Studying Conditioning Regimen In Pediatric Transplantation - AML , SCRIPT-AML

Study Overview
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Brief Summary
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It is a randomized phase 3 study comparing two conditioning regimens in children with Acute Myeloid Leukemia, AML, undergoing allogenic stem cell transplantation. The primary aim is to investigate if a conditioning regimen containing one alkylator (Bu) combined with two antimetabolites (Clo and Flu) results in superior 2-year acute grade III to IV-free, chronic non-limited GvHD-free, relapse free survival than a conditioning regimen combining three alkylating agents (BuCyMel)

Detailed Description
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The study is designed as an open-label randomized phase III, multicenter superiority trial comparing two conditioning regimens CloFluBu and BuCyMel in children with acute myeloid leukemia (AML) with per-protocol indications to allogeneic hematopoietic stem cell transplantation with a myeloablative conditioning. This study is composed of two parts - an interventional part that includes randomization, and an observational part. The interventional part is a phase III randomized, open label, multicenter parallel group trial comparing two conditioning regimens used in pediatric HCT: a three alkylator combination of busulfan, cyclophosphamide and melphalan (BuCyMel, standard arm) and a combination of clofarabine, fludarabine and busulfan in which two alkylators are replaced by antimetabolites (CloFluBu, experimental arm). The observational part will prospectively register outcome measures of transplantation in patients not fulfilling criteria for participation in the interventional part of the study (due to lack of complete remission, lack of matched sibling or unrelated donor, who were not recruited to a national upfront protocol or who decline participation in randomization) but consenting to registration of the data.

Official Title
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A Randomized, Multi-Center Phase III Trial Comparing Two Conditioning Regimens (CloFluBu and BuCyMel) in Children With Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation.

Conditions
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Acute Myeloid Leukemia (AML) in Remission, Stem Cell Transplantation

Intervention / Treatment
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* Drug: busulfan, cyclophosphamide and melphalan, BuCyMel
* Drug: clofarabine, fludarabine and busulfan, CloFluBu


Participation Criteria
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Eligibility Criteria
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Inclusion criteria for randomization part of the study: Age ≤18 years at time of initial AML, age ≤ 21 years at transplantation. HCT is performed in a study participating center 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: < 5 % leukemic blasts confirmed by flow cytometry (in patients with an informative leukemia associated immunophenotype) in a bone marrow sample taken ≤14 days prior to start of conditioning and no evidence of extramedullary disease, including in CNS and 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: HLA 10/10 allelic matched, identical, sibling BM donor or HLA 10/10 or 9/10 allelic matched related/unrelated BM or PBSC donor orHLA 5-6/6 unrelated or 6-7-8/8 unrelated Cord Blood (UCB) Inclusion criteria for observation/registration only: Diagnosis of acute myeloid leukemia 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. 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. Exclusion criteria for the randomization part of the study : 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 immunotherapeutic 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 or men who have sexual contact with females of childbearing potential 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: Diagnosis of Myelodysplastic syndrome (MDS). Diagnosis of Juvenile myelomonocytic leukemia (JMML). Age above 21 years at time of transplantation No consent is given to prospectively register outcome data Prior autologous or allogeneic hematopoietic stem cell transplant.

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: AML patient eligible for stem cells transplantation will be randomized either get conditioning regimens CloFluBu or BuCyMel.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: BuCyMel<br>a combination of busulfan, cyclophosphamide and melphalan, conditioning regimen | Drug: busulfan, cyclophosphamide and melphalan, BuCyMel<br>* a three alkylator combination of busulfan, cyclophosphamide and melphalan (BuCyMel, standard arm)<br>* Other names: BuCyMel;|
| Experimental: CloFluBu<br>a combination of clofarabine, fludarabine and busulfan conditioning regimen | Drug: clofarabine, fludarabine and busulfan, CloFluBu<br>* combination of clofarabine, fludarabine and busulfan in which two alkylators are replaced by antimetabolites (CloFluBu, experimental arm)<br>* Other names: CloFluBu;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year, acute grade III to IV-free, chronic non-limited GvH-free, relapse-free survival (GREF) | To investigate if a conditioning regimen containing one alkylator (Bu) combined with two antimetabolites (Clo and Flu) results in superior 2-year acute grade III to IV-free, chronic non-limited GvHD-free, relapse free survival (GRFS) than a conditioning regimen combining three alkylating agents (BuCyMel) | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neutrophil and platelet engraftment | time to engraftment after stem cells transplantation, in all patients | 28 days post transplantation | 
| Primary graft failure | The incidence of graft failure defined as neutrophil recovery by day +28 post transplantation | +28 days post transplantation | 
| Secondary graft failure | The incidence of secondary graft failure | 2 years | 
| Cumulative incidence of relapse | The incidence of cumulative incidence of relapse during the first two years after transplantation | 2 years | 
| The association between pre-HCT MRD and relapse | % of remaining leukemic cells in the last bone marrow sample taken before start of conditioning | 2 years | 
| Cumulative incidence of transplant-related mortality | The incidence of transplant-related mortality at 2 years | 2 years | 
| Disease-free survival | Disease-free survival at 2 years | 2 years | 
| Overall survival | Overall survival at 2 years | 2 years | 
| Immunological recovery | Immunological recovery of CD3+ and CD4+ cells in peripheral blood | 2 years | 
| Incidence of grade II-IV and III-IV acute GVHD | The incidence of acute GvHD | +180 days post transplantation | 
| Incidence of chronic GVHD | The incidence of cGVHD | 2 years | 
| Incidence of grade ≥ 3 toxicity Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease | The rates of grade ≥ 3 Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease | + 100 days post transplantation | 
| Incidence of grade ≥ 3 toxicity Engraftment Syndrome (ES) | The incidence of engraftment syndome | 2 years | 
| Incidence of grade ≥ 3 toxicity Transplant-associated thrombotic microangiopathy (TA-TMA) | The incidence of TA-TMA | 2 years | 
| Incidence of grade ≥ 3 toxicity Hemorrhagic Cystitis (HC) | The incidence of HC | 2 years | 
| Incidence of grade ≥ 3 infections | The incidence of grade ≥ 3 infections of bacterial, viral and fungal origin | 2 years | 
| Health-Related Quality of Life, HRQoL. | HRQoL will be measured at baseline and at certain intervals using the quality of life instrument EQ-5D-Y, (Youth)™which include 2 measurements, the descriptive scale ( i.g. the score 1 is no problems and 3 is a lot of problems) and the VAS scale( 1 is the worst health and 100 is the best health that day). | 2 years | 
| Transplant-associated hormonal and gonadal late effects | the date of spontaneous puberty, date of spontaneous menarche for female patients and mean testicular volume for male patients, use of hormonal replacement therapy and use of fertility preservation | 2 years | 
| Nutritional status | BMI in kg/m^2 at baseline and post transplantation | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, Leukemia, Myeloid, Acute, Neoplasms, Haematopoietic cell transplantation, Paediatric