Clinical trial NCT05477589: Studying Conditioning Regimen In Pediatric Transplantation - AML , SCRIPT-AML
Official title: 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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Acute Myeloid Leukemia (AML) in Remission
Stem Cell Transplantation
Keywords: Leukemia
Leukemia, Myeloid, Acute
Neoplasms
Haematopoietic cell transplantation
Paediatric
Lead sponsor: Vastra Gotaland Region
Sponsor class: OTHER_GOV
First posted: 2022-07-28
Enrollment: 170
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: AML patient eligible for stem cells transplantation will be randomized either get conditioning regimens CloFluBu or BuCyMel.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: 2-year, acute grade III to IV-free, chronic non-limited GvH-free, relapse-free survival (GREF)
timeFrame: 2 years
Secondary outcomes:
measure: Neutrophil and platelet engraftment
timeFrame: 28 days post transplantation
measure: Primary graft failure
timeFrame: +28 days post transplantation
measure: Secondary graft failure
timeFrame: 2 years
measure: Cumulative incidence of relapse
timeFrame: 2 years
measure: The association between pre-HCT MRD and relapse
timeFrame: 2 years
measure: Cumulative incidence of transplant-related mortality
timeFrame: 2 years
measure: Disease-free survival
timeFrame: 2 years
measure: Overall survival
timeFrame: 2 years
measure: Immunological recovery
timeFrame: 2 years
measure: Incidence of grade II-IV and III-IV acute GVHD
timeFrame: +180 days post transplantation
measure: Incidence of chronic GVHD
timeFrame: 2 years
measure: Incidence of grade ≥ 3 toxicity Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease
timeFrame: + 100 days post transplantation
measure: Incidence of grade ≥ 3 toxicity Engraftment Syndrome (ES)
timeFrame: 2 years
measure: Incidence of grade ≥ 3 toxicity Transplant-associated thrombotic microangiopathy (TA-TMA)
timeFrame: 2 years
measure: Incidence of grade ≥ 3 toxicity Hemorrhagic Cystitis (HC)
timeFrame: 2 years
measure: Incidence of grade ≥ 3 infections
timeFrame: 2 years
measure: Health-Related Quality of Life, HRQoL.
timeFrame: 2 years
measure: Transplant-associated hormonal and gonadal late effects
timeFrame: 2 years
measure: Nutritional status
timeFrame: 2 years
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: L'Hôpital Universitaire des Enfants Reine Fabiola (HUDERF)
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc (CUSL)
city: Ghent
country: Belgium
facility: Department of Pediatric Hematology, Oncology and SCT, Ghent University Hospital
city: Leuven
country: Belgium
facility: University Hospital Leuven
city: Liège
country: Belgium
facility: Centre Hospitalier Régional de la Citadelle (CHR)/CHU Liège
city: Copenhagen
country: Denmark
facility: Paediatric Stem Cell Transplant and Immune Deficiency, Department of Pediatric and Adolescent Medicine, Section 4072, Rigshospitalet University Hospital of Copenhagen
city: Helsinki
country: Finland
facility: Division of Hematology, Oncology, and Stem Cell Transplantation, The New Children's Hospital, Helsinki University Hospital
city: Hong Kong
country: Hong Kong
facility: Department of Pediatrics and Adolescent Medicine, Hong King Children's Hospital
city: Petach Tikva
country: Israel
facility: Schneider Children's Medical Center of Israel
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital Santaros Klinikos Center for Pediatric Oncology and Hematology
city: Utrecht
country: Netherlands
facility: Princess Máxima Center for Pediatric Oncology
city: Oslo
country: Norway
facility: Department of Pediatric Hematology and Oncology, Oslo University HospitalOslo University Hospital
city: Madrid
country: Spain
facility: Stemcelltransplant unit Hospital Niño Jesús
city: Gothenburg
country: Sweden
facility: Queen Silvia Children's Hospital, Sahlgrenska University Hospital
city: Lund
country: Sweden
facility: Barncancercentrum, avdelning 64, Skane University Hospital
city: Stockholm
country: Sweden
facility: Pediatric Hematology immunology and stem cell transplantation Astrid Lindgren children's Hospital Huddinge K86-88
city: Uppsala
country: Sweden
facility: Childrens department for Blood and tumor diseases Uppsala University Hospital
Study officials:
affiliation: Sahlgrenska University Hospital
name: Karin Mellgren, Prof. MD
role: STUDY_CHAIR
affiliation: Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
name: Birgitta Versluys, MD, Phd
role: PRINCIPAL_INVESTIGATOR
References: