Comparison of Treosulfan-based with Busulfan-based conditioning in paediatric patients with non-malignant diseases

• Register: EUCTR
• Last refreshed on: 5 April 2021
• Main ID: EUCTR2013-005508-33-DE
• Date of registration: 06/06/2014
• Prospective Registration: Yes
• Primary sponsor: medac Gesellschaft für klinische Spezialpräparate mbH
• Public title: Comparison of Treosulfan-based with Busulfan-based conditioning in paediatric patients with non-malignant diseases
• Scientific title: Clinical phase II trial to compare Treosulfan-based conditioning therapy with Busulfan-based conditioning prior to allogeneic haematopoietic stem cell transplantation (HSCT) in paediatric patients with non-malignant diseases - Treosulfan-based versus Busulfan-based conditioning in paediatric patients with non-malignant diseas
• Date of first enrolment: 29/09/2014
• Target sample size: 100
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-005508-33
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Czech Republic, Germany, Italy, Poland

Contacts

• Name: Ghalia Hachem
• Affiliation: Syneos Health UK Limited

• Name: Ghalia Hachem
• Affiliation: Syneos Health UK Limited

Key inclusion & exclusion criteria

Inclusion criteria:
1. Non-malignant disease indicated for first myeloablative allogeneic HSCT, including inborn errors of metabolism, primary immunodeficiencies, haemoglobinopathies and bone marrow failure syndromes.
2. First allogeneic 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 at least 9/10 allele matches after four digit typing in human leucocyte antigen (HLA)-A, -B, -C, –DRB1 and DQB1 antigens. For umbilical cord blood (UCB) match is defined as at least 5/6 matches after two digit typing in HLA-A and -B and four digit typing in DRB1 antigens.
4. Age at time of registration from 28 days to less than 18 years of age.
5. Lansky (patients <16 years of age) or Karnofsky (patients = 16 years of age) performance score of at least 70%.
6. Written informed consent of the parents/legal guardians and patient’s assent/consent according to national regulations.
7. Female patients of child-bearing potential or partner of male patients 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 six months thereafter. For female patients on the study, the vasectomised male partner should be the sole partner for that patient.
8. Negative pregnancy test for females of child-bearing potential.

Are the trial subjects under 18? yes
Number of subjects for this age range: 100
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Second or later HSCT.
2. HSCT from mismatched donor (less than 9/10 BM/peripheral blood stem cells (PBSC) or less than 5/6 matched cord donor).
3. Preterm newborn infants (<37 weeks gestational age) and term newborn infants aged 0 – 27 days at time of registration.
4. Obese paediatric patients with body mass index weight (kg)/[height (m)]² > 30 kg/m².
5. Diagnosis of Fanconi anaemia and other chromosomal breakage disorders, radiosensitivity disorders (deoxyribonucleic acid (DNA) Ligase 4, Cernunnos- X-ray repair cross-complementing protein 4 (XRCC4) like factor (XLF), Nijmegen Breakage Syndrome (NBS)) and Dyskeratosis Congenita.
6. Treatment with cytotoxic drugs within 10 days prior to day 7.
7. Impaired liver function indicated by Bilirubin > three times the upper limit of normal (ULN) or aspartate aminotransferase/alanine aminotransferase (AST/GOT, ALT/GPT) > ten times ULN, or clinically significant coagulopathy, or active infectious hepatitis with clinical evidence.
8. Impaired renal function indicated by estimated glomerular filtration rate ([GFR], according to the Schwartz formula) < 60 mL/min/1.73m2.
9. Impaired cardiac function: severe cardiac insufficiency indicated by left ventricular ejection fraction (LVEF) ? 35%.
10. Requirement for supplementary continuous oxygen.
11. Severe active infection requiring deferral of conditioning.
12. Human immunodeficiency virus (HIV) positivity.
13. Severe concomitant illness, comorbidity or condition that would severely limit life expectancy.
14. Known pregnancy, breast feeding.
15. Known hypersensitivity to Treosulfan, Busulfan, Fludarabine and/or Thiotepa.
16. Participation in another interventional clinical study with an experimental drug, within four weeks prior to patient inclusion.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Male and female children with non-malignant diseases requiring myeloablative conditioning treatment with following allogeneic haematopoietic stem cell transplantation (allo-HSCT) – i.e. primary immunodeficiencies, inborn errors of metabolism, haemoglobinopathies and bone marrow failure syndromes.
MedDRA version: 20.0 Level: HLT Classification code 10021606 Term: Inborn errors of metabolism NEC System Organ Class: 100000004850
MedDRA version: 20.0 Level: HLT Classification code 10036700 Term: Primary immunodeficiency syndromes System Organ Class: 100000004870
MedDRA version: 20.0 Level: HLT Classification code 10018903 Term: Haemoglobinopathies congenital System Organ Class: 100000004850

Intervention(s)

Trade Name: Ovastat 1000 (Treosulfan injection)
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: TREOSULFAN
CAS Number: 299-75-2
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1000-

Trade Name: Ovastat 5000 (Treosulfan injection)
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: TREOSULFAN
CAS Number: 299-75-2
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5000-

Trade Name: Busilvex
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: BUSULFAN
CAS Number: 55-98-1
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 6-

Primary Outcome(s)

Primary end point(s): Comparative evaluation of freedom from transplant (treatment)-related
mortality (TRM), defined as death from any transplant-related cause
from start of conditioning treatment (day -7) until day +100 after HSCT.

Timepoint(s) of evaluation of this end point: Day +100 after HSCT

Main Objective: Comparative evaluation of freedom from transplant (treatment)-related mortality (TRM), defined as death from any transplant-related cause from start of conditioning treatment (day -7) until day +100 after HSCT.

Secondary Objective: Comparative evaluation of:
1. Neutrophil and platelet engraftment after HSCT.
2. Safety including early toxicity (defined as toxicities occurring until day
+28), until day +100 after HSCT, SARs until the end of longer-term
follow-up phase.
3. HSOS, lung toxicity, hepatic toxicity and infections of any CTCAE grade
until day +100.
4. Chimerism on day +28, day +100 and 12 months after HSCT.
5. OS until 12 months after HSCT.
6. Graft failure until 12 months after HSCT.
7. Acute (until day +100) and chronic (until 12 months after HSCT)
GvHD.
8. Use of rescue therapies including DLIs, stem cell infusions with or
without further conditioning regimens, re-occurrence of transfusion
dependence (i.e. necessity of regular transfusions of red blood cells or
platelets.
9. PK parameters of Treosulfan and its epoxides and to develop a PK
model for assessing relevant covariates.
10. Graft failure, cGvHD, donor-type chimerism, OS and TRM during the
longer-term follow-up phase.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Day +28, day +100 and 12 months after HSCT and/or until the end of the longer-term follow-ip phase.

Secondary end point(s): 1. Comparative evaluation of engraftment after HSCT, defined as the 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 x109/L
- a platelet count of at least 20 x109/L
- a platelet count of at least 50 x109/L.
2. Comparative evaluation of safety including early toxicity (defined as
toxicities occurring until day +28), 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 (three years after HSCT of last patient).
3. Comparative evaluation of hepatic sinusoidal obstruction syndrome
(HSOS), lung toxicity (CTCAE term pulmonary fibrosis), hepatic toxicity
(according Bearman's criteria) and infections of any CTCAE grade (nonserious
and serious) until day +100.
4. Comparative evaluation of donor-type chimerism on day +28, day
+100 and 12 months after HSCT.
5. Comparative evaluation of overall survival (OS) until 12 months after
HSCT.
6. Comparative evaluation of primary and secondary graft failure until 12
months after HSCT.
7. Comparative evaluation of incidence and severity of acute (until day
+100) and chronic (until 12 months after HSCT) graft versus host
disease (aGvHD/cGvHD).
8. Comparative evaluation of use of rescue therapies including donorlymphocyte
infusions (DLIs), stem cell infusions with or without further conditioning regimens, re-occurrence of transfusion dependence (i.e.
necessity of regular transfusions of red blood cells or platelets.
9. Evaluation of PK parameters of Treosulfan and its epoxides and to
develop a PK model for assessing relevant covariates.
10. Comparative evaluation of secondary graft failure, cGvHD, donortype
chimerism, OS and TRM during the longer-term follow-up phase.

Secondary ID(s)

MC-FludT.16/NM

Source(s) of Monetary Support

medac GmbH

Ethics review

Status: Approved
Approval date: 16/09/2014
Contact: