Clinical Trials Register

Summary
EudraCT Number:	2015-002584-41
Sponsor's Protocol Code Number:	CEPOETA-2015-01
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2016-10-24
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

Czechia - SUKL

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

Rekurentní neuroblastom a Ewingův sarkom: Na treosulfanu založená vysokodávaková chemoterapie s podporou autologní transplantace periferních kmenových buněk

A.3.1

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

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

Léčba nádorů (neuroblastom a Ewingův sarkom), které se znovu objevily, založená na vysokých dávkách chemoterapie a transplantaci pacientových vlastních buněk

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

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Masarykova univerzita
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	Masarykova univerzita
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	Masarykova univerzita- Lékařská fakulta
B.5.2	Functional name of contact point	Centrum pro klinická hodnocení
B.5.3	Address:
B.5.3.1	Street Address	Kamenice 5
B.5.3.2	Town/ city	Brno
B.5.3.3	Post code	62500
B.5.3.4	Country	Czech Republic
B.5.4	Telephone number	00420549496526
B.5.6	E-mail	demlova@med.muni.cz

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	Czech Republic
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.2.1.2	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.3.9.4	EV Substance Code	SUB11235MIG
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

Ewingův sarkomu, neuroblastom

E.1.1.1

Medical condition in easily understood language

Tumors: Ewing's sarcoma, neuroblastoma

Nádory: Ewingův sarkomu, neuroblastom

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 6 months.

Zhodnotit efektivitu treosulfan/melfalan (TREO/MEL) vysokodávkové chemoterapie v kombinaci s autologní transplantací periferních kmenových buněk (aPBSCT) u pacientů s rNB a rES ve smyslu odpovědi na léčbu definovanou jako nepřítomnost progrese v 6 měsících.

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 conditioning Treo/Mel regimen and aPBSCT in children, adolescents and young adults with rES or rNB 6, 12, 18 and 24 months after hight dose chemotherapy with TREO / MEL.
• To evaluate time to progression in the study population.
• To evauate overall survival (OS) of the study population 6, 12, 18 and 24 months after hight dose chemotherapy with TREO / MEL.
• To compare the study population survival data trends with available historical data.

• Zhodnotit výskyt venookluzivní choroby / sinusoidálního obstrukčního syndromu (VOD/SOS) 4 týdny po autologní transplantaci kmenových buněk periferní krve.
• Zhodnotit bezpečnost a snášenlivost chemoterapeutického režimu TREO/MEL a autologní transplantace kmenových buněk periferní krve u dětí, adolescentů a mladých dospělých s rNB a rES 6, 12, 18, 24 měsíců po podání TREO/MEL chemoterapie.
• Zhodnotit čas do progrese u sledované populace.
• Zhodnotit celkové přežití (OS) sledované populace v 6, 12, 18 a 24 měsících po podání TREO /MEL vysokodávkové chemoterapie.
• Porovnat trendy přežití u sledované populace s dostupnými historickými daty.

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 therapyb.
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. Podepsaný informovaný souhlas (participant a v případě, kde je to nutné i zákonný zástupce).
2. Věk méně než 25 let v době zařazení.
3. Diagnóza: relabovaný neuroblastom s vysokým rizikem (rNB), relabovaný Ewingův sarkom (rES)
a. Bioptické nebo cytologické potvrzení rNB a/nebo rES
b. Alespoň parciální remise po reindukční terapii (minimálně 2 cykly konvenční chemoterapie nebo 3 měsíce metronomické léčby) a/nebo lokální terapie.
4. Performance status (Karnovsky/ Lansky ≥ 40).
5. Renální, jaterní a kardiální funkce ne horší než stupeň III (CTC v4.0).
6. Negativní těhotenský test u fertilních žen.
7. Produkce kmenových buněk minimálně 2,0 x 10 na 6 CD34 + / kg hmotnosti.
8. Minimálně 28 dní po ukončení předchozí protinádorové terapie.

E.4

Principal exclusion criteria

1. Performance status (Karnofsky/Lansky < 40).
2. Toxicity levels related to prior therapy preventing the HDCt application
3. Pregnancy or breastfeeding.
4. Patients taking part in a clinical trial testing another anticancer drug or a drug with a potential anticancer effect 14 days or less before the screening visit.
5. Confirmed allergy reaction to any of the study drug.
6. Patient with uncontrolled psychiatric disorder.

1. Performance status (Karnofsky/Lansky < 40).
2. Toxicita související s předchozí léčbou pacienta, která znemožňuje podání vysokodávkové chemoterapie.
3. Těhotenství, kojení.
4. Pacient zařazen do klinického zkoušení jiné protinádorové terapie, případně terapie s potenciálním protinádorovým efektem 14 dní před skríningem.
5. Prokazatelná předchozí alergická reakce na hodnocené léčivo.
6. Pacient s nekontrolovanou psychiatrickou diagnózou.

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint of efficacy
• Absence of the primary disease progression 6 months after aPBSCT.

Primární parametr účinnosti
• Absence progrese primární choroby 6 měsíců po aPBSCT.

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months after aPBSCT

6 měsíců po 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) in 6, 12, 18, 24 months.

Sekundární parametry
• Výskyt VOD/SOS (venookluzivní choroba/sinusoidální obstrukční syndrom) u každého pacienta.
• Výskyt orgánové toxicity grade III nebo IV dle CTCAE (v4.0)* (se speciálním zaměřením na kardiální, renální a hepatální toxicitu)
• Čas do progrese (TTP).
• Celkové přežití (OS) v 6, 12, 18, 24 měsících.

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 6, 12, 18 and 24 months for OS

Během celého průběhu klinického hodnocení pro výskyt VOD/SOS, výskyt orgánové toxicity grade III nebo IV a TTP.
V 6, 12, 18 a 24 měsících pro 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

poslední návštěva posledního subjektu

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

standardní

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

2016-10-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-10-05

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

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