dell’aspettativa di vita ≥ 12 settimane

E.4

Principal exclusion criteria

1. Patients who have received anti-angiogenic therapy other than Bevacizumab for the first-line treatment of MBC.
2. Patients who have exclusively received endocrine treatment in combination with Bevacizumab until the first progression.
3. Positive or unknown HER2/neu status or for whom determination of HER2 status is not possible.
4. Current, recent (within 4 weeks or 2 half-lives, whichever is greater, before day 1) or planned participation in an experimental drug study - other than a Bevacizumab breast cancer study.
5. Active malignancy, other than superficial basal cell and superficial squamous (skin) cell, or carcinoma in situ of the cervix or breast within the last 5 years.
6. Any laboratory values at baseline as follows:
Hematology:
- ANC <1.5x109/L or 1500/mm3
- Platelet count <75x109/L
- Hemoglobin <8 g/dL (Note: hemoglobin levels may be supported by transfusion or erythropoietin or other approved hematopoietic growth factors).
Coagulation:
- INR >1.5 except for patients on stable anticoagulant therapy
- aPTT ≥1.5 times ULN or greater than the lower limit of the therapeutic range
Note: The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose of anticoagulants for at least two weeks at the time of Day 1, Cycle 1.
Serum chemistry:
- Total bilirubin >1.5 volte ULN
- AST or ALT >2 volte ULN (>5 times ULN for patients with known liver involvement)
- ALP >2 times ULN (>5 times ULN for patients with known liver involvement and >7 times ULN for patients with known bone involvement).
7. Inadequate renal function, defined as:
a. Creatinine clearance <50 mL/min
b. Urine dipstick for proteinuria ≥2+ unless a 24-hour protein ≤1 g is demonstrated.

8. Psychiatric or addictive disorders
9. Serious active infection requiring i.v. antibiotics and/or hospitalization at study entry.
10. Patients who are treated with any medicinal product that contraindicates the use of any of the study drugs, may interfere with the planned treatment, affects patient compliance or puts the patient at high risk for treatment-related complications.
11. Bevacizumab-specific exclusions
12. Eribulina-specific exlusions

1. Pazienti che hanno ricevuto terapia anti-angiogenica oltre al bevacizumab per il trattamento di prima linea del MBC
2. Pazienti che hanno ricevuto esclusivamente trattamento endocrino in combinazione con bevacizumab prima della prima progressione
3. Stato dell’HER2/neu positivo o sconosciuto o per chi la determinazione dello stato HER2 non è possibile
4. Partecipazione ad una sperimentazione clinica con farmaco in corso, recente (entro 4 settimane o 2 emivite, cosa è maggiore, prima del giorno 1) o pianificata diversa da studi con Bevacizumab per tumore alla mammella
5. Altre patologie maligne, diverse da quelle delle cellule basali superficiali e squamose superficiali (cute), o carcinoma in situ della cervice o della mammella negli ultimi 5 anni.
6. Valori di laboratorio al baseline:
Ematologia:
- ANC <1.5x109/L or 1500/mm3
- Conta piastrinica <75x109/L
- emoglobina <8 g/dL (Nota: i livelli di emoglobina possono essere mantenuti da trasfusioni o eritropoietina o da altri fattori di crescita ematopoietici approvati).
Coagulazione:
- INR >1.5 eccetto per pazienti con terapia coagulante stabile
- aPTT ≥1.5 volte l' ULN o maggiore rispetto al limite più basso del range terapeutico
Nota: l’uso di anticoagulanti parenterali orali a dose piena è permesso fino a quando l’INR o aPTT è entro i limiti terapeutici (in accordo alla pratica medica in uso nell’istituzione) e il paziente ha assunto anticoagulanti a dose stabile per almeno due settimane al momento del giorno 1, ciclo 1
Analisi chimica del siero:
- Bilirubina totale >1.5 volte l' ULN
- AST o ALT >2 volte l' ULN (>5 volte l' ULN per pazienti con coinvolgimento epatico conosciuto)
- ALP >2 volte l' ULN (>5 volte l' ULN per pazienti con coinvolgimento epatico conosciuto e >7 volte l' ULN per pazienti con coinvolgimento osseo conosciuto).
7. Funzioni renali inadeguate:
a. Clearance della creatinina <50 mL/min;
b. Stick urine per la proteinuria ≥2+ a meno che le proteine delle 24 ore non siano ≤1 g
8. Disordini psichiatrici
9. Infezioni attive serie che richiedono antibiotici o ospedalizzazione all'ingresso nello studio
10. Pazienti che sono trattati con qualunque farmaco che controindica l’uso dei farmaci sperimentali, può interferire con il trattamento pianificato, influenza la compliance de paziente o mette in alto rischio il paziente per complicazioni correlate al trattamento
11. Esclusioni specifiche da Bevacizumab
12. Esclusioni specifiche da Eribulina

E.5 End points

E.5.1

Primary end point(s)

Overall response rate (ORR) based on BOR

Overall response rate (ORR) basato su BOR

E.5.1.1

Timepoint(s) of evaluation of this end point

Until approximately 30 months

Fino a approssimativamente 30 mesi

E.5.2

Secondary end point(s)

- Clinical Benefit Rate (CBR)
- Second Line Progression Free Survival (PFS)
- Overall survival (OS)
- 1 year OS
- Safety and tolerability
- Duration of response
- Quality of Life (QoL)

- Clinical Benefit Rate (CBR)
- Progression Free Survival in seconda linea (PFS)
- Sopravvivenza totale (OS)
- OS a un anno
- Sicurezza e tollerabilità
- Durata della risposta
- Quality della vita (QoL)

E.5.2.1

Timepoint(s) of evaluation of this end point

Until approximately 30 months

Fino a approssimativamente 30 mesi

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

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

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

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

Estimated LPLV: September 2016

LPLV attesa: Settembre 2016

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.1.1.1

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:

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

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

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)

During the follow-up period every nine weeks a physical examination will be performed, vital signs will be measured and the ECOG PS evaluated . A test for pregnancy and tumor assessment will be performed (the frequency of visits, however, will follow the local standards). The survival status and the adverse events will be monitored until resolution.

Nella fase di follow-up i pazienti ogni 9 settimane effettueranno un esame fisico, verranno misurati i segni vitali e valutato l’ECOG PS. Verrà effettuato un test per la gravidanza e un tumor assessment (la frequenza delle visite segue comunque gli standard locali). Verranno monitorati gli eventi avversi fino a risoluzione e lo stato di sopravvivenza attraverso contatti telefonici se il paziente verrà seguito presso altri Centri di Trattamento.

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

2014-06-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-05-21

P. End of Trial
P.	End of Trial Status	Ongoing

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