Clinical Trials Register

Summary
EudraCT Number:	2018-001075-20
Sponsor's Protocol Code Number:	IOV-2018-STS-METROPHOLYS
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:	2020-11-04
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

2018-001075-20

A.3

Full title of the trial

The METROPHOLYS Study - Metronomic cyclophosphamide vs doxorubicin in elderly patients with advanced soft tissue sarcomas.
Randomized, controlled open label clinical trial

A.3.1

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

Study with the aim to compare a chemotherapy based on low doses of oral cyclophosphamide administered daily vs standard doxorubicin in elderly patients with advanced soft tissue sarcomas.

Studio di confronto tra un trattamento costituito da ciclofosfamide somministrata per os giornalmente a piccole dosi verso il trattamento standard a base di doxorubicina in pazienti anziani affetti da sarcomi dei tessuti molli in fase avanzata.

A.3.2

Name or abbreviated title of the trial where available

The METROPHOLYS Study

Studio METROPHOLYS

A.4.1

Sponsor's protocol code number

IOV-2018-STS-METROPHOLYS

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	ISTITUTO ONCOLOGICO VENETO - IRCCS
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	Ministero della Salute
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	Istituto Oncologico Veneto
B.5.2	Functional name of contact point	Unità di ricerca Clinica - Istituto
B.5.3	Address:
B.5.3.1	Street Address	Via Gattamelata, 64
B.5.3.2	Town/ city	Padova
B.5.3.3	Post code	35128
B.5.3.4	Country	Italy
B.5.4	Telephone number	0498215704
B.5.5	Fax number	0498215706
B.5.6	E-mail	clinical.trial@iov.veneto.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	ENDOXAN BAXTER - 50 MG COMPRESSE RIVESTITE 50 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	BAXTER S.P.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.3.1	Product name	Ciclofosfamidde
D.3.2	Product code	[Ciclofosfamide]
D.3.4	Pharmaceutical form	Coated 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.3.9.1	CAS number	50-18-0
D.3.9.2	Current sponsor code	Ciclofosfanide
D.3.9.3	Other descriptive name	Cyclophosphamide
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
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	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	Yes
D.3.11.13.1	Other medicinal product type	di natura chimica
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Doxorubicina Aurobindo
D.2.1.1.2	Name of the Marketing Authorisation holder	Aurobindo Pharma (Italia) Srl
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	Doxorubicina
D.3.2	Product code	[Doxorubicina]
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	doxorubicina
D.3.9.1	CAS number	23214-92-8
D.3.9.2	Current sponsor code	doxorubicina
D.3.9.3	Other descriptive name	doxorubicin
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
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

soft tissue sarcomas

sarcomi dei tessuti molli

E.1.1.1

Medical condition in easily understood language

A rare type of cancer that developes in connective tissue.

Forma di cancro rara che si sviluppa nel tessuto connettivo

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	PT
E.1.2	Classification code	10075333
E.1.2	Term	Soft tissue sarcoma
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

to compare the efficacy, as measured by time to treatment failure, of metronomic cyclophosphamide compared to doxorubicin in elderly patients affected by mSTS.

Confrontare l’efficacia, misurata come tempo di fallimento del trattamento, di ciclofosfamide metronomica verso doxorubicina in pazienti anziani affetti da mSTS.

E.2.2

Secondary objectives of the trial

Efficacy, Toxicity profile and to explore other possible predictive or prognostic factors and their interaction with treatment arms.

Efficacia, profilo di tossicità e identificazione di fattori predittivi o prognostici e la loro interazione con i bracci di trattamento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients may be included in the study only if they meet all the following criteria:
1- Histologically proven diagnosis of soft tissue sarcoma.
2- Advanced unresectable or metastatic soft tissue sarcoma not previously treated with chemotherapy for metastatic disease.
3- At least one measurable lesion according to RECIST1.1 criteria.
4- Availability of a tumor sample
5- Age = 70 years
6- ECOG PS 0-2.
7- Life expectancy of at least 12 weeks.
8- Neutrophils =1.5 x 109/L, Platelets =100 x 109/L, Hgb = 9 g/dl.
9- Normal hepatic, renal anf cardiac function.
10- Male subjects with female partners of childbearing potential must be willing to use adequate contraception.
11- Geriatric assessment by means of G8 screening tool and CRASH score.
12- Written informed consent.

I pazienti possono essere inclusi nello studio solo se presentano i seguenti criteri:
1- Diagnosi dimostrata istologicamente di sarcoma dei tessuti molli.
2- Sarcoma dei tessuti molli metastatico o avanzato non resecabile non precedentemente trattato con chemioterapia per malattia metastatica.
3- Almeno una lesione misurabile in accordo con i criteri RECIST1.1.
4- Disponibilità di un campione tumorale
5- Età = 70 anni
6- ECOG PS 0-2.
7- Aspettativa di vita di almeno 12 settimane.
8- Neutrofili =1.5 x 109/L, Piastrine =100 x 109/L, Hgb = 9 g/dl.
9- Funzionalità epatica, renale e cardiaca nella
norma,
10- Soggetti maschi con partner donne in età fertile,
disposti ad utilizzare un'adeguata contraccezione
11- Valutazione geriatrica mediante strumento di
screening G8 e punteggio CRASH.
12- Firma del Consenso informato.

E.4

Principal exclusion criteria

Patients will be excluded from the study for any of the following reasons:
1- Previous treatment for metastatic disease.
2- Previous (neo) adjuvant chemotherapy with anthracyclines.
3- Radiotherapy to any site within 4 weeks before the study.
4- Untreated brain metastases or spinal cord compression or primary brain tumors.
5- Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration.
6- Clinically significant cardiovascular disease
7- Treatment with any investigational drug within 30 days prior to enrollment or 2 investigational agent half-lives (whichever is longer)
8- Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ.
9- Lack of physical integrity of the upper gastrointestinal tract, .
10- Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs.
11- Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies.
12- Sexually active males unwilling to practice contraception

I pazienti saranno esclusi dallo studio per qualunque delle seguenti ragioni:
1- Precedenti trattamenti per malattia metastatica.
2- Precedente chemioterapia (neo) adiuvante con antracicline.
3- Radioterapia a qualsiasi sito entro 4 settimane prima dello studio.
4- Metastasi cerebrali non trattate o compressione del midollo spinale o tumore primitivo cerebrale.
5- Infezioni attive non controllate o altra malattia concomitante clinicamente rilevante per cui risulta controindicata la somministrazione chemioterapia.
6- Malattia cardiovascolare clinicamente importante.
7- Trattamento con qualunque farmaco sperimentale entro 30 giorni prima dell’arruolamento o che sia trascorso il tempo corrispondente a 2 emi-vite dell’ultimo trattamento sperimentale (a seconda di quale è più lungo)
8- Altre neoplasie coesistenti o neoplasie diagnosticate negli ultimi 5 anni con l'eccezione del carcinoma localizzato a cellule squamose e basale o del carcinoma cervicale in situ.
9- Mancanza di integrità fisica del tratto gastrointestinale superiore,
10- Ipersensibilità nota ai farmaci sperimentali o ad un eccipiente.
11- Necessità di assumere qualsiasi farmaco concomitante, controindicato in associazione ai farmaci sperimentali, in base alle relative schede tecniche.
12- Maschi sessualmente attivi che non accettano di utilizzare metodi contraccettivi validi

E.5 End points

E.5.1

Primary end point(s)

time to treatment failure

tempo di fallimento del trattamento

E.5.1.1

Timepoint(s) of evaluation of this end point

every 8 weeks and at progression disease

ogni 8 settimane ed alla progressione di malattia

E.5.2

Secondary end point(s)

Progression free survival (PFS)
• Overall survival time (OS);
• Objective response rate (ORR);
; Toxicity profile; Traslarional research

Sopravvivenza libera da progressione (PFS)
• Tempo di sopravvivenza globale (OS);
• Tasso di risposta totale (ORR);
; Profilo di tossicità; Ricerca traslazionale

E.5.2.1

Timepoint(s) of evaluation of this end point

every 8 weeks and at PD ; Time from the signing of the IC to 30 days after the end of the treatment, and at PD; At the screening

ogni 8 settimane e alla PD ; Tempo che intercorre tra la firma del consenso informato e la fine del trattamento, ed alla PD; Allo screening

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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)

Yes

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

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)

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

132

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

132

F.4.2

For a multinational trial

F.4.2.1

In the EEA

132

F.4.2.2

In the whole clinical trial

132

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 of care

secondo pratica 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

2018-05-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-04-16

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

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