Clinical Trials Register

Summary
EudraCT Number:	2012-001010-42
Sponsor's Protocol Code Number:	2012-001010-42
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:	2012-08-07
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

2012-001010-42

A.3

Full title of the trial

A multicenter, prospective, randomized clinical trial for patients with relapsed osteosarcoma

Studio clinico multicentrico, prospettico, randomizzato per il trattamento dei pazienti con osteosarcoma in recidiva

A.3.1

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

A study Protocol for patients with relapsed osteosarcoma

Studio per il trattamento di pazienti con ricaduta di osteosarcoma

A.3.2

Name or abbreviated title of the trial where available

ISG Os Rec

A.4.1

Sponsor's protocol code number

2012-001010-42

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	Italian Sarcoma Group
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	Italian Sarcoma Group
B.5.2	Functional name of contact point	Clinical Trial Office
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.5.4	Telephone number	051 6366400
B.5.5	Fax number	051 6366277
B.5.6	E-mail	emanuela.marchesi@ior.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*EV 1FL 1G
D.2.1.1.2	Name of the Marketing Authorisation holder	BAXTER SpA
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	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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	6055-19-2
D.3.9.3	Other descriptive name	Cyclophosphamide
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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.IMP: 2
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	ETOPOSIDE TEVA*FL 10ML 20MG/ML
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA 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.3.4	Pharmaceutical form	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	etoposide
D.3.9.1	CAS number	33419-42-0
D.3.9.4	EV Substance Code	L01CB01
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	20
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.IMP: 3
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	HOLOXAN*EV 1FL 1G
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	Powder 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	IFOSFAMIDE
D.3.9.1	CAS number	3778-73-2
D.3.9.4	EV Substance Code	SUB08125MIG
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	1000
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

High malignancy grade of osteosarcoma relapse

recidiva di osteosarcoma ad alto grado di malignità

E.1.1.1

Medical condition in easily understood language

relapsed osteosarcoma

Ricaduta in pazienti affetti da osteosarcoma

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

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	10031296
E.1.2	Term	Osteosarcoma recurrent
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 and tollerability of two chemotherapeutic regimens (either Cyclophosphamide+ Etoposide or high dose Ifosfamide) currently used to treat relapsed Osteosarcoma patients

confrontare l’efficacia/tollerabilità di due regimi chemioterapici (Ciclofosfamide ed Etoposide o Ifosfamide ad alte dosi) attualmente utilizzati nel trattamento delle recidive di Osteosarcoma

E.2.2

Secondary objectives of the trial

To evaluate Clinical Benefit, Toxicity, Quality of life, Overall Survival, Progression Free Survival

Valutare: Beneficio clinico,Tossicità,Qualità della vita,Overall Survival,Progression Free Survival

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.patients with high-grade malignant relapsed osteosarcoma 2.age at diagnosis <50 years 3.Lansky score o Karnofsky Performance status > 60% 4.First or subsequent relapse of osteosarcoma surgically unresectable or for whom surgery was oncologically not appropriate 5.Good organ function defined by: 1) serum creatinine < 2 times the upper limit for age, 2) total bilirubin <1.5 times the upper limit of age, 3) transaminases ≤ 2.5 times the upper limit for age, 4) alkaline phosphatase ≤ 5 times the upper limit for age (with the exclusion of patients with skeletal metastases) 6.Normal Heart function (VEF > 50%) 7.White blood cells >3 x 109/l and platelets >100 x 109/l 8.For female patients with childbearing potential, a negative test for pregnancy is to be considered before entry on study 9.Written signed informed consent from patients or from parents or legal guardians for minor patients, according to local law and regulations

1.Diagnosi iniziale di recidiva di osteosarcoma ad alto grado di malignità 2.Età alla diagnosi di recidiva di osteosarcoma <50 anni 3.Lansky score o Karnofsky Performance status > 60% 4.Malattia in prima o ulteriore recidiva non resecabile chirurgicamente o per i quali l’intervento chirurgico viene giudicato oncologicamente non adeguato. 5.Buona funzionalità epatica e renale definita dai seguenti parametri: 1) creatinina serica < 2 volte il limite superiore per età; 2) bilirubina totale < 1.5 volte il limite superiore per età; 3) transaminasi ≤ 2.5 volte il limite superiore per età; 4) fosfatasi alcalina < 5 volte il limite superiore per età (con l’esclusione dei pazienti con metastasi scheletriche). 6.Frazione di eiezione ventricolare > 50%. 7.Globuli bianchi >3 x 109/l e piastrine >100 x 109/l. 8.I soggetti di sesso femminile che abbiano già avuto menarca, devono presentare un test di gravidanza negativo prima dell’inizio dello studio. 9.Sottoscrizione del modulo di consenso alla partecipazione allo studio da parte del soggetto interessato o da chi ne esercita la patria potestà.

E.4

Principal exclusion criteria

1.Medical contraindications to the use of the drugs included in the Protocol. 2.Psychological conditions that don’t ensure either a good adhesion to the Protocol or a proper management of toxicity or a proper understanding of the study 3.Either HBV or HCV or HIV active infection 4.Previouly treatment with either Cyclophosphamide+ Etoposide or high dose Ifosfamide Pregnant or lactating patients

1.Controindicazioni mediche all'uso dei farmaci previsti dal Protocollo. 2.Condizioni mentali o sociali che non garantiscano una adeguata adesione al protocollo, una corretta gestione domiciliare della tossicità, una adeguata comprensione della partecipazione allo studio. 3.Infezione da HBV, HCV e HIV in fase attiva. 4.Precedente trattamento con Ciclofosfamide-Etoposide oppure con Ifosfamide ad alte dosi. 5.Gravidanza o allattamento in atto al momento della diagnosi di recidiva.

E.5 End points

E.5.1

Primary end point(s)

Evaluation of the Overall Response Rate (ORR) defined as the percentage of patients with complete or partial response

Determinare la Overall Response Rate (ORR), cioè la percentuale di pazienti che presentano una risposta completa o parziale

E.5.1.1

Timepoint(s) of evaluation of this end point

after 2 chemotherapy cycles

dopo il 2° ciclo di chemioterapia

E.5.2

Secondary end point(s)

Evaluate: Number of patients with complete response or stable disease >=4 months Number of patients with toxicity grade ≥3 (NCI CTAE version 4.0) Number of patients with death for any cause since the date of randomization to the date of last available follow-up Number of patients with relapse/progression/death for any cause since the date of randomization to the date of last available follow-up Quality of life evaluation by PedsQLTM and EORTC QLQ-C30 criteria

Determinare:
Proporzione di pazienti che presentano risposta completa o stabilizzazione di malattia per ≥ 4 mesi,
Proporzione di pazienti che sviluppano tossicità di grado ≥3 secondo i criteri CTCAE versione 4.0 , Proporzione di pazienti che giungono al decesso per qualsiasi causa dalla data della randomizzazione alla data dell’ultimo follow-up disponibile, Proporzione di pazienti che presentano recidiva/progressione/decesso per qualsiasi causa dalla data della randomizzazione alla data dell’ultimo follow up disponibile, Valutazione della qualità della vita misurata con i criteri PedsQLTM (pz pediatrici) e EORTC QLQ-C30 (pz adulti)

E.5.2.1

Timepoint(s) of evaluation of this end point

After each cycle for toxicity,after 2 month for response and within 5 years for follow-up evaluations

La tossicità viene rilevata ad ogni ciclo, la risposta viene valuata dopo 2 mesi, gli altri endpoints vengono valuati entro i 5 anni di follow-up

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)

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)

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

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

5 years after the last completed treatment

5 anni dal completamento della terapia dell'ultimo paziente

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

Yes

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

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)

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

104

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)

at the end of trial all the subjects will be follow-up by sites on the basis of the osteosarcoma ISG guidelines

al termine dello studio i pazienti verranno seguiti presso i centri di riferimento, secondo le
linee guida ISG per l'osteosarcoma

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

2012-11-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-06-06

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

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