Clinical Trials Register

Summary
EudraCT Number:	2013-003604-39
Sponsor's Protocol Code Number:	MC-FludT.17/M
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-07-08
Trial results	View 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

Austria - BASG

A.2

EudraCT number

2013-003604-39

A.3

Full title of the trial

Clinical phase II trial to describe the safety and efficacy of Treosulfan-based conditioning therapy prior to allogeneic haematopoietic stem cell transplantation in paediatric patients with haematological malignancies

Klinische Phase II Studie zur Beschreibung der Verträglichkeit und Wirksamkeit der Treosulfan basierten Konditionierungstherapie vor allogener Stammzelltransplantation bei pädiatrischen Patienten mit malignen hämatologischen Erkrankungen

A.3.1

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

Clinical study to examine the safety and efficacy of Treosulfan used as part of a conditioning therapy prior to a stem cell transplantation in children with blood cancer.

Klinische Studie zur Untersuchung der Sicherheit und Wirksamkeit von treosulfan als Teil der Konditionierungstherapie bei Kindern mit bösartigen Bluterkrankungen.

A.3.2

Name or abbreviated title of the trial where available

Treosulfan-based conditioning in paediatric patients with haematological malignancies

Treosulfan basierte Konditionierung bei pädiatrischen Patienten mit malignen Bluterkrankungen

A.4.1

Sponsor's protocol code number

MC-FludT.17/M

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/104/2013

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	medac GmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	medac GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	INC Research UK Limited
B.5.2	Functional name of contact point	Ghalia Hachem
B.5.3	Address:
B.5.3.1	Street Address	Riverview, The Meadows Business Park, Station Approach,
B.5.3.2	Town/ city	Camberley, Surrey
B.5.3.3	Post code	GU17 9AB
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	00311207528717
B.5.6	E-mail	Ghalia.Hachem@INCResearch.com

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	Ovastat 1000 (Treosulfan injection)
D.2.1.1.2	Name of the Marketing Authorisation holder	medac GmbH
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	EU/3/04/186
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.3.8	INN - Proposed INN	TREOSULFAN
D.3.9.1	CAS number	299-75-2
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.3.11 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 5000 (Treosulfan injection)
D.2.1.1.2	Name of the Marketing Authorisation holder	medac GmbH
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	EU/3/04/186
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.3.8	INN - Proposed INN	TREOSULFAN
D.3.9.1	CAS number	299-75-2
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

Male and female children with haematologic malignant diseases as acute lymphoblastic leukaemias (ALL), acute myeloid leukaemias (AML), myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukaemias (JMML), requiring myeloablative conditioning treatment with following allogeneic haematopoietic stem cell transplantation (allo-HSCT)

Kinder, männlichen und weiblichen Geschlechts, mit malignen hämatologischen Erkrankungen, wie akute lymphoblastische Leukämien (ALL), akute myeloische Leukämien (AML), myelodysplastische Syndrome (MDS) und juvenile myelomonocytische Leukämien (JMML), die eine myeloablative Konditionierung mit anschließender allogener Stammzelltransplantation (allo-HSZT) benötigen

E.1.1.1

Medical condition in easily understood language

Children with blood cancer requiring conditioning treatment with following stem cell transplantation

Kinder mit bösartigen Bluterkrankungen, die eine Konditionierungstherapie vor Stammzellentransplantation benötigen

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10054439
E.1.2	Term	Juvenile chronic myelomonocytic leukemia
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10060355
E.1.2	Term	Acute myeloid leukaemia in remission
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10028534
E.1.2	Term	Myelodysplastic syndrome NOS
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10000844
E.1.2	Term	Acute lymphoblastic leukaemia
E.1.2	System Organ Class	100000004864

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

Freedom from transplant (treatment)-related mortality, defined as death from any transplant-related cause from the day of first administration of study medication until day +100 after HSCT.

E.2.2

Secondary objectives of the trial

Evaluation of:
1. leukocyte, neutrohil and platelet engraftment after HSCT
2. safety including early toxicity, until day +100 after HSCT, SARs until the end of the longer-term follow-up phase
3. HSOS, lung toxicity, hepatic toxicity and infections of any CTCAE grade until day +100
4. donor-type chimerism on day +28, day +100 and 12 months after HSCT
5. NRM, TRM, graft failure rate, incidence of relapse/progression, RFS/PFS and OS until 12 months after HSCT
6. incidence and severity of acute (until day +100) and chronic (until 12 months after HSCT) graft versus host disease (aGvHD/cGvHD)
7. use of rescue therapies including DLIs and further conditioning regimens
8. PK parameters of Treosulfan and its epoxides and to develop a PK model for assessing relevant covariates
9. NRM, TRM, secondary graft failures, relapse/progression, RFS/PFS, OS and cGvHD during the longer-term follow-up phase

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Haematologic malignant disease i.e. ALL, AML, MDS or JMML, indicated for allo-HSCT.
2.Indication for first allo-HSCT or second allo-HSCT due to disease relapse, graft failure or secondary malignancy after previous HSCT.
3. Available matched sibling donor (MSD), matched family donor (MFD) or matched unrelated donor (MUD). For bone marrow (BM) and peripheral blood (PB) match is defined as 9/10 or 10/10 allele match after four digit typing in human leucocyte antigen (HLA)-A, B, C, DRB1 and DQB1 antigens.
4. Patients with ALL or AML in complete morphologic remission (blast counts <5% in BM) and patients with MDS or JMML with blast counts < 20% in BM at study entry.
5. Age at time of registration from 28 days to less than 18 years of age.
6. Lansky (patients aged <16 years) or Karnofsky (patients aged ≥ 16 years) performance score of at least 70%.
7. Written informed consent of the parents/ legal guardians and patient assent/consent according to national regulations.
8. Females of child-bearing potential or male patients’ partners with child-bearing potential must use a highly effective method of contraception (pearl index < 1%) such as complete sexual abstinence, combined oral contraceptive, hormone intrauterine contraceptive device (IUCD), vaginal hormone ring, transdermal contraceptive patch, contraceptive implant or depot contraceptive injection in combination with a second method of contraception like a condom or a cervical cap / diaphragm with spermicide or surgical sterilisation (vasectomy) in male patients or male partners during the study and at least 6 months thereafter.
9. Negative pregnancy test for females of child-bearing potential.

E.4

Principal exclusion criteria

1. Third or later allo-HSCT.
2. HSCT from haploidentical or umbilical cord blood donor.
3. Concomitant involvement of central nervous system (CNS) e.g.
presence of the leukaemic blasts in the cerebrospinal fluid (CSF) at study entry.
4. Treatment with cytotoxic drugs within 10 days prior to day 6.
5. Obese paediatric patients with body mass index: weight (kg)/[height (m)]² > 30 kg/m².
6. Concomitant solid tumours (e.g. neuroblastoma, peripheral neuroectodermal tumour [PNET], Ewing sarcoma).
7. Fanconi anaemia and other deoxyribonucleic acid (DNA) breakage repair disorders; secondary leukaemia
developed from the Fanconi anaemia or other DNA breakage repair disorders.
8. Impaired liver function indicated by Bilirubin > three times the upper limit of normal (ULN) or aspartate aminotransferase/alanine aminotransferase (AST/ALT) > ten times ULN or clinical significant coagulopathy, or active infectious hepatitis with clinical evidence.
9. Impaired renal function indicated by estimated glomerular filtration rate ([GFR], according to the Schwartz formula) < 60 mL/min/1,73m2.
10. Impaired cardiac function: severe cardiac insufficiency indicated by left ventricle ejection fraction (LVEF) 35%.
11. Requirement for supplementary continuous oxygen.
12. Severe active infection requiring deferral of conditioning.
13. Human immunodeficiency virus (HIV) positivity.
14. Known pregnancy, breast feeding.
15. Known hypersensitivity to Treosulfan and/or Fludarabine.

E.5 End points

E.5.1

Primary end point(s)

Freedom from transplant (treatment)-related mortality (TRM), defined as death from any transplant-related cause from the day of first administration of study medication until day +100 after HSCT

E.5.1.1

Timepoint(s) of evaluation of this end point

Day + 100 after HSCT

E.5.2

Secondary end point(s)

Evaluation of:
1. donor type engraftment after HSCT, defined as first of three consecutive days for each of the following four criteria:
- a leukocyte count of more than 1 x 109/L
- an absolute neutrophil count (ANC) of more than 0.5 x 109/L
- a platelet count of at least 20 x 109/L
- a platelet count of at least 50 x 109/L
2. safety including early toxicity, based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 until day +100 after HSCT, serious adverse reactions (SARs) until the end of longer-term follow-up phase
3. hepatic sinusoidal obstruction syndrome (HSOS), lung toxicity (CTCAE term pulmonary fibrosis), hepatic toxicity and infections of any CTCAE grade (non-serious and serious) until day +100
4. donor-type chimerism on day +28, day +100 and 12 months after HSCT
5. non relapse mortality (NRM), TRM, incidence of relapse/progression, relapse-free/progression-free survival (RFS/PFS) and overall survival (OS) until 12 months after HSCT
6. incidence and severity of acute (until day +100) and chronic (until 12 months after HSCT) graft versus host disease (aGvHD/cGvHD)
7. use of rescue therapies including donor-lymphocyte infusions (DLIs) and further conditioning regimens
8. PK parameters of Treosulfan and its epoxides and to develop a PK model for assessing relevant covariates
9. secondary graft failure, cGvHD, OS, TRM and NRM during the longer-term follow-up phase

E.5.2.1

Timepoint(s) of evaluation of this end point

Day 28, 12 months after HSCT and/or until the end of the longer-term follow-up phase

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

Yes

E.6.7

Pharmacodynamic

Yes

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.8.2.4

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

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

Yes

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

The end of the clinical study is defined as the day of the last longer-term follow-up visit of the last patient to be performed three years after HSCT.
EOS: planned Q3/2019

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)

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Children

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)

After study participation, patients will receive treatment/medical care as routinely used in medical conditions after conditioning treatment and subsequent allogeneic stem cell transplantation.

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

2014-08-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-07-31

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-09-30

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