| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute myeloid leukemia (AML) in children |
|
| E.1.1.1 | Medical condition in easily understood language |
| AML is a type of blood cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| 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 |
| Primary objectives: To investigate if a conditioning regimen containing one alkylator (Bu) combined with two antimetabolites (Clo and Flu) results in superior 2-year GvHD- and relapse-free survival than a conditioning regimen combining three alkylating agents (BuCyMel) |
|
| E.2.2 | Secondary objectives of the trial |
Exploratory objectives of the randomized part of the study
1) To compare the following outcomes between the 2 arms of the trial:
- neutrophil and platelet engraftment,
- rate of primary and secondary graft failure,
- cumulative incidence of disease relapse,
- cumulative incidence of transplant-related mortality,
- disease-free and overall survival,
- incidence of grade II-IV and III-IV acute GVHD,
- incidence of chronic GVHD,
- rates of Grade ≥ 3 toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0,
- incidence of infections,
- immunological recovery.
- quality of life,
- late effects,
- nutritional status.
2) To analyze the association between pre-HCT Minimal Residual Disease and incidence of relapse, disease-free survival, and overall survival.
Exploratory objectives of the observational part of the study
1) To estimate outcomes as above
2) To analyze the association as above |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1) Investigation of new determinants of busulphan pharmacokinetics in children receiving an allogeneic hematopoietic cell transplantation for acute myeloid leukemia.
Date 06 06 2021
Version:1.0
Aims of the study:
Develop a population popPK model for busulfan based on the collected samples, using currently available busulfan popPK models1–3 as backbone.
2) Validation of the population pharmacokinetics of fludarabine and clofarabine in children receiving an allogeneic hematopoietic cell transplantation for acute myeloid leukemia.
Date 06 06 2021
Version:1.0
Aims of the study
External validation of recently developed population popPK model for clofarabine and fludarabine.
3) Determination of population pharmacokinetics and the therapeutic window of melphalan in children receiving an allogeneic hematopoietic cell transplantation for acute myeloid leukemia: towards individualized dosing
Date: 0606 2021
Version:1.0
Aims of the study
Final goal of the study is to develop an individualized dosing regimen for melphalan in children, aiming for desired exposure to reach optimal clinical outcome.
4) Development and validation of microsampling for agents used in the conditioning for pediatric hematopoietic cell transplantation
Date: 06062021
Version:1.0
Aims of the study
Development and validation of microsampling techniques for agents used in the conditioning including busulfan, fludarabine and clofarabine
5)Impact of different regimens of anti-thymocyte globulin on T-cell immune recovery
in children receiving an allogeneic hematopoietic cell transplantation for acute myeloid leukemia.
Date: 06062021
Version: 1.0
Aims of the study
Investigate the predictive power of early CD4+ T-cell recovery, defined as a CD4+ T-cell count >50x106/L in two consecutive samples within 100 days after HCT, on survival and relapse parameters. Furthermore, we will investigate the impact of individualized versus empirical dosing of ATG on early CD4+ T-cell recovery.
6)Hemorrhagic cystitis (HC) following HCT in AML, comparing conditioning regimes
date: 06062021
Version:1.0
The overall aim of this project is to investigate the frequency, potential risk and predictive factors for developing Hemorraghic cystitis (HC) following allogenic hematopoietic cell transplantation (HCT) within the context of the SCRIPT-AML study.
7)Veno Occlusive Disease (Sinusoidal Obstruction Syndrome)
Date:06062021
Version:1.0
Aim of the study: To explore if different Bufulfex containing pre-transplant conditioning regimens influence the incidence and severity of SOS/VOD in a young patient undergoing stem cell transplantation for treatment of acute myeloid leukemia
8) Transplant-associated thrombotic microangiopathy in children with acute myeloid leukemia: incidence, outcome, predictive factors and prognostic factors
Date 06062021
Version: 1.0
Aims of the study
1. To describe the incidence of TA-TMA in children transplanted for AML
2. To describe the frequency of TA-TMA related mortality in these children; and in those who survive, the time to resolution of TA-TMA and the frequency of residual renal impairment
3. To identify early predictive factors for development of TA-TMA
4. To identify prognostic factors for survival in patients with TA-TMA
9) Deep immune-phenotyping
Date: 06062021
Version: 1.0
Aim of the study: an addon study on immunereconstitution
10) The role of micro chimerism post SCT in childhood AML
Date 06062021
Versions: 1.0
Aim of the study: To prospectively use a new NGS-based method to detect dynamics of recipient DNA and to associate the findings with 1) relapse 2) virus re-activation post SCT and 3) early immune reconstitution
11) Immune escape in relapsed acute myeloid leukemia after hematopoietic cell transplantation
Date: 06062021
Version:1.0
Aims of the study
To study the mechanisms of immune-escape versus immune-recognition in relapsed AML post- SCT |
|
| E.3 | Principal inclusion criteria |
Inclusion criteria for randomization part of the study
- Age ≤18 years at time of initial AML, age ≤ 21 years at transplantation.
-All women of childbearing potential who have to have a negative pregnancy test within 2 weeks prior to the start of treatment.
- Signed informed consent.
- Any relapsed AML after initial treatment according to a defined international AML protocol. (NOPHO-DBH AML 2012/new protocol), OR AML in first remission with transplant indications and treatment according to national AML protocol (NOPHO-DBH AML 2012 or new protocol).
- In hematological remission, defined as
o < 5 % leukemic blasts confirmed by flow cytometry in a bone marrow sample taken ≤14 days prior to start of conditioning and
o no evidence of extramedullary disease, including in CNS and
o no leukemic blasts in the peripheral blood (verified by flow cytometry in case immature cells are detected in the peripheral blood differential).
- Patients must have a related or unrelated donor fulfilling any of the following criteria
o HLA 10/10 allelic matched, identical, sibling BM donor or
o HLA 10/10 or 9/10 allelic matched related/unrelated BM or PBSC donor or
o HLA 5-6/6 unrelated or 6-7-8/8 unrelated Cord Blood (UCB)
- HCT is performed in a study participating center.
7.2 Inclusion criteria for observation/registration only
- Diagnosis of Acute Myeloid Leukemia (AML).
- Indication for allogeneic stem cell transplantation, as defined by primary treatment protocol or treating physician.
- Age ≤18 years at time of initial AML, age ≤ 21 years at transplantation.
- HCT is performed in a study participating center.
- Not eligible for randomization, either due to lack of consent or not fulfilling inclusion criteria for interventional part of the study.
- Signed informed consent to prospectively register follow-up data. |
|
| E.4 | Principal exclusion criteria |
Exclusion criteria for the randomization part of the study
Patients are excluded from the randomization part of the study if any of the criteria below are present:
- Diagnosis of Myelodysplastic syndrome (MDS).
- Diagnosis of Juvenile myelomonocytic leukemia (JMML).
- History of previous malignancy (AML diagnosed as secondary cancer).
- Known diagnosis of Fanconi anemia.
- Prior autologous or allogeneic hematopoietic stem cell transplant.
- Planned prophylactic DLI or other immunotherapy interventions after HCT that are not included in the upfront protocol,
- Planned anti-leukemic medication after HCT that are not included in the upfront protocol
- Known intolerance to any of the chemotherapeutic drugs in the protocol.
- Major organ failure precluding administration of planned chemotherapy.
- Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment.
- Severe concomitant disease that does not allow treatment according to the protocol at the investigator’s discretion; e.g. malformation syndromes, cardiac malformations, metabolic disorders, renal impairment (<30% of normal glomerular filtration rate), severe pulmonary, hepatic or cardiac impairment due to toxicity or infection.
- Karnofsky / Lansky score < 50%
- Females who are pregnant (positive serum or urine βHCG) or breastfeeding.
- Females of childbearing potential (FCBP) or men who have sexual contact with FCBP unwilling to use effective forms of birth control or abstinence for one year after transplantation.
- Subjects unwilling or unable to comply with the study procedures
Exclusion criteria for the observational part of the study
Patients are excluded from the observational part of the study if any of the criteria below are present:
- Diagnosis of Myelodysplastic syndrome (MDS).
- Diagnosis of Juvenile myelomonocytic leukemia (JMML).
- Age above 21 years at time of transplantation
- No consent is given
- Prior autologous or allogeneic hematopoietic stem cell transplant. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the 2-year acute grade III to IV-free, chronic non-limited GVHD-free, relapse free survival (GRFS) measured from the time of HCT to the first event (acute GvHD III-IV, chronic non-limited GvHD, relapse, death) or last follow-up. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 2 years after transplantation |
|
| E.5.2 | Secondary end point(s) |
Exploratory endpoints:
Exploratory endpoints in both interventional and observational parts of the study are as follows:
- Disease free Survival (DFS)
- Overall Survival (OS)
- Cumulative incidence of relapse (CIR)
- Transplant-related Mortality (TRM)
- Hematologic Recovery
- Graft Failure (GF)
- Immune Reconstitution.
- Acute GVHD
- Chronic GVHD
- Infections
- Toxicity
- Transplant-associated hormonal and gonadal late effects
- Nutritional status |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Between 30 days and two years after transplantation |
|
| 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 | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 8 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Hong Kong |
| Israel |
| Belgium |
| Denmark |
| Finland |
| Lithuania |
| Netherlands |
| Norway |
| Spain |
| Sweden |
|
| 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
|
Recruitment period is 5y and follow up after 2y and yearly up until 10y after transplantation.
Enrollment will be stopped after required number of randomized patients has been included. The study might be prolonged if the required number of events has not been reached or the recruitment is slower than expected. For the substudies the end will be the date of the last visit of the last study subject and for some the follow-up time will continue after the master protocol has been closed.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 15 |
| 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 | 15 |
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