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) |
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E.1.1.1 | Medical condition in easily understood language |
Children with blood cancer requiring conditioning treatment with following stem cell transplantation |
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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 | 20.0 |
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 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
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 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
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 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
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 |
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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. |
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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 |
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E.2.3 | Trial contains a sub-study | No |
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. |
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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. |
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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 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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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 |
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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
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
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 | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
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 | 5 |