Clinical Trials Register

Summary
EudraCT Number:	2012-005352-41
Sponsor's Protocol Code Number:	TACT-2C-TRIAL
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:	2014-03-07
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

2012-005352-41

A.3

Full title of the trial

A phase II randomized, open-label study evaluating the addition of trastuzumab to (nabTM)-paclitaxel as first line treatment in primary HER2 negative metastatic breast cancer patients with HER2 positive Circulating Tumor Cells (CTCs).

Studio di fase II randomizzato in aperto volto a valutare l’utilizzo di trastuzumab in aggiunta a (nabTM)-paclitaxel come trattamento di prima linea metastatica in pazienti con carcinoma mammario primitivo HER2-negativo e cellule tumorali circolanti (CTC) HER2-positive.

A.3.1

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

Multicenter Clinical Trial in subjects with HER2-negative primary tumors. The subjects will be evaluated for the presence of HER2 positive Circulating Tumor Cells (CTCs) in blood. In case of at least one HER2-positive CTC in blood, the subject will be randomized to receive either (nabTM)-paclitaxel + trastuzumab (ARM A) or (nabTM)-paclitaxel (ARM B).

Studio multicentrico in pazienti con tumori primari HER2 negativi. I pazienti saranno valutati per la presenza di cellule tumorali circolanti (CTC) HER2 positive nel sangue. In caso di positività di HER2 su almeno una CTC, il paziente sarà randomizzato per il trattamento con (nabTM)-paclitaxel + trastuzumab (BRACCIO A) oppure con (nabTM)-paclitaxel (BRACCIO B).

A.3.2

Name or abbreviated title of the trial where available

Trastuzumab and (nabTM)-paclitaxel as first line MBC in HER2+ve CTC with primary HER2-ve.

Trastuzumab e (nabTM)-paclitaxel in prima linea MBC con CTC HER2+ve e primitivo HER2-ve

A.4.1

Sponsor's protocol code number

TACT-2C-TRIAL

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	AZIENDA OSPEDALIERA ISTITUTI OSPITALIERI DI CREMONA
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	AZIENDA OSPEDALIERA ISTITUTI OSPITALIERI DI CREMONA
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	CELGENE Italia S.r.l.
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	Regione Lombardia (for CLIOSS activity)
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	AZIENDA OSPEDALIERA ISTITUTI OSPITALIERI DI CREMONA
B.5.2	Functional name of contact point	U.O.M. PATOLOGIA MAMMARIA
B.5.3	Address:
B.5.3.1	Street Address	VIALE CONCORDIA, 1
B.5.3.2	Town/ city	CREMONA
B.5.3.3	Post code	26100
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390372408278
B.5.5	Fax number	+390372405172
B.5.6	E-mail	d.generali@ospedale.cremona.it

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	ABRAXANE
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene Europe Limited
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	Paclitaxel albumin (nab-paclitaxel)
D.3.4	Pharmaceutical form	Powder for suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous drip use (Noncurrent) Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PACLITAXEL
D.3.9.1	CAS number	33069-62-4
D.3.9.4	EV Substance Code	SUB09583MIG
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	100
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	Chemotherapic agent
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	HERCEPTIN
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
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	Trastuzumab
D.3.4	Pharmaceutical form	Powder for 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.3.8 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.3.9.4	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	Monoclonal Antibody

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

Metastatic Breast Cancer in HER2- positive CTC with primary HER2-negative.

Tumore mammario metastatico con CTC HER2-positive e tumore primario al seno HER2-negativo.

E.1.1.1

Medical condition in easily understood language

Metastatic Breast Cancer

Tumore della Mammella 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	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 determine the overall Clinical Benefit (CB) of the two regimens (nab-paclitaxel plus trastuzumab (ARM A) versus nab-paclitaxel alone (ARM B)) among evaluable patients.

Determinare il beneficio clinico complessivo (CB) dei due regimi nab-paclitaxel più trastuzumab (braccio A) rispetto al nab-paclitaxel (braccio B) da solo tra i pazienti valutabili.

E.2.2

Secondary objectives of the trial

To determine the prognostic and predictive significance of HER2-positive CTC.
To evaluate additional measures of tumor control to further characterize the efficacy of the nab-paclitaxel plus trastuzumab vs. nab-paclitaxel.

Determinare il valore prognostico e predittivo dI CTC HER2-positive.
Valutare misure aggiuntive di controllo tumorale per caratterizzare ulteriormente l'efficacia del regime di combinazione vs. nab-paclitaxel.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Signed written informed consent.
2.Age ≥18 years.
3.ECOG 0-2
4.At least one clinically or radiologically measurable lesion and/or non-measurable disease evaluable according to Response Evaluation Criteria In Solid Tumors (RECIST version 1.1). Osteoblastic/osteolytic bone metastasis will be included.
5.HER2 negative on primary tumor (HER-2 score of 0 or 1+/2+ with FISH not amplified) as locally diagnosed.
6.Detection of at least 1 HER2+ve CTC.
7.Patients may have received chemotherapy/hormonotherapy as neo/adjuvant treatment.
8.Adequate bone marrow, renal and hepatic functions: ANC greater than 1.5x10^9/l, platelets greater than 100x10^9/l, serum creatinine < 1.5 x UNL, serum AST/ALT < 1.5 x UNL unless liver metastasis < 2.5 x UNL.
9.Adequate cardiac function: left ventricular ejection fraction (LVEF) at rest measured by echocardiography or MUGA scan must be no lower than the local normal limit.
10.Troponin level below the cut-off.
11.Absence of clinically significant cardiovascular disease (e.g. myocardial infarction, unstable angina), New York Hearth Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, or grade II or greater peripheral vascular disease within 12 months prior to day 1 on study.
12.Geographically accessible for follow-up.
13.Pregnancy test negative.
14.For women of childbearing potential who are sexually active, agreement to use a highly effective, non-hormonal form of contraception or two effective forms of non-hormonal contraception during and for at least 6 months post-study treatment.

1.Firma del consenso informato.
2.Età ≥ 18 anni.
3.ECOG 0-2.
4.Almeno una lesione clinicamente o radiologicamente misurabile e/o malattia non misurabile valutabile in accordo al Response Evaluation Criteria in Solid Tumor (RECIST versione 1.1). Le metastasi ossee osteoblastiche/osteolitiche saranno incluse.
5.Tumore primitivo HER2 negativo (HER-2 punteggio di 0 o 1 + / 2 + con FISH non amplificato) come da diagnosi locale.
6.Rilevamento di almeno 1 CTC HER2 positiva.
7.I pazienti possono essere stati sottoposti a chemioterapia /ormonoterapia come trattamento neo / adiuvante.
8.Adeguata funzionalità midollare, renale ed epatica:
ANC superiore a 1.5x10^9 /l, piastrine superiori a 100x10^9 / l, creatinina
sierica <1,5 x UNL, siero AST / ALT <1,5 x UNL, in presenza di metastasi
epatiche <2,5 x UNL.
9.Adeguata funzionalità cardiaca: la frazione di eiezione ventricolare sinistra (LVEF) misurata a riposo mediante ecocardiografia o scansione con MUGA non deve essere inferiore ail limiti di normalità.
10.Livello di troponina al di sotto del cut-off
11.Assenza di malattia cardiovascolare clinicamente significativa (per esempio infarto del miocardio, angina instabile), insufficienza cardiaca congestizia di grado II o superiore secondo New York Hearth Association (NYHA), gravi aritmie cardiache che richiedono trattamento, malattia vascolare periferica di grado II o maggiore nei 12 mesi precedenti l’entrata dello studio.
12.Accessibilità geografica per il follow-up.
13.Test di gravidanza negativo.
14.Per donne potenzialmente fertili, consenso ad utilizzare metodi di contraccezione non ormonali altamente efficaci o due forme efficaci di contraccettivi non ormonali durante e per almeno 6 mesi dopo il trattamento di studio.

E.4

Principal exclusion criteria

1.Previous chemotherapy or hormonotherapy for metastatic disease
2.Any psychiatric disorder that would impair the understanding and giving of informed consent.
3.Male patients
4.Non evaluable lesions as ascitic, pleural and pericardial effusions, carcinomatous lymphangitis of the lung, meningeal involvement.
5.Pregnant or lactating patients.
6.History of atrial ventricular arrhythmia, congestive heart failure or angina pectoris, even if medically controlled; uncontrolled hypertension; history of 2nd or 3rd degree heart blocks.
7.Any history of a second neoplasm except for curatively treated non melanoma skin cancer or carcinoma in situ of the cervix.
8.Concomitant treatment with other anticancer drugs.
9.Concomitant treatment with any other experimental drug.
10.Patients with not adequate haematological, hepatic and renal function.
11.Current known infection with HIV, HBV or HCV.
12.Any other serious illness or medical condition.

1.Precedente chemioterapia o ormonoterapia per la malattia metastatica.
2.Qualsiasi disturbo psichiatrico che comprometta la comprensione della terapia e del consenso informato
3.Pazienti di sesso maschile
4.Lesioni non valutabili come liquido ascitico, pleurico e pericardico, linfangite carcinomatosa del polmone, interessamento meningeo.
5.Pazienti in gravidanza o in allattamento.
6.Storia di aritmia atrio-ventricolare, insufficienza cardiaca congestizia
o angina pectoris, anche se clinicamente controllate; ipertensione non
controllata; anamnesi positiva per blocchi atrio-ventricolari di 2 ° o 3 °grado.
7.Qualsiasi storia di una seconda neoplasia ad eccezione del trattamento curativo del cancro della pelle non melanoma o carcinoma in situ della cervice.
8.Il trattamento concomitante con altri farmaci antitumorali.
9.Il trattamento concomitante con qualsiasi altro farmaco sperimentale.
10.I pazienti con non adeguata funzionalità ematologica, epatica e renale.
11.Infezione nota in corso per HIV, HBV e HCV.
12.Qualsiasi altra malattia grave o condizione medica.

E.5 End points

E.5.1

Primary end point(s)

The evaluation of the overall CB among evaluable patients.

Valutazione del beneficio clinico complessivo CB tra i pazienti eleggibili.

E.5.1.1

Timepoint(s) of evaluation of this end point

24 weeks after treatment initiation

24 settimane dopo l’inizio del trattamento

E.5.2

Secondary end point(s)

•To evaluate the early response based on CTCs variations as a predictor of patients’ outcome;
•To validate the prognostic significance of HER2+ve CTCs in patients with primary HER2-ve MBC;
•To obtain RNA from EpCAM+ve CTC isolated from MBC patients using the Veridex® Profile kit for pharmacodynamic evaluation (HER2-neu, PI3K, PTEN, pAKT, mTOR).
•To determine HER2 expression, proliferation index in fine needle aspirate (FNA) biopsies (optional).
•To evaluate the prognostic and predictive role of circulating HER2 and EGFR.
•To evaluate the Progression Free Survival.
•To evaluate the Overall Survival.
•To determine patient’s tolerability and safety of the treatment.
•To evaluate the Quality of Life.

•Valutare la risposta precoce sulla base delle variazioni CTC come un predittore di outcome dei pazienti;
•Convalidare il significato prognostico di CTC HER2 positive nel setting metastatico in pazienti con carcinoma mammario primitivo HER2 negativo;
•Ottenere RNA da CTC EpCAM positive isolate dai pazienti carcinoma mammario metastatico con il kit Profile-Veridex® per la valutazione farmacodinamica (HER2-neu, PI3K, PTEN, pAKT, mTOR).
•Determinare l'espressione di HER2, indice di proliferazione su aspirato eseguito con ago sottile (FNA) o biopsia (opzionale).
•Valutare il ruolo prognostico e predittivo di HER2 ed EGFR circolanti
•Valutare la PFS
•Valutare l’OS
•Determinare tollerabilità e sicurezza del trattamento
•Valutare la qualità della vita

E.5.2.1

Timepoint(s) of evaluation of this end point

24 months from the end of last treatment of LSI.

24 mesi dalla fine dell'ultimo trattamento del LSI (Last Subject In).

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

Yes

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

Yes

E.6.13.1

Other scope of the trial description

Quality of Life

Qualità della vita

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

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

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.8.2.4

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

2 years follw up after last subject last study treatment

2 anni di Follow Up dalla fine dell'ultimo trattamento dell'ultimo paziente

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

Yes

F.3.3.7.1

Details of other specific vulnerable populations

Women with breast cancer

Donne con cancro alla mammella

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)

Standard medical care for that condition. Each Centre will follow its own internal protocol.

Terapie per la patologia secondo la pratica clinica e le procedure interne del centro

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

2014-09-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-12-05

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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