Clinical Trials Register

Summary
EudraCT Number:	2014-004796-23
Sponsor's Protocol Code Number:	REP0114
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:	2015-04-29
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

2014-004796-23

A.3

Full title of the trial

A randomized, double-blind, placebo-controlled phase 2 study of paclitaxel in combination with reparixin compared to paclitaxel alone as front-line therapy for Metastatic Triple-Negative Breast Cancer (FRIDA)

Studio randomizzato, in doppio cieco, controllato con placebo, di fase 2 di confronto tra paclitaxel in associazione con reparixin e paclitaxel da solo come terapia di prima linea per il cancro della mammella metastatico triplo negativo (FRIDA)

A.3.1

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

Study of Reparixin combined with paclitacel compared to paclitaxel alone in patients with metastatic Triple-negative breast cancer

Studio di confronto tra paclitaxel in associazione con reparixin e paclitaxel da solo in pazienti affette da cancro della mammella metastatico triplo negativo

A.4.1

Sponsor's protocol code number

REP0114

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	Dompé Farmaceutici s.p.a.
B.1.3.4	Country	Italy
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	Dompé Farmaceutici s.p.a.
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	Dompé Farmaceutici s.p.a.
B.5.2	Functional name of contact point	clinical trial information REP0114
B.5.3	Address:
B.5.3.1	Street Address	Via Santa Lucia, 6
B.5.3.2	Town/ city	Milan
B.5.3.3	Post code	20122
B.5.3.4	Country	Italy
B.5.4	Telephone number	3902 58383.606
B.5.6	E-mail	cti.rep0114@dompe.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	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	Reparixin
D.3.2	Product code	Reparixin
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	Reparixin
D.3.9.1	CAS number	266359-83-5
D.3.9.2	Current sponsor code	DF 1681Y
D.3.9.3	Other descriptive name	REPARIXIN
D.3.9.4	EV Substance Code	SUB130481
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	600
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Metastatic triple negative Breast Cancer

Cancro della mammella metastatico triplo negativo

E.1.1.1

Medical condition in easily understood language

Metastatic triple negative Breast Cancer

Cancro della mammella metastatico triplo 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	18.0
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

Progression Free Survival (PFS)

Sopravvivenza libera da progressione (PFS, Progression Free Survival)

E.2.2

Secondary objectives of the trial

To determine the median PFS (mPFS)
To determine Overall Survival (OS).
To evaluate Objective Response Rates (ORR)
To assess the safety of the combination of paclitaxel and orally administered reparixin.

Determinare la PFS mediana (mPFS)
Determinare la sopravvivenza globale (OS, Overall Survival)
Valutare i tassi di risposta obiettiva (ORR, Objective Response Rates)
Valutare la sicurezza tra paclitaxel in associazione con reparixin amministrata per via orale

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

evaluation of CD24-CD44+CSC, ALDH+CSC.

Valutazione di CD24-CD44+CSC, ALDH+CSC.

E.3

Principal inclusion criteria

1.Female aged > 18 years.
2.Patients with pathologically documented metastatic triple negative breast cancer (TNBC), eligible for treatment with paclitaxel. Paraffin-embedded tissue must be available from metastatic sites, if reasonably accessible, or from the primary tumor, to confirm the diagnosis of TNBC and for correlative studies (only on metastatic tissue). Fifteen slides can be obtained if the full block is not available to be sent or released.
TNBC will be defined as breast cancer with <1% ER+ and <1% PgR+ cells, and HER2 immunohistochemistry score of 0 or 1+ and/or in situ hybridization (ISH) with HER2 gene copy number <4 or a ratio of less than 2 between HER2 gene copy number and centromere of chromosome 17. Patients whose metastatic disease is TNBC are eligible even when their primary tumor expressed hormone receptors and/or HER2.
3.Patients must have relapsed following a prior (neo)adjuvant chemotherapy regimen. If a taxane (i.e., paclitaxel or docetaxel) was administered as part of the (neo)adjuvant regimen, PD must have occurred > 12 months from the end of previous (neo)adjuvant treatment. For non-taxane (neo)adjuvant regimen, PD must have occurred > 6 months from the end of previous (neo)adjuvant treatment
4.Patients with at least one baseline measurable lesion according to RECIST criteria version 1.1.
5.Zubrod (Eastern Co-operative Oncology Group [ECOG]) Performance Status (PS) of 0 1.
6.Life expectancy of at least three months.
7.Patients must be able to swallow and retain oral medication (intact tablet).
8.Able to undergo all screening assessments outlined in the protocol.
9.Adequate organ function (defined by the following parameters):
a)Serum creatinine < 140 µmol/L (< 1.6 mg/dL) or creatinine clearance > 60 mL/min.
b)Serum hemoglobin ≥ 9 g/dL; absolute neutrophil count ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L.
c)Serum bilirubin ≤ 1.5 x upper normal limit (UNL) except patients with Gilbert’s syndrome
d)Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 x UNL but ≤ 5.0 x UNL in case of liver metastases; alkaline phosphatase (ALP) ≤ UNL but ≤ 2.5 x ULN in case of liver metastases; albumin within normal limits.
10.No history or evidence by CT scan or MRI, of brain metastases or leptomeningeal disease.
11.No known hepatitis B virus (not due to immunization), hepatitis C virus, human immunodeficiency virus I and II positive status.
12.Dated and signed IEC/IRB-approved informed consent.

1. Donne di almeno 18 anni di età.
2. Pazienti con cancro della mammella triplo negativo (TNBC) metastatico con documentazione anatomopatologica, idonee al trattamento con paclitaxel. Deve essere disponibile del tessuto incluso in paraffina ottenuto dalle sedi metastatiche, se ragionevolmente accessibili, o dal tumore primitivo, per confermare la diagnosi di TNBC e per gli studi di correlazione (solo sul tessuto metastatico). Se il blocchetto completo non è disponibile per l'invio o il rilascio, si possono ottenere quindici sezioni.
Si definirà il TNBC come un cancro della mammella con < 1% di cellule ER+ e < 1% di cellule PgR+ e con un punteggio immunoistochimico per HER2 di 0 o 1+ e/o un'ibridazione in situ (ISH, in situ hybridization) con un numero di copie del gene HER2 < 4 o con un rapporto tra il numero di copie del gene HER2 e il centromero del cromosoma 17 inferiore a 2. Le pazienti con malattia metastatica TNBC sono idonee anche nel caso in cui il tumore primitivo avesse espresso i recettori ormonali e/o HER2.
3. Le pazienti devono essere recidivate dopo un precedente regime chemioterapico (neo)adiuvante. Se il regime (neo)adiuvante aveva comportato la somministrazione di un taxano (paclitaxel o docetaxel), la PM deve essere avvenuta > 12 mesi dalla fine del precedente trattamento (neo)adiuvante. Nel caso di un regime (neo)adiuvante non a base di taxani, la PM deve essere avvenuta > 6 mesi dalla fine del precedente trattamento (neo)adiuvante.
4. Pazienti con almeno una lesione misurabile all'ingresso sulla base dei criteri RECIST, versione 1.1.
5. Performance status (PS) Zubrod (Eastern Cooperative Oncology Group [ECOG]) di 0-1.
6. Aspettativa di vita di almeno tre mesi.
7. Le pazienti devono essere in grado di ingerire e trattenere il farmaco per via orale (compressa integra).
8. In grado di sottoporsi a tutte le valutazioni di screening indicate nel protocollo.
9. Funzionalità adeguata degli organi (definita dai seguenti parametri):
a) Creatinina sierica < 140 μmol/l (< 1,6 mg/dl) o clearance della creatinina > 60 ml/min.
b) Emoglobina sierica ≥ 9 g/dl; conta assoluta dei neutrofili ≥ 1,5 x 109/l; piastrine ≥ 100 x 109/l.
c) Bilirubina sierica ≤ 1,5 volte il limite superiore della norma (LSN), con l'eccezione delle pazienti con sindrome di Gilbert.
d) Alanina amminotrasferasi (ALT) sierica e aspartato amminotransferasi (AST) sierica ≤ 2,5 volte il LSN ma ≤ 5,0 volte il LSN in caso di metastasi del fegato; fosfatasi alcalina (FA) ≤ al LSN ma ≤ 2,5 volte il LSN in caso di metastasi del fegato; albumina nei limiti della norma.
10. Anamnesi negativa o assenza di segni di metastasi cerebrali o malattia leptomeningea alla scansione TC o alla RM.
11. Assenza di positività nota per il virus dell'epatite B (se non per immunizzazione), il virus dell'epatite C o il virus dell'immunodeficienza umana (HIV) I e II.
12. Consenso informato approvato dal CEI/IRB datato e firmato.

E.4

Principal exclusion criteria

1.Newly diagnosed metastatic TNBC and TNBC not previously treated with (neo)adjuvant chemotherapy
2.Prior therapy for metastatic TNBC (chemotherapy, hormone therapy or biological therapy), Patients may receive bisphosphonates and other therapies to treat bone metastases, however if used, bone lesions will not be considered as measurable disease.
3.Less than four weeks since last radiotherapy (excluding palliative radiotherapy).
4.Pregnancy or lactation or unwillingness to use adequate method of birth control.
5.Neurological or psychiatric disorders which may influence understanding of study and informed consent procedures.
6.Active or uncontrolled infection.
7.Malabsorption syndrome, disease significantly affecting gastrointestinal function.
8.G>1 pre-existing peripheral neuropathy
9.Any other invasive malignancy from which the patient has been disease-free for less than 5 years with the exception of curatively treated basal or squamous cell skin cancer
10.Hypersensitivity to:
a)paclitaxel
b)ibuprofen or to more than one non-steroidal anti-inflammatory drug.
c)more than one medication belonging to the class of sulfonamides, such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib; hypersensitivity to sulphanilamide antibiotics alone (e.g.sulfamethoxazole) does not qualify for exclusion.

1.TNBC metastatico di nuova diagnosi e TNBC non trattato in precedenza con chemioterapia (neo)adiuvante.
2. Precedente terapia per il TNBC metastatico (chemioterapia, ormonoterapia o terapia biologica), Le pazienti possono assumere bifosfonati e altre terapie per il trattamento delle metastasi ossee, tuttavia in tal caso le lesioni ossee non saranno considerate come malattia misurabile.
3. Meno di quattro settimane dall'ultima radioterapia (fatta eccezione per la radioterapia palliativa).
4. Gravidanza o allattamento o non disponibilità all'impiego di un metodo contraccettivo adeguato.
5. Disturbi neurologici o psichiatrici che potrebbero influire sulla comprensione delle procedure dello studio e del consenso informato.
6. Infezione in atto o non controllata.
7. Sindrome da malassorbimento, malattia che incida in modo significativo sulla funzione gastrointestinale.
8. Neuropatia periferica preesistente di grado > 1.
9. Altra neoplasia invasiva per la quale la paziente sia stata dichiarata libera dalla malattia da meno di 5 anni, fatta eccezione per i tumori cutanei a cellule basali e squamosi trattati in modo radicale.
10. Ipersensibilità a:
a) paclitaxel
b) ibuprofene o più di un farmaco antinfiammatorio non steroideo.
c) più di un farmaco appartenente alla classe dei sulfamidici, come sulfametazina, sulfametossazolo, sulfasalazina, nimesulide o celecoxib; l’ipersensibilità ai soli antibiotici sulfamidici (ad es. sulfametossazolo) non qualifica per l'esclusione.

E.5 End points

E.5.1

Primary end point(s)

Progression Free Survival (PFS) defined as the interval (days) between randomization and the date of progression or death from any cause, whichever occurs first, as assessed by Independent Radiology Review)

Sopravvivenza libera da progressione (PFS), definita come l'intervallo (giorni) tra la randomizzazione e la data di progressione o morte per qualsiasi causa, a seconda di quale si verifica prima, come valutato dall’Independent Radiology Review

E.5.1.1

Timepoint(s) of evaluation of this end point

disease progression or death from any cause, whichever occurs first

Progressione della malattia o morte per qualsiasi causa, a seconda di quale evento si verifica per primo

E.5.2

Secondary end point(s)

1)median PFS (mPFS)defined as the number of days between the date of randomization and the date of clinical disease progression (PD) according to RECIST criteria version 1.1, or death for any cause, whichever occurs first
2)overall Survival defined as the interval (days) between randomization and death from any cause.
3)objective response rates (ORR) defined as the percentage of the patients reaching complete remission (CR), partial remission (PR) or stable disease (SD) according to RECIST criteria version 1.1.
• CR rate
• PR rate
• SD rate
• PD rate
4) safety of the combination treatment

1) PFS mediana (mPFS) definita come il numero di giorni tra la data di randomizzazione e la data di progressione della malattia clinica (PD) secondo criteri RECIST versione 1.1, o morte per qualsiasi causa, a seconda di quale evento si verifica per primo
2) sopravvivenza globale definita come l'intervallo (giorni) tra la randomizzazione e morte per qualsiasi causa.
3) percentuale di risposta obiettiva (ORR) definita come la percentuale di pazienti che hanno raggiunto remissione completa (CR), remissione parziale (PR) o malattia stabile (SD) secondo i criteri RECIST versione 1.1.
• tasso di CR
• tasso di PR
• tasso di SD
• tasso di PD

E.5.2.1

Timepoint(s) of evaluation of this end point

1) at disease progression or death
2) death
3) every eight weeks until disease progresion or death wichever occurs first
4) throughout the study

1) progressione della malattia o morte
2) morte
3) ogni otto settimane fino alla progressione della malattia o alla morte a seconda di quale evento si verifica per primo
4) durante lo studio

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

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

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

Yes

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Belgium

Czech Republic

France

Italy

Poland

Spain

United States

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

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

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:

127

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.4.2

For a multinational trial

F.4.2.1

In the EEA

126

F.4.2.2

In the whole clinical trial

190

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)

After the End of treatment the patients will return to their normal SOC medication.

Dopo la fine del trattamento le pazienti torneranno alla loro normale cura standard

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

2015-10-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-05-11

P. End of Trial
P.	End of Trial Status	Completed

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