Clinical Trials Register

Summary
EudraCT Number:	2013-002684-25
Sponsor's Protocol Code Number:	SICOG13/01
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:	2013-10-30
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

2013-002684-25

A.3

Full title of the trial

Phase II study of liposomal doxorubicin in combination with trastuzumab
plus cyclophosphamide followed by docetaxel plus trastuzumab as primary systemic therapy for patients with locally advanced breast cancer with HER2 overexpression or amplification.

Studio di fase II con doxorubicina liposomiale più ciclofosfamide in
associazione a trastuzumab, seguita da docetaxel più trastuzumab, come
terapia sistemica primaria per pazienti con carcinoma mammario
localmente avanzato con iperespressione o amplificazione di HER2.

A.3.1

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

Phase II study evaluating the combination of liposomal doxorubicin plus
cyclophosphamide with trastuzumab followed by docetaxel plus
trastuzumab as therapy to be performed before surgery (neoadjuvant
chemotherapy) for patients with breast cancer more than 2 cm in size and possible involvement of the lymph nodes adjacent and with the receptor HER2 positive.

Studio di fase II che valuta l'associazione della doxorubicina liposomiale
più il ciclofosfamide con il trastuzumab, seguita da docetaxel più
trastuzumab, come terapia da eseguire prima dell'intervento chirurgico
(neoadiuvante) per pazienti con tumore della mammella di dimensioni oltre i 2 cm ed eventuale coinvolgimento dei linfonodi limitrofi e con il recettore HER2 positivo.

A.3.2

Name or abbreviated title of the trial where available

MYETT

A.4.1

Sponsor's protocol code number

SICOG13/01

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	S.I.C.O.G. ONLUS
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	S.I.C.O.G. ONLUS
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	S.I.C.O.G. ONLUS
B.5.2	Functional name of contact point	Data Management
B.5.3	Address:
B.5.3.1	Street Address	Strada Statale 554 Km 4,500
B.5.3.2	Town/ city	Monserrato
B.5.3.3	Post code	09042
B.5.3.4	Country	Italy
B.5.4	Telephone number	+3907051096614
B.5.5	Fax number	+3907051096614
B.5.6	E-mail	sicog.segreteriascientifica@gmail.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	MYOCET
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA
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 and solvent for dispersion for injection
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	DOXORUBICIN
D.3.9.1	CAS number	23214-92-8
D.3.9.4	EV Substance Code	SUB06391MIG
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	50
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.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.2.1.2	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	CYCLOPHOSPHAMIDE
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	CYCLOPHOSPHAMIDE
D.3.9.1	CAS number	6055-19-2
D.3.9.3	Other descriptive name	CYCLOPHOSPHAMIDE MONOHYDRATE
D.3.9.4	EV Substance Code	SUB16414MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000
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.IMP: 3
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	DOCETAXEL
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	DOCETAXEL
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DOCETAXEL
D.3.9.3	Other descriptive name	docetaxel
D.3.9.4	EV Substance Code	SUB12492MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	20 to 150
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.IMP: 4
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.2.1.2	Country which granted the Marketing Authorisation	European Union
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	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

Local advanced breast cancer resectable, neoadjuvant setting

Carcinoma mammario localmente avanzato operabile, in setting neoadiuvante

E.1.1.1

Medical condition in easily understood language

Cancer involving the breast than can be treated with chemotherapy before surgery

Tumori avanzati del seno che possono essere trattati con chemioterapia

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	LLT
E.1.2	Classification code	10072740
E.1.2	Term	Locally advanced 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

Patological Complete Response Rate, considered as a total absence of primary infiltrating tumour on breast and nodes

percentuali di risposta patologica completa sul tumore mammario primitivo e sui linfonodi

E.2.2

Secondary objectives of the trial

Clinical Response rate;
Radiological response rate;
Conservative surgery rate;
Evaluation of cardiac toxicity;

Tasso di risposte cliniche;
tasso di risposte radiologiche;
percentuale di interventi conservativi;
Valutazione della tossicità cardiaca.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

HER2-positive (immunohistochemistry (IHC 3 +) or amplification detected by fluorescence in situ hybridization [FISH +])
- Age >18
- Performance status ECOG 0-1
- Life expectancy> 3 months
- Neutrophils ≥ 1.5 x 10 9 / L and PLatelets ≥ 100 x 10 9 /L
- Total bilirubin ≤ 1.5 times upper normal limit (UNL) of the Centre
- ASAT (GOT) and / or ALT (GPT) ≤ 2.5 UNL
- Alkaline phosphatase ≤ 5 UNL (unless they are bones metastases in the absence of any liver disease. Patients with AST and / or ALT> 1.5 x UNL associated with alkaline phosphatase > 2.5 xUNL are not eligible in the study
- Creatinine within normal institutional limit
- Ventricular ejection fraction (LVEF) ≥ 55% (assessed by MUGA scan or ultrasound - only one method should be used for each patient)
-Written informed consent

 Carcinoma mammario HER2-positivo (immunoistochimica [IHC 3+] o ibridazione in situ mediante fluorescenza [FISH+]).
 Età >18
 Performance status ECOG 0-1.
 Neutrofili > 1.5 x 109/L e Piastrine >100 x 109/L
 Bilirubina totale 1,5 volte il limite superiore di normalità (UNL) del Centro and ASAT (GOT) e/o ALAT (GPT) </=2.5 UNL, fosfatasi alcalina </=5 UNL. Pazienti con ASAT e/o ALAT >1.5 x UNL associate con fosfatasi alcalina >2.5 x UNL non sono eleggibili nello studio.
 Creatinina </= 140 mol/L (1.6 mg/dL).
 Frazione di eiezione ventricolare (LVEF) >55% (valutata con MUGA scan o ecografia – soltanto una metodica deve essere impiegata per ciascun paziente).
 Consenso informato scritto

E.4

Principal exclusion criteria

- absence of Written informed consent
- Previous chemotherapy
- History of cancer in the previous 10 years (except skin cancer,non-melanoma,cervical carcinoma in situ excised)
- Other serious illnesses
- Congestive heart failure or angina pectoris even if controlled, previous history of myocardial infarction, uncontrolled hypertension, or arrhythmia.
- History of neurological or psychiatric disorders including dementia and epilepsy.
- Active Infection
- Treatment with other experimental drugs
- Geographical inaccessibility for treatment and follow-up
- Women who are pregnant or lactating

• Assenza di Consenso informato scritto
• Precedente chemioterapia.
• Storia di neoplasie nei precedenti 10 anni (eccetto tumori cutanei, non-melanoma, o carcinoma cervicale in situ escisso).
• Altre malattie gravi.
• Insufficienza cardiaca congestizia o angina pectoris anche se controllate. Precedente storia di infarto miocardico, ipertensione non controllata, o aritmia.
• Storia di disordini neurologici o psichiatrici inclusi demenza ed epilessia.
• Infezione in atto.
• Trattamento con altri farmaci sperimentali.
• Inaccessibilità geografica per il trattamento e follow up.
• Donne in gravidanza o in allattamento.

E.5 End points

E.5.1

Primary end point(s)

The sample size is calculated according to the two-stage (Minimax design) Simon method. Taking into account that the primary endpoint, the rate of pRC, is 40% for the optimal regimes (phase II studies unconfirmed) while the conventional schemes is 20%, with a difference p1-p0 = 20% between chemotherapy treatment "standard" (p0 = 20%) and "trial treatment" (p1 = 40%), and by fixing the probability of error α = 0.05 and β = 0.20, the number of patients to be enrolled is a total of 37 (increased of 10% for predictable dropouts).

La dimensione del campione è calcolata in base al metodo di Simon a due stadi (Minimax design). Tenendo conto che l’endpoint primario, il tasso di pRC, è del 40% per i regimi ottimali (studi di fase II non confermati) mentre per gli schemi convenzionali è del 20%, con una differenza p1-p0=20% tra un trattamento chemioterapico “standard” (p0=20%) e “il trattamento in studio” (p1=40%), e fissando la probabilità di errore (=0.05 e =0.20), il numero di pazienti da arruolare complessivamente è di 37 (aumentato del 10% per i prevedibili dropouts).

E.5.1.1

Timepoint(s) of evaluation of this end point

The study will be stopped if less than 3 responses will be observed in the first 19 patients, otherwise will continue to enroll until a total of 41 patients.

Lo studio sarà terminato qualora non venissero osservate 3 risposte nei primi 19 pazienti, altrimenti lo studio continuerà fino ad arruolare un totale di 41 pazienti.

E.5.2

Secondary end point(s)

No secondary end point has been fixed in this protocol

In questo protocollo non è stato previsto nessun endpoint secondario

E.5.2.1

Timepoint(s) of evaluation of this end point

No secondary end point has been fixed in this protocol

In questo protocollo non è stato previsto nessun endpoint secondario

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)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

Ultima visita 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

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)

None

Nessuno

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

2013-12-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-03-19

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

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