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: 1
Conditions
Sponsors
medac GmbH
Eligibility
Sex/Gender
All
Inclusion 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 =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
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 ( 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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. Neutropihil 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. ; 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 | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 o | — |
Countries
Austria, Czech Republic, Germany, Italy, Poland
Contacts
Public ContactGhalia Hachem
INC Research UK Limited
Outcome results
None listed