Clinical Trials Register

Summary
EudraCT Number:	2013-001467-23
Sponsor's Protocol Code Number:	2013-001467-23
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:	2013-06-06
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

2013-001467-23

A.3

Full title of the trial

SAFETY AND ACTIVITY OF TRABECTEDIN AS FIRST LINE IN ADVANCED SOFT TISSUE SARCOMA (STS) PATIENTS UNFIT TO RECEIVE STANDARD CHEMOTHERAPY: A PROSPECTIVE PHASE II STUDY WITH CLINICAL AND MOLECULAR CORRELATES
(TR1US)

Sicurezza e attività della trabectedina, come prima linea di trattamento nei pazienti affetti da sarcoma dei tessuti molli (STS) con malattia avanzata/non operabile non idonei a ricevere la chemioterapia standard con antraciclina e/o ifosfamide: studio prospettico di fase II con correlati clinici e molecolari

A.3.1

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

Safety and Efficacy evaluation in soft tissue sarcoma unfit to received standard chemotherapy

Valutazione dell’efficacia e della sicurezza in pazienti con sarcoma dei tessuti molli, non idonei a ricevere chemioterapia standard

A.3.2

Name or abbreviated title of the trial where available

ISG_TR1US

A.4.1

Sponsor's protocol code number

2013-001467-23

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	Italian Sarcoma Group
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	Italian Sarcoma Group
B.5.2	Functional name of contact point	Piero Picci
B.5.3	Address:
B.5.3.1	Street Address	Via di Barbiano 1/10
B.5.3.2	Town/ city	Bologna
B.5.3.3	Post code	40136
B.5.3.4	Country	Italy
B.5.6	E-mail	clinicaltrials@italiansarcomagroup.org

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
D.2.1.1.2	Name of the Marketing Authorisation holder	Pharmamar
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/01/039
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Metastatic or local advanced Soft tissue sarcoma, not amenable for standard chemotherapy regimen (doxorubicine/epirubicine and/or ifosfamide).

Sarcoma dei tessuti molli metastatico o localmente avanzato non candidato al trattamento standard con doxorubicina/epirubicina e/o ifosfamide.

E.1.1.1

Medical condition in easily understood language

Advanced sof tissue sarcoma not amenable for standard chemotherapy

Sarcoma dei tessuti molli in fase avanzata per i quali non è possibile il trattamento con epirubicina/doxrubicina e/o ifosfamide

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	16.0
E.1.2	Level	HLGT
E.1.2	Classification code	10041299
E.1.2	Term	Soft tissue sarcomas
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

The objective of this study is to assess the activity of trabectedin as a first line treatment in locally advanced/metastatic STS patients unfit to receive standard chemotherapy

Valutazione dell’attività della trabectedina come trattamento di prima linea nei pazienti con STS localmente avanzato/metastatico non idonei a ricevere il trattamento standard.

E.2.2

Secondary objectives of the trial

The secondary endpoints are:
Tolerability and intolerable adverse reaction rate.
Intolerable toxicity is defined as every AEs leading to treatment discontinuation or dose-reduction; furthermore, any AEs of at least grade 3 not resolved within 3 weeks of appropriate management should be regarded as an intolerable toxicity event. For haematological toxicity, given that the use of growth factors will be allowed, an intolerable toxicity is defined either as any grade 4 event, or a grade 3 event not resolved with adequate treatment. AEs will be graded according to NCI-CTCAE criteria v4.0 at the first cycle of therapy.
- Objective response rate (ORR)
- Progression free survival (PFS)
- Overall survival (OS).

*Valutazione della tossicità intollerabile e il tempo all’insorgenza di reazioni avverse.
La tossicità intollerabile è definita come ogni evento avverso che porti alla sospensione del trattamento o alla riduzione della dose, inoltre l’insorgenza di eventuali eventi avversi di grado almeno pari a 3 che nonstante la corretta gestione degli stessi, non si risolvano entro 3 settimane sono considerati di tossicità intollerabile. Per la tossicità ematologica, dato che l'uso di fattori di crescita sarà consentito, la tossicità intollerabile è definita come qualsiasi evento di grado 4, o un evento di grado 3 non risolto con un trattamento adeguato. Gli eventi avversi saranno classificati secondo i criteri NCI-CTCAE v 4.0 al primo ciclo di terapia.
* Probabilità di risposta obiettiva (ORR)
* Sopravvivenza libera da progressione (PFS)
* Sopravvivenza globale (OS).

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

Translational study related to the first line trabectedine treatment in peatient unfit to receive standard chemotherapy

Studio transazionale relativo al trattamento con trabectedina in prima linea nel sarcoma dei tessuti molli in pazienti non idonei a ricevere chemioterapia standard

E.3

Principal inclusion criteria

* Adult patients (≥18 years), who, in the judgment of the clinician, is deemed not suitable to receive an anthracycline and/or ifosfamide based chemotherapy;
* Pathological diagnosis of STS;
*Inoperable, locally advanced or metastatic tumor;
*Unsuited to receive doxorubicine and ifosfamide: ie stable arrhythmia, previous myocardial infarction; age≥80 years
*Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2
*Glomerular filtration rate (GFR) ≥30 mL per min
*Adequate hematologic function: Hemoglobin ≥9 g/dL; Absolute neutrophil count (ANC) ≥1,500/μL, and Platelet count ≥100,000/μL
*Creatinine phosphokinase (CPK) < 2.5 ULN
*Adequate hepatic function: total bilirubin < ULN, total alkaline phosphatase < 2.5 ULN, or if > 2.5 ULN consider alkaline phosphatase liver fraction or GGT or 5’ nucleotidase must be < ULN, AST and ALT <2.5 x ULN, Albumin > 20 g/L.
*Patient´s written informed consent

•Pazienti adulti (≥ 18 anni), che, a giudizio clinico, non sono idonei a ricevere chemioterapia con antracicline e/o ifosfamide
•Diagnosi patologica di STS;
•Tumore inoperabile metastatico e/o localmente avnzato;
•Soggetti non idonei a ricevere doxorubicina e ifosfamide per aritmia stabile, precedente infarto miocardico, età ≥ 80 anni
•Performance Status secondo ECOG (Eastern Cooperative Oncology Group) 0-2
•Velocità di filtrazione glomerulare (GFR) ≥ 30 mL per min
•Adeguata funzionalità ematologica: emoglobina ≥ 9 g / dl; conta assoluta dei neutrofili (ANC) ≥ 1.500 / mL, piastrine ≥ 100.000 / mL
•Creatinina fosfochinasi (CPK) <2,5 ULN
•Adeguata funzionalità epatica: bilirubina totale <ULN, fosfatasi alcalina <2,5 ULN, o se> 2,5 ULN considerare frazione alcalina fosfatasi epatica o GGT o 5 'nucleotidasi deve essere <ULN, AST e ALT <2,5 x ULN, albumina> 20 g / L.
•Consenso informato scritto fornito dal paziente

E.4

Principal exclusion criteria

* Prior exposure to Trabectedin.
* PS≥2
* Prior treatment with anthracyclines and or ifosfamide.
* History of other malignancies (except basal cell carcinoma or cervical carcinoma in situ, adequately treated), unless in remission for 5 or more years and judged of negligible potential of relapse.
* Active viral hepatitis or chronic liver diseases, which in the judgement of the primary investigator represents a clinical contraindication to the therapy.
* Unstable cardiac condition, including congestive heart failure or angina pectoris, myocardial infarction within 6 months before enrolment, uncontrolled arterial hypertension or arrhythmias, LVEF<40%
* Active major infection.
* Other serious concomitant illnesses.
*Pregnant subjects or breast feeding, or planning to become pregnant within 6 months after the end of treatment All sexually active female patients with reproductive potential must have a negative pregnancy test (serum or urine) within the 7 days prior to enrollment and must agree to use highly effective contraception during treatment and for 6 months after the end of treatment.

•Precedente esposizione a Trabectedina.
•Precedente trattamento con antracicline e/o ifosfamide.
•Storia di altre neoplasie maligne (eccetto il carcinoma delle cellule basali o carcinoma cervicale in situ, adeguatamente trattati), a meno che in remissione per 5 o più anni e giudicati non recidivabili.
•Presenza di epatite virale attiva o con patologie epatiche croniche, che, a giudizio dello sperimentatore principale rappresenta una controindicazione clinica alla terapia.
•Condizione di instabilità cardiaca, inclusa insufficienza cardiaca congestizia o angina pectoris, infarto al miocardico entro 6 mesi prima dell'arruolamento, ipertensione arteriosa non controllata o aritmie, FEVS <40%
• Presenza di infezione attiva maggiore.
•Altre gravi malattie concomitanti.
•Soggetti in stato di gravidanza o allattamento, o che stanno pianificando una gravidanza entro 6 mesi dalla fine del trattamento. Tutti i pazienti sessualmente attivi di sesso femminile in età fertile devono avere un test di gravidanza negativo (siero o urine) entro i 7 giorni precedenti l'arruolamento e devono accettare di utilizzare un contraccettivo altamente efficace durante il trattamento e per 6 mesi dopo la fine del trattamento.

E.5 End points

E.5.1

Primary end point(s)

The primary end point of this trial is the Progression Free Survival Rate at 3 months (PFS3). Non progression is defined as CR, PR or SD according to RECIST v.1.1 criteria.

Probabilità di sopravvivenza libera da progressione a 3 mesi (PFS3)
La progressione è definita come CR, PR o SD secondo i criteri RECIST v.1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

3 months from the start therapy

a 3 Mesi dall’inizio della terapia

E.5.2

Secondary end point(s)

Tolerability and intolerable adverse reaction rate.
Intolerable toxicity is defined as every AEs leading to treatment discontinuation or dose-reduction; furthermore, any AEs of at least grade 3 not resolved within 3 weeks of appropriate management should be regarded as an intolerable toxicity event. For haematological toxicity, given that the use of growth factors will be allowed, an intolerable toxicity is defined either as any grade 4 event, or a grade 3 event not resolved with adequate treatment. AEs will be graded according to NCI-CTCAE criteria v4.0 at the first cycle of therapy.
- Objective response rate (ORR)
- Progression free survival (PFS)
- Overall survival (OS).

E.5.2.1

Timepoint(s) of evaluation of this end point

For Tolerability and intolerable adverse reaction rate: during all the study
For Objective Response Rate (ORR): form study entry up to the end
For Progression-free survival (PFS): after 6/7 weeks from the start of therapy and then every 9 weeks
For Overall survival (OS): from studt entry up to death

Tasso di reazioni avverse tollerabili ed intollerabili: per tutto il corso della terapia
Sopravvivenza libera da progressione (PFS): dopo 6/7 settimane dall’inizio terapia e successivamente ogni 9 settimane
Sopravvivenza globale (OS): a partire dall’ingresso in studio sino al decesso

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

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

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)

E.8.2.2

Placebo

E.8.2.3

Other

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.8.5

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

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:

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

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

Information not present in EudraCT

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)

All the patients will be treated, at the end of study, with the standard of care planned for their pathology and with the best available option for support care

I pazienti al termine dello studio saranno seguiti con lo standard of care previsto per la loro patologia

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

2013-07-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-09-04

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

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