Clinical Trials Register

Summary
EudraCT Number:	2015-002584-41
Sponsor's Protocol Code Number:	CEPOETA-2015-01
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-06-08
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2015-002584-41

A.3

Full title of the trial

RECURENT NEUROBLASTOMA AND EWING´S SARCOMA: TREOSULPHAN BASED HIGH DOSE CHEMOTHERAPY WITH AUTOLOGOUS PBSC SUPPORT

A REKURRENS NEUROBLASZTÓMA ÉS AZ EWING-SZARKÓMA KEZELÉSE NAGY DÓZISÚ TREOSZULFÁNNAL ÉS AZT KÖVETŐEN A PERIFÉRIÁS ŐSSEJTEK AUTOLÓG ÁTÜLTETÉSÉVEL

A.3.1

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

TREATMENT OF TUMORS THAT OCCURRED AGAIN (NEUROBLASTOMA AND EWING´S SARCOMA) BASED ON HIGH DOSE CHEMOTHERAPY WITH TRANSPLANTATION OF PATIENT'S PROPER CELLS

A.3.2

Name or abbreviated title of the trial where available

ReNETA

A.4.1

Sponsor's protocol code number

CEPOETA-2015-01

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/197/2017

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	CEPOETA (Central European Pediatric Oncology Early Trials Alliance, z.s.)
B.1.3.4	Country	Czech Republic
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	CEPOETA
B.4.2	Country	Czech Republic
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ReKnoS Science s.r.o.
B.5.2	Functional name of contact point	Edita Plevová
B.5.3	Address:
B.5.3.1	Street Address	Jeneweinova 98/41
B.5.3.2	Town/ city	Brno
B.5.3.3	Post code	617 00
B.5.3.4	Country	Czech Republic
B.5.4	Telephone number	+420605768549
B.5.6	E-mail	plevova@reknos.eu

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.2.1.2	Country which granted the Marketing Authorisation	Hungary
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	melphalan
D.3.4	Pharmaceutical form	Powder and solvent 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	MELPHALAN
D.3.9.1	CAS number	148-82-3
D.3.9.4	EV Substance Code	SUB08728MIG
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	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	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	Ovastat 1000 mg, Ovastat 5000 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Medac Gesellschaft fur klinische Spezielpreparate mbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	ORPHA90799
D.3 Description of the IMP
D.3.1	Product name	treosulfan
D.3.4	Pharmaceutical form	Powder for solution for injection/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	TREOSULFAN
D.3.9.1	CAS number	299-75-2
D.3.9.3	Other descriptive name	Ovastat 1000mg
D.3.9.4	EV Substance Code	SUB11235MIG
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TREOSULFAN
D.3.9.1	CAS number	299-75-2
D.3.9.3	Other descriptive name	Ovastat 5000mg
D.3.9.4	EV Substance Code	SUB11235MIG
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	5000
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

Ewing's sarcoma, neuroblastoma

EWING-SZARKÓMA, NEUROBLASZTÓMA

E.1.1.1

Medical condition in easily understood language

Tumors: Ewing's sarcoma, neuroblastoma

TUMOROK:
EWING-SZARKÓMA , NEUROBLASZTÓMA

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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 evaluate efficacy of TREO/MEL high dose chemotherapy conditioning + aPBSCT in patients with rNB and rES in terms of response rate defined as absence of progression* in 3 months.

• nagy dózisú TREO/MEL kemoterápia + az aPBSCT hatásosságának értékelése az rNB ben és az rES ben szenvedő betegek esetében, 3 hónapos progressziómentes* időszakként meghatározott válaszarány alapján.

E.2.2

Secondary objectives of the trial

• To evaluate occurrence of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) 4 weeks after high dose chemotherapy.
• To evaluate safety and tolerability of high-dose chemotherapy TREO/MEL regimen and aPBSCT in children, adolescents and young adults with rES or rNB after FU 1 Visit (4 weeks after high-dose chemotherapy with TREO/MEL).
• To evaluate time to progression in the study population.
• To evaluate overall survival (OS) of the study population.
• To compare the study population survival data trends with available historical data.

• a vénaelzáródás (venookkluzív betegség) / szinuszoidális obstrukciós szindróma (VOD/SOS) előfordulásának értékelése 4 héttel az aPBSCT után,
• a nagy dózisú TREO/MEL kemoterápia és az aPBSCT biztonságosságának és tolerálhatóságának értékelése az rES ben vagy az rNB ben szenvedő gyermekek, serdülők és fiatal felnőttek esetében a kezelést követő 1. orvosi vizsgálat után (4 héttel a nagy dózisú TREO/MEL kemoterápia után),
• a progresszióig eltelt idő értékelése a vizsgált betegcsoportban,
• a teljes túlélés (OS) értékelése a vizsgált betegcsoportban,
• a vizsgált betegcsoportban mért túlélési adatok alakulásának összehasonlítása a rendelkezésre álló régebbi adatokkal.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed written informed consent (participant and parents when required).
2. Age: less than 25 years at the time of enrolement.
3. Diagnosis: relapsed high-risk neuroblastoma (rNB) or relapsed Ewing´s sarcoma (rES).
a. Confirmation of rES or rNB by biopsy or cytology.
b. At least partial remission to reinduction chemotherapy (at least 2 cycles of conventional chemotherapy or 3 months of metronomic therapy) and/or local therapy.
4. Performance status (Karnovsky/Lansky) ≥ 40.
5. Renal, liver and cardiac functions not worse than grade III (CTC v4.0).
6. Negative pregnancy test in fertile women.
7. Stem cell product with a minimum of 2,0 x 106 CD34+/kg.
8. At least 28 days from the prior antitumour therapy.

1. A résztvevő – illetve szükség esetén a törvényes képviselője – aláírta a tájékoztatáson alapuló írásos beleegyezést.
2. Életkor a vizsgálatba való bevonás időpontjában: kevesebb, mint 25 év.
3. Diagnózis: magas kockázatú neuroblasztóma relapszusa (rNB) vagy Ewing-szarkóma relapszusa (rES):
a) biopsziával vagy citológiai lelettel igazolt rNB, illetve rES,
b) legalább részleges remisszió a reindukciós kemoterápia (a konvencionális kemoterápia legalább 2 ciklusa vagy legalább 3 hónapos metronom terápia) és/vagy lokális kezelés eredményeként,
4. A teljesítménystátusz (Karnofsky/Lansky)  40.
5. A vese-, a máj- és a szívműködés nem rosszabb a III. fokozatúnál (CTC v4.0)*.
6. Negatív terhességi teszt a fogamzóképes korú nők esetében.
7. Az őssejttermelés legalább 2,0 × 106 CD34+/ttkg.
8. Az előző daganatellenes kezelés befejezése óta legalább 28 nap telt el.

E.4

Principal exclusion criteria

1. Performance status (Karnofsky/Lansky < 40).
2. Toxicity levels related to prior therapy preventing the high-dose chemotherapy administration.
3. Pregnancy or breastfeeding.
4. Patient taking experimental study treatment with anticancer drug 14 days or less before the RENETA screening visit and concomitantly until the assessment of the primary objective at 3 months.
5. Confirmed allergic reaction to any of the study drugs.
6. Confirmed contraindication according to SmPC of any study drug.
7. Patient with uncontrolled psychiatric disorder and/or other life threatening conditions.
8. Refusal to use adequate contraception in fertile women.

1. A teljesítménystátusz (Karnofsky/Lansky) < 40.
2. Az előző kezeléshez kapcsolódó toxicitási szintek nem teszik lehetővé a nagy dózisú kemoterápia alkalmazását.
3. Terhesség vagy szoptatás.
4. A beteg daganatellenes gyógyszerrel végzett kísérleti kezelésben részesül 14 vagy kevesebb nappal a RENETA szűrővizsgálat előtt, valamint a vizsgálati kezeléssel egyidejűleg, az elsődleges végpont 3 hónap elteltével tervezett kiértékelésig tartó időszakban.
5. Igazolt allergiás reakció a vizsgált gyógyszerek valamelyikére.
6. Bármelyik vizsgált gyógyszer adása igazoltan ellenjavallott a gyógyszer alkalmazási előírása szerint.
7. A beteg egy nem kontrollált pszichiátriai kórképben szenved és/vagy egyéb életveszélyes állapotban van.
8. Fogamzóképes korú nőbeteg elutasítja a megfelelő fogamzásgátló módszer alkalmazását.

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint of efficacy
• Absence of the primary disease progression 3 months after aPBSCT.

Az elsődleges hatásossági végpont:
• az elsődleges betegség progressziójának hiánya aPBSCT t követő 3 hónapos időszakban

E.5.1.1

Timepoint(s) of evaluation of this end point

3 months after aPBSCT

E.5.2

Secondary end point(s)

Secondary endpoints
• Occurrence of VOD/SOS in each patient.
• Occurrence of organ toxicity grade III or IV according to CTCAE (v4.0)* (with special interest to cardiac, renal, hepatic toxicity)
*Common Terminology Criteria for Adverse Events (CTCAE), v4.0
• Time to progression (TTP).
• Overall survival (OS).

A másodlagos végpontok:
• a VOD/SOS előfordulása bármelyik betegnél,
• a CTCAE (v4.0)* szerinti III. vagy IV. fokozatú szervi toxicitás fellépése (különös tekintettel a szív-, a vese- és a májtoxicitásra),
* Common Terminology Criteria for Adverse Events (CTCAE), v4.0
• a progresszióig eltelt idő (TTP),
• a teljes túlélés (OS).

E.5.2.1

Timepoint(s) of evaluation of this end point

During the whole course of the clinical trial for occurence of VOD/SOS, occurence of organ toxicity grade III or IV and TTP.
In 3, 6, 12, 18 and 24 months for OS

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

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

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

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

Last Visit of the Last Subject

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

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

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

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

F.4.2.2

In the whole clinical trial

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

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-12-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-12-10

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

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