Clinical Trials Register

Summary
EudraCT Number:	2016-000871-26
Sponsor's Protocol Code Number:	ABC-Trial
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:	2021-06-08
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

2016-000871-26

A.3

Full title of the trial

Studio di Fase II, randomizzato, in aperto, controllato di fattibilit¿ dell¿impiego di doxiciclina nel tumore mammario in stadio precoce

A Phase II Open-Label Randomized Controlled Pre-Surgical Feasibility Study of Doxycycline in Early Breast Cancer

A.3.1

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

Uso della doxiciclina nel trattamento del tumore al seno in stadio precoce

Use of doxycycline for the treatment of the early-stage breast cancer

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

ABC-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 OSPEDALIERO-UNIVERSITARIA PISANA
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	Fondazione Pisana per la Scienza
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 OSPEDALIERO-UNIVERSITARIA PISANA
B.5.2	Functional name of contact point	U.O. Senologia
B.5.3	Address:
B.5.3.1	Street Address	via Roma, 57
B.5.3.2	Town/ city	Pisa
B.5.3.3	Post code	56126
B.5.3.4	Country	Italy
B.5.4	Telephone number	050992019
B.5.5	Fax number	050993146
B.5.6	E-mail	m.ghilli@ao-pisa.toscana.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	BASSADO - 100 MG COMPRESSE 10 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER ITALIA S.R.L.
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	BASSADO
D.3.2	Product code	NA
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DOXICICLINA ICLATO
D.3.9.1	CAS number	564-25-0
D.3.9.2	Current sponsor code	NA
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
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	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

Breast cancer - Stage 1-2 to or Stage 3 that is candidate for primary surgery

Carcinoma mammario - Stage 1-2 o Stage 3 candidato alla chirurgia

E.1.1.1

Medical condition in easily understood language

Early breast cancer

Carcinoma mammario in stadio precoce

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10006213
E.1.2	Term	Breast carcinoma stage I
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10006215
E.1.2	Term	Breast carcinoma stage III
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10006214
E.1.2	Term	Breast carcinoma stage II
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 whether short-term (2 weeks) pre-operative treatment with oral doxycycline of stage I-to-III early breast cancer patients results in inhibition of tumor proliferation markers, as determined by a reduction in tumor Ki67 from baseline (pre-treatment) to post-treatment (at time of surgical excision)

Valutare se la somministrazione di dossiciclina per via orale per 2 settimane prima dell¿intervento chirurgico per carcinoma mammario stadio 1-3 sia in grado di ridurre i marcatori di proliferazione cellulare, come determinato dalla riduzione del marcatore ki67 dal momento della biopsia diagnostica all¿exeresi chirurgica (prima e dopo il trattamento con dossiciclina).

E.2.2

Secondary objectives of the trial

In tumour tissue collected at the time of diagnosis (biopsy) and at the surgical excision of the neoplasm, before and after doxycycline administration, the following objectives will be pursued:
o Evaluation of markers of cell proliferation, apoptosis, p27, angiogenesis (CD31), stem cells (markers ALDH, CD44/24), mitochondria (TOMM20).
o In primary tumour culture, the formation of mammosphere will be evaluated, along with their molecular status and response to doxycycline.
Moreover, the following secondary objectives will be taken into account:
¿ Doxycycline pharmacokinetics
¿ Treatment safety

Nel tessuto tumorale raccolto alla biopsia diagnostica e all¿exeresi chirurgia, rispettivamente prima e dopo trattamento con dossiciclina saranno perseguiti i seguenti obiettivi:
o Valutazione dei markers di proliferazione cellulare, di apoptosi, di p27, dell¿angiogenesi (marker CD31), delle cellule staminali (markers ALDH, CD44/24), del marker mitocondriale TOMM20
o Nelle colture primarie tumorali, sar¿ valutata la formazione di mammosfere, il loro status molecolare e la risposta a dossiciclina.
Inoltre, saranno considerati i seguenti obiettivi secondari:
¿ Studio farmacocinetico di dossiciclina
¿ Sicurezza del trattamento

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Provision of written informed consent.
2. World Health Organization (WHO) performance status 0-1 with no deterioration over the previous 2 weeks
3. Patients must be able to swallow and retain oral medication
4. Female patients, age over 18, with histological confirmation of invasive breast carcinoma
5. AJCC Stage 1-2 or Stage 3 that is candidate for primary surgery
6. Scheduled to have definitive breast surgery two or more weeks after study entry
7. Renal and liver biochemistry within 10% of laboratory normal limits
8. Presence of diagnostic biopsy

1. Consenso informato scritto.
2. Performance status 0-1 World Health Organization (WHO) senza aggravamenti nelle due settimane precedenti.
3. Le pazienti devono essere in grado di deglutire la preparazione farmaceutica
4. Pazienti di sesso femminile, di età uguale o superiore a 18 anni, con diagnosi istologica di carcinoma mammario invasivo
5. Stadi 1-2 o 3 AJCC cadidate alla chirurgia primaria.
6. In programma per una chirurgia mammaria definitiva 2-3 settimane prima dell’entrata nello studio.
7. Parametri biochimici di funzionalità renale ed epatica entro il 10% dei limiti di normalità.
8. Disponibilità di una biopsia diagnostica

E.4

Principal exclusion criteria

1. Subjects cannot be homeless persons
2. Subjects cannot have active drug/alcohol dependence or abuse history
3. Subject cannot have prior treatment for breast or other cancer (excluding non-melanoma skin cancer)
4. Subject cannot have major surgery or antibiotic therapy within 4 weeks before the first dose of study treatment
5. Subject cannot have known allergy to antibiotics
6. As judged by the Investigator, no evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
7. No other concomitant neoadjuvant breast cancer therapy (for example Tamoxifen, aromatase inhibitors, chemotherapy or Trastuzumab)
8. Less than 2 weeks from the time the subject signs the informed consent and the day of the curative surgery for invasive breast cancer.
9. Pregnancy and breast feeding are absolute contraindications.
10. Known intolerance/allergy to the drug or excipients will be an additional exclusion criterium.
11. Concomitant treatment with drugs known to interact with doxycycline (i.e., antacids, penicillins, oral antocoagulants, antiepileptics, oral contraceptives, cyclosporine, and others listed in the technical note of doxycycline) will be an exclusion criterium.
12. Obstructive disorders of the oesophagus.
13. Inability to give the informed consent.

1. Le pazienti devono avere un domicilio
2. Nessuna dipendenza o stria di abuso di alcool o di sostanze stupefacenti
3. Nessun precedente trattamento per carcinoma mammario o altra neoplasia (ad eccezione di tumori cutanei non melanotici)
4. Nessuna chirurgia maggiore o antibioticoterapia nelle 4 settimane precedenti l’ingresso nello studio.
5. Nessuna allergia nota a chemioterapici antibatterici
6. Su giudizio dell’investigatore, nessuna evidenza di malattie sistemiche gravi o senza controllo, inclusa ipertensione non controllata, diatesi emorragica (anche attiva), infezioni in atto incluse epatiti da virus epatitici B e C, infezioni da HIV. Lo screening per condizioni croniche non è richiesto.
7. Nessun altro trattamento neoadiuvante per il carcinoma mammario (per esempio tamoxifene, inibitori dell’aromatasi, chemioterapia o Trastuzumab)
8. Meno di due settimane tra la firma del consenso informato ed il giorno della chirurgia curativa per il tumore mammario.
9. Gravidanza o allattamento soo controindicazioni assolute.
10. Anamnesi positiva per intolleranza/allergia al principio attivo o agli eccipienti è da considerare un criterio di esclusione.
11. Trattamenti concomitanti con farmaci noti per interagire con le tetracicline (esempio, antiacidi, penicillinem anticoagulanti orali, antiepilettici, contraccettivi orali, ciclosporina, ed altri inseriti nella nota tecnica di dossiciclina).
12. Disordini ostruttivi dell’esofago.
13. Incapacità a fornire il consenso informato.

E.5 End points

E.5.1

Primary end point(s)

Ki67 evaluation

Valutazione di ki67

E.5.1.1

Timepoint(s) of evaluation of this end point

Before (diagnostic biopsy) and after doxycycline administration (surgically-excissed tumour tissue)

Prima (biopsia diagnostica) e dopo trattamento con dossiciclina (tessuto tumorale asportato)

E.5.2

Secondary end point(s)

Evaluation of markers predictive of:
- apoptosis;
- cell cycle inhibition (p27)
- angiogenesis (CD31)
- stem cells (ALDH, CD44/24)
- mitochondria (TOMM20)
-mammosphere formation from primary culture of patients¿ neoplastic tissues
- molecular status (genetic profile) and effects of doxycycline
- tissue and plasma concentrations of doxycycline
- safety

Valutazione di markers di:
- apoptosi;
- inibizione del ciclo cellulare (p27)
- angiogenesi (CD31)
- di cellule staminali (ALDH, CD44/24)
- mitocondriale (TOMM20)
- formazione di mammosfere da colture primarie di tessuto neoplastico dei pazienti
- status molecolare (profilo genetico) e risposta a dossiciclina
- livelli tissutali e plasmatici di dossiciclina
- safety

E.5.2.1

Timepoint(s) of evaluation of this end point

Before (diagnostic biopsy) and after doxycycline administration (surgically-excissed tumour tissue)

Prima (biopsia diagnostica) e dopo trattamento con dossiciclina (tessuto tumorale asportato)

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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

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

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

Terapia standard

Standard of care

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.5.1

Number of sites anticipated in the EEA

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

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

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

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:

100

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

130

F.4.2

For a multinational trial

F.4.2.1

In the EEA

130

F.4.2.2

In the whole clinical trial

130

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)

Patients will continue with standard of care

Le pazienti preseguiranno con i programmi assistenziali previsti dalla routine clinica

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

2016-06-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-03-22

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

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