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

December 16, 2024 updated by: Vastra Gotaland Region

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.

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)

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

170

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Belgium
      • Brussels, Belgium, 1020
        • Not yet recruiting
        • L'hôpital Universitaire des enfants Reine Fabiola (Huderf)
        • Contact:
        • Contact:
        • Principal Investigator:
          • Pauline Mazilier, MD, PhD
      • Brussels, Belgium, 1200
        • Not yet recruiting
        • Cliniques Universitaires Saint-Luc (CUSL)
        • Contact:
          • Cécile Boulanger, MD, PhD
        • Principal Investigator:
          • Cécile Boulanger, MD, PhD
      • Ghent, Belgium, 9000
        • Not yet recruiting
        • Department of Pediatric Hematology, Oncology and SCT, Ghent University Hospital
        • Contact:
        • Contact:
        • Principal Investigator:
          • Victoria Bordon, MD, PhD
      • Leuven, Belgium, 3000
        • Not yet recruiting
        • University Hospital Leuven
        • Contact:
        • Contact:
        • Principal Investigator:
          • Anne Uyttebroeck, MD, PhD
      • Liège, Belgium, 4000
        • Not yet recruiting
        • Centre Hospitalier Régional de la Citadelle (CHR)/CHU Liège
        • Contact:
        • Contact:
        • Principal Investigator:
          • Evelyne Willems, MD, PhD
  • Denmark
      • Copenhagen, Denmark, DK-2100
        • Recruiting
        • Paediatric Stem Cell Transplant and Immune Deficiency, Department of Pediatric and Adolescent Medicine, Section 4072, Rigshospitalet University Hospital of Copenhagen
        • Contact:
        • Contact:
        • Principal Investigator:
          • Marianne Ifversen, MD, PhD
  • Finland
      • Helsinki, Finland, FIN-00290
        • Recruiting
        • Division of Hematology, Oncology, and Stem Cell Transplantation, The New Children's Hospital, Helsinki University Hospital
        • Contact:
        • Contact:
        • Principal Investigator:
          • Samppa Ryhänen, MD, PhD
  • Hong Kong
      • Hong Kong, Hong Kong
        • Not yet recruiting
        • Department of Pediatrics and Adolescent Medicine, Hong King Children's Hospital
        • Contact:
        • Principal Investigator:
          • Daniel Cheuk, MD, PhD
  • Israel
      • Petach Tikva, Israel, 4920235
        • Not yet recruiting
        • Schneider Children's Medical Center of Israel
        • Contact:
        • Principal Investigator:
          • Jerry Stein, MD, PhD
  • Lithuania
      • Vilnius, Lithuania, 08661
        • Not yet recruiting
        • Vilnius University Hospital Santaros Klinikos Center for Pediatric Oncology and Hematology
        • Contact:
        • Contact:
        • Principal Investigator:
          • Jelena Rascon, MD, PhD
  • Netherlands
      • Utrecht, Netherlands, 3584CS
        • Recruiting
        • Princess Máxima Center for Pediatric Oncology
        • Contact:
        • Principal Investigator:
          • Birgitta Versluys, MD, PhD
  • Norway
      • Oslo, Norway, 0424
        • Recruiting
        • Department of Pediatric Hematology and Oncology, Oslo University HospitalOslo University Hospital
        • Contact:
        • Principal Investigator:
          • Jochen Buechner, MD, PhD
  • Spain
      • Madrid, Spain, 28009
        • Not yet recruiting
        • Stemcelltransplant unit Hospital Niño Jesús
        • Contact:
        • Contact:
        • Principal Investigator:
          • José M Fernandez, MD, PhD
  • Sweden
      • Gothenburg, Sweden, 41685
        • Recruiting
        • Queen Silvia Children's Hospital, Sahlgrenska University Hospital
        • Contact:
        • Contact:
        • Principal Investigator:
          • Cecilia Langenskiöld, MD, PhD
      • Lund, Sweden, SE- 221 85
        • Recruiting
        • Barncancercentrum, avdelning 64, Skane University Hospital
        • Contact:
        • Contact:
        • Principal Investigator:
          • Kees-Jan Pronk, MD, PhD
        • Sub-Investigator:
          • Dominik Turkiewicz, MD, PhD
      • Stockholm, Sweden, 141 86
        • Not yet recruiting
        • Pediatric Hematology immunology and stem cell transplantation Astrid Lindgren children's Hospital Huddinge K86-88
        • Principal Investigator:
          • Mikael Sundin, MD, PhD
        • Contact:
        • Contact:
      • Uppsala, Sweden, SE-751 85
        • Not yet recruiting
        • Childrens department for Blood and tumor diseases Uppsala University Hospital
        • Contact:
        • Principal Investigator:
          • Natalja Jackmann, MD, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 14 years (Child, Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: None (Open Label)

Arms and Interventions

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

What is the study measuring?

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)
Time Frame: 2 years
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 Frame: 28 days post transplantation
time to engraftment after stem cells transplantation, in all patients
28 days post transplantation
Primary graft failure
Time Frame: +28 days post transplantation
The incidence of graft failure defined as neutrophil recovery by day +28 post transplantation
+28 days post transplantation
Secondary graft failure
Time Frame: 2 years
The incidence of secondary graft failure
2 years
Cumulative incidence of relapse
Time Frame: 2 years
The incidence of cumulative incidence of relapse during the first two years after transplantation
2 years
The association between pre-HCT MRD and relapse
Time Frame: 2 years
% of remaining leukemic cells in the last bone marrow sample taken before start of conditioning
2 years
Cumulative incidence of transplant-related mortality
Time Frame: 2 years
The incidence of transplant-related mortality at 2 years
2 years
Disease-free survival
Time Frame: 2 years
Disease-free survival at 2 years
2 years
Overall survival
Time Frame: 2 years
Overall survival at 2 years
2 years
Immunological recovery
Time Frame: 2 years
Immunological recovery of CD3+ and CD4+ cells in peripheral blood
2 years
Incidence of grade II-IV and III-IV acute GVHD
Time Frame: +180 days post transplantation
The incidence of acute GvHD
+180 days post transplantation
Incidence of chronic GVHD
Time Frame: 2 years
The incidence of cGVHD
2 years
Incidence of grade ≥ 3 toxicity Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease
Time Frame: + 100 days post transplantation
The rates of grade ≥ 3 Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease
+ 100 days post transplantation
Incidence of grade ≥ 3 toxicity Engraftment Syndrome (ES)
Time Frame: 2 years
The incidence of engraftment syndome
2 years
Incidence of grade ≥ 3 toxicity Transplant-associated thrombotic microangiopathy (TA-TMA)
Time Frame: 2 years
The incidence of TA-TMA
2 years
Incidence of grade ≥ 3 toxicity Hemorrhagic Cystitis (HC)
Time Frame: 2 years
The incidence of HC
2 years
Incidence of grade ≥ 3 infections
Time Frame: 2 years
The incidence of grade ≥ 3 infections of bacterial, viral and fungal origin
2 years
Health-Related Quality of Life, HRQoL.
Time Frame: 2 years
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
Time Frame: 2 years
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
Time Frame: 2 years
BMI in kg/m^2 at baseline and post transplantation
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Vastra Gotaland Region

Investigators

  • Principal Investigator: Birgitta Versluys, MD, Phd, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
  • Study Chair: Karin Mellgren, Prof. MD, Sahlgrenska University Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 7, 2022

Primary Completion (Estimated)

December 31, 2029

Study Completion (Estimated)

December 31, 2031

Study Registration Dates

First Submitted

July 13, 2022

First Submitted That Met QC Criteria

July 25, 2022

First Posted (Actual)

July 28, 2022

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

December 16, 2024

Last Verified

November 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2021-003282-36

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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