Clinical Trials Register

Summary
EudraCT Number:	2011-001288-32
Sponsor's Protocol Code Number:	I3CPh1-FSM-01.11
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:	2012-03-05
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

2011-001288-32

A.3

Full title of the trial

A Pilot Study to Evaluate the Safety and Tolerability of the combination ot Trabectidin and Indole-3-Carbinol in refractory ER-positive metastatic breast cancer

Studio pilota per valutare la sicurezza e la tollerabilita' della combinazione Trabectidina e Indolo-3-Carbinolo nel tumore metastatico della mammella,refrattario ER-positivo

A.3.1

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

Preliminary Study to Evaluate the Safety and Tolerability of the combination ot Trabectidin and Indole-3-Carbinol in advanced breast cancer hormonal receptor positive who failed previous chemioterapy treatment

Studio iniziale per valutare la sicurezza e la tollerabilita' della combinazione Trabectidina e Indolo-3-Carbinolo nel tumore della mammella con recettori ormonali positivi in fase avanzata,gia' trattato senza beneficio con terapie precedenti

A.4.1

Sponsor's protocol code number

I3CPh1-FSM-01.11

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	FONDAZIONE SALVATORE MAUGERI - CLINICA DEL LAVORO E DELLA RIABILITAZIONE
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	Pharmamar
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fondazione Salvatore Maugeri, IRCCS
B.5.2	Functional name of contact point	Uo Oncologia Medica I
B.5.3	Address:
B.5.3.1	Street Address	via Salvatore Maugeri, 10
B.5.3.2	Town/ city	Pavia
B.5.3.3	Post code	27100
B.5.3.4	Country	Italy
B.5.4	Telephone number	0039-382-592676
B.5.5	Fax number	0039-382-592650
B.5.6	E-mail	alberto.zambelli@fsm.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	YONDELIS*EV 1FL POLV 1MG
D.2.1.1.2	Name of the Marketing Authorisation holder	PHARMA MAR S.A.
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	Concentrate for solution 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	TRABECTEDIN
D.3.9.1	CAS number	114899-77-3
D.3.10	Strength
D.3.10.1	Concentration unit	µg/m2 microgram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1300
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	Antineoplastico di natura chimica

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

Refractory ER-positive metastatic breast cancer

Carcinoma mammario metastatico e refrattario ER-positivo

E.1.1.1

Medical condition in easily understood language

Hormonal receptor positive advanced brast cancer brast cancer who failed previous treatment

Tumore mammario con recettori ormonali positivi in fase avanzata che non ha beneficiato di terapie precedenti

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	PT
E.1.2	Classification code	10055113
E.1.2	Term	Breast cancer metastatic
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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 safety and tolerability of I3C when administered orally to patients receiving T for refractory ER-positive metastatic breast cancers, focusing on the potential modulation of T-induced hepatotoxicity

Determinare la sicurezza e la tollerabilità di I3C quando somministrato per via orale a pazienti che ricevono T per un carcinoma mammario metastatico refrattario ER-positivo, concentrandosi sulla potenziale modulazione dell’epatotossicità indotta da T

E.2.2

Secondary objectives of the trial

To compare pharmacokinetic parameters of T when given in combination with I3C at different doses. To perform a preliminary assessment of the anti-tumour activity of T and I3C combination in ER-positive metastatic breast cancer.

Confrontare i parametri di farmacocinetica della T quando somministrata in associazione con I3C a diverse dosi
Eseguire una valutazione preliminare dell’attività anti-tumorale della combinazione T e I3C nelle pazienti con carcinoma mammario metastatico ER-positivo.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Signed, informed consent 2.Histologically or cytologically confirmed ER positive breast cancer refractory to standard therapy or for which no standard therapy exists 3.Recovered from all acute adverse effects of prior therapies (excluding alopecia and grade 1 neuropathy) 4.Adequate bone marrow, hepatic and renal function including the following a.Hb ≥ 9.0 g/dL, absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥100 x 109/L b.Total bilirubin ≤ 1.5 x upper normal limit, excluding cases where elevated bilirubin can be attributed to Gilberts Syndrome c.AST (SGOT), ALT (SGPT) ≤ 2.5 x upper normal limit (or 5x UNL in the presence of liver metastases) d.Creatinine ≤ 1.5 x upper normal limit 5.Age ≥ 18 years 6.Performance status (PS) ≤ 2 (ECOG scale) 7.Estimated life expectancy greater than 3 months 8.Female patients with reproductive potential must have a negative serum pregnancy test within 7 days prior to start of trial. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for 3 months after discontinuation of treatment. Acceptable methods of contraception include IUD, oral contraceptive, subdermal implant and double barrier (condom with a contraceptive sponge)

1.Consenso informato scritto firmato
2.Carcinoma mammario ER positivo confermato citologicamente o istologicamente, refrettario ad una terapia standard o per cui non esiste una terapia
3.Recupero da tutti gli eventi avversi clinicamente significativi correlati alle terapie pregresse (con l’esclusione di alopecia o neuropatia di I grado)
4.Valori degli esami di laboratorio eseguiti allo screening che rientrano nei seguenti parametri:
a.Hb ≥ 9.0 g/dL, conta assoluta dei neutrofili ≥ 1.5 x 109/L, conta delle piastrine ≥100 x 109/L
b.Bilirubina totale ≤ 1.5 x limite superiore di normalità (ULN), esclusi i casi in cui un incremento della bilirubina può essere attribuita alla Sindrome di Gilbert
c.AST (SGOT), ALT (SGPT) ≤ 2.5 x limite superiore di normalità (or 5x UNL in presenza di metastasi epatiche)
d.Creatinina ≤ 1.5 x limite superiore di normalità (ULN)
5.Età ≥ 18 anni
6.Performance status (PS) ≤ 2 (scala ECOG)
7.Aspettativa di vita superiore a 3 mesi
8.Pazienti di sesso femminile potenzialmente fertili devono avere un test di gravidanza sierico negativo effettuato entro i 7 giorni precedenti all’inizio dello studio. Sia gli uomini che le donne devono accettare di utilizzare un metodo di contraccezione affidabile durante il periodo di trattamento e per 3 mesi dopo la sua interruzione. Metodi accettabili di contraccezione sono rappresentati dallo IUD, dai contraccettivi orali, dall’impianto sottocutaneo e dalla doppia barriera (preservativo con una spugna contraccettiva)

E.4

Principal exclusion criteria

1.Anti-cancer therapy including chemotherapy, radiotherapy, endocrine therapy, immunotherapy or use of other investigational agents within the 4 weeks prior to trial entry (or a longer period depending on the defined characteristics of the agents used e.g. 6 weeks for mitomycin or nitrosourea, 3 months for antibodies). In patients with progressive disease, bisphosphonates for bone disease and corticosteroids are permitted provided the dose does not change during the trial 2.Patients with a prior allogeneic haematopoietic stem cell transplant 3.Co-existing active infection or serious concurrent illness 4.Patients with significant cardiovascular disease as defined by: a.LVEF below the normal range at the study centre b.Uncontrolled hypertension c.A history of QTc abnormalities or with a mean QTc interval >450 msec at screening 5.Any medical or other condition that in the Investigator’s opinion renders the patient unsuitable for this study due to unacceptable risk 6.Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies 7.Gastrointestinal disorders that may interfere with absorption of the study drug. 8.Patients with known brain tumours or metastases should be excluded from this clinical trial because of their poor prognosis 9.More than 6 prior chemotherapy regimens 10.Patients requiring palliative radiotherapy within the last 4 weeks prior to study entry 11.Uncontrolled hypercalcaemia (>CTCAE v3 grade I) 12.Pregnant or breast-feeding women

1.Terapia sistemica antineoplastica pregressa, comprendente chemioterapia, radioterapia, terapia endocrina, immunoterapia o altre terapie antineoplastiche in fase sperimentale entro 4 settimane precedenti l’ingresso nello studio (o un periodo più lungo dipendente dalle caratteristiche dei farmaci impiegati es. 6 settimane per la mitomicina e la nitrosurea, 3 mesi per gli anticorpi). Nei pazienti con progressione di malattia , i bifosfonati per le metastasi scheletriche e i corticosteroidi sono consentiti purché non si modifichi il dosaggio durante il periodo di studi
2.Pazienti sottoposti a precedente di trapianto allogenico di cellule staminali
3.Infezione attiva co-esistente o grave malattia concomitante
4.Pazienti con disturbi cardiovascolari significativi come definito da:
a.LVEF al di sotto del normale range proprio del Centro in cui si svolge lo studio
b.Ipertensione non controllata
c.Storia di anomalie del QTc o con un intervallo medio del QTc>450msec allo screening
5.Qualsiasi condizione medica o altre condizioni che secondo il parere dell’Investigatore rendono il paziente non idoneo a questo studio a causa di un inaccettabile rischio
6.Disturbi psichiatrici o alterazioni dello stato mentale che precludono la comprensione del consenso informato e/o il completamento degli esami
7.Patologia gastrointestinale che possa interferire con l’assorbimento del farmaco in studio.
8.Pazienti con tumore cerebrale o con metastasi note a tale livello dovrebbero essere esclusi da questo protocollo a causa della loro cattiva prognosi
9.Più di 6 precedenti regimi di chemioterapia
10.Pazienti che necessitano di radioterapia nelle ultime 4 settimane precedenti all’ingresso nello studio
11.Ipercalcemia non controllata (>CTCAE v3 grade I)
12.Donne in gravidanza o in allattamento

E.5 End points

E.5.1

Primary end point(s)

1. Hepatotoxicity through liver function control 2. Evaluation of hematologic and nonhematologic toxicities according to CTCAE version 3.0 criteria

1. Misura dell'epatotossicità attraverso controllo di funzionalità epatica 2. Valutazione delle altre tossicità ematologiche e non ematologiche secondo i criteri CTCAE versione 3.0

E.5.1.1

Timepoint(s) of evaluation of this end point

Every 28 days during treatment and every 3 months after treatment

Ogni 28 giorni durante la terapia e ogni 3 mesi al termine del trattamento

E.5.2

Secondary end point(s)

1. Measurement of T plasma concentration according to measures of pharmacokinetics during the first 2 cycles of treatment 2. Antitumor efficacy evaluation according to RECIST criteria after 3 and 6 cycles of treatment or whenever in the case of clinical progression

1. Misura della concentrazione plasmatica di T secondo misure di farmacocinetica durante i primi 2 cicli di trattamento 2. Valutazione efficacia antitumorale secondo i criteri RECIST dopo il 3 e 6 ciclo di trattamento ovvero ogni volta in caso di progressione clinica

E.5.2.1

Timepoint(s) of evaluation of this end point

1 T0 2 1 min before the end of the 3 hours infusion 3 0.5 h after the end of infusion 4 1 h after the end of infusion 5 2 h after the end of infusion 6 6 h after the end of infusion “ “ 7 10-12 h after the end of infusion 8 24 h after the end of infusion 9 48 h after the end of infusion 10 72 h after the end of infusion ______________________________________ Antitumor efficacy evaluation according to RECIST criteria after the 3rd and 6th course of treatment or whenever in case of clinical progression

1 T0, 2 1 min prima della fine della infusione di 3 ore, 3 0,5 h dopo la fine della infusione, 4 1 h dopo la fine dell'infusione, 5 2 ore dopo il termine dell'infusione, 6 6 ore dopo la fine dell'infusione "", 10-12 ore ore dopo il termine dell'infusione, 8 24 ore dopo il termine dell'infusione, 9 48 ore dopo la fine dell'infusione, 10 72 h dopo la fine dell'infusione
______________________________________
Valutazione efficacia antitumorale secondo i criteri RECIST DOPO il 3o e 6o ciclo di Trattamento ovvero ogni volta in caso di progressione clinica

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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

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

E.8.1.6

Cross over

Yes

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

- Stesso farmaco ad altro dosaggio

- same IMP used at different dosage

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.8.6 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

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

Number of subjects for this age range:

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)

According to the investigator advice the patients would recive standard treatment

A giudizio dell'investigatore i pazienti riceveranno i trattamenti convenzionali

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

2011-04-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-04-18

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

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