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

Stem Cell Transplantation Clinical Trial

— 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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05477589
• Other study ID #: 2021-003282-36
• Status: Recruiting
• Phase: Phase 3
• Start date: June 7, 2022
• Est. completion date: December 31, 2031

Study information

• Verified date: June 2022
• Source: Vastra Gotaland Region
• Contact: Karin Mellgren, Prof. MD
• Phone: +46 (0)31 3421000
• Email: karin.mellgren[@]vgregion.se
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 170
• Est. completion date: December 31, 2031
• Est. primary completion date: December 31, 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

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 ßHCG) 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.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Stem Cell Transplantation

Intervention

Drug:
• busulfan, cyclophosphamide and melphalan, BuCyMel
a three alkylator combination of busulfan, cyclophosphamide and melphalan (BuCyMel, standard arm)
• clofarabine, fludarabine and busulfan, CloFluBu
combination of clofarabine, fludarabine and busulfan in which two alkylators are replaced by antimetabolites (CloFluBu, experimental arm)

Locations

Country	Name	City	State
Belgium	Cliniques Universitaires Saint-Luc (CUSL)	Brussels
Belgium	L'Hôpital Universitaire des Enfants Reine Fabiola (HUDERF)	Brussels
Belgium	Department of Pediatric Hematology, Oncology and SCT, Ghent University Hospital	Ghent
Belgium	University Hospital Leuven	Leuven
Belgium	Centre Hospitalier Régional de la Citadelle (CHR)/CHU Liège	Liège
Denmark	Paediatric Stem Cell Transplant and Immune Deficiency, Department of Pediatric and Adolescent Medicine, Section 4072, Rigshospitalet University Hospital of Copenhagen	Copenhagen
Finland	Division of Hematology, Oncology, and Stem Cell Transplantation, The New Children's Hospital, Helsinki University Hospital	Helsinki
Hong Kong	Department of Pediatrics and Adolescent Medicine, Hong King Children's Hospital	Hong Kong
Israel	Schneider Children's Medical Center of Israel	Petach Tikva
Lithuania	Vilnius University Hospital Santaros Klinikos Center for Pediatric Oncology and Hematology	Vilnius
Netherlands	Princess Máxima Center for Pediatric Oncology	Utrecht
Norway	Department of Pediatric Hematology and Oncology, Oslo University HospitalOslo University Hospital	Oslo
Spain	Stemcelltransplant unit Hospital Niño Jesús	Madrid
Sweden	Queen Silvia Children's Hospital, Sahlgrenska University Hospital	Gothenburg
Sweden	Barncancercentrum, avdelning 64, Skane University Hospital	Lund
Sweden	Pediatric Hematology immunology and stem cell transplantation Astrid Lindgren children's Hospital Huddinge K86-88	Stockholm
Sweden	Childrens department for Blood and tumor diseases Uppsala University Hospital	Uppsala

Sponsors (1)

Lead Sponsor	Collaborator
Vastra Gotaland Region

Countries where clinical trial is conducted

Belgium,  Denmark,  Finland,  Hong Kong,  Israel,  Lithuania,  Netherlands,  Norway,  Spain,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Neutrophil and platelet engraftment	time to engraftment after stem cells transplantation, in all patients	28 days post transplantation
Secondary	Primary graft failure	The incidence of graft failure defined as neutrophil recovery by day +28 post transplantation	+28 days post transplantation
Secondary	Secondary graft failure	The incidence of secondary graft failure	2 years
Secondary	Cumulative incidence of relapse	The incidence of cumulative incidence of relapse during the first two years after transplantation	2 years
Secondary	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
Secondary	Cumulative incidence of transplant-related mortality	The incidence of transplant-related mortality at 2 years	2 years
Secondary	Disease-free survival	Disease-free survival at 2 years	2 years
Secondary	Overall survival	Overall survival at 2 years	2 years
Secondary	Immunological recovery	Immunological recovery of CD3+ and CD4+ cells in peripheral blood	2 years
Secondary	Incidence of grade II-IV and III-IV acute GVHD	The incidence of acute GvHD	+180 days post transplantation
Secondary	Incidence of chronic GVHD	The incidence of cGVHD	2 years
Secondary	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
Secondary	Incidence of grade = 3 toxicity Engraftment Syndrome (ES)	The incidence of engraftment syndome	2 years
Secondary	Incidence of grade = 3 toxicity Transplant-associated thrombotic microangiopathy (TA-TMA)	The incidence of TA-TMA	2 years
Secondary	Incidence of grade = 3 toxicity Hemorrhagic Cystitis (HC)	The incidence of HC	2 years
Secondary	Incidence of grade = 3 infections	The incidence of grade = 3 infections of bacterial, viral and fungal origin	2 years
Secondary	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
Secondary	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
Secondary	Nutritional status	BMI in kg/m^2 at baseline and post transplantation	2 years