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.

Overview

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.

Interventions

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

Primary outcome measures

• 2-year, acute grade III to IV-free, chronic non-limited GvH-free, relapse-free survival (GREF) [Time frame: 2 years]

Secondary outcome measures (12)

• Neutrophil and platelet engraftment [Time frame: 28 days post transplantation]
• Primary graft failure [Time frame: +28 days post transplantation]
• Secondary graft failure [Time frame: 2 years]
• Cumulative incidence of relapse [Time frame: 2 years]
• The association between pre-HCT MRD and relapse [Time frame: 2 years]
• Cumulative incidence of transplant-related mortality [Time frame: 2 years]
• Disease-free survival [Time frame: 2 years]
• Overall survival [Time frame: 2 years]
• Immunological recovery [Time frame: 2 years]
• Incidence of grade II-IV and III-IV acute GVHD [Time frame: +180 days post transplantation]
• Incidence of chronic GVHD [Time frame: 2 years]
• Incidence of grade ≥ 3 toxicity Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease [Time frame: + 100 days post transplantation]

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Factorial

Masking

Open label

Primary purpose

Treatment

Study locations

Belgium · 5 centers

• L'Hôpital Universitaire des Enfants Reine Fabiola (HUDERF) — Brussels
• Cliniques Universitaires Saint-Luc (CUSL) — Brussels
• Department of Pediatric Hematology, Oncology and SCT, Ghent University Hospital — Ghent
• University Hospital Leuven — Leuven
• Centre Hospitalier Régional de la Citadelle (CHR)/CHU Liège — Liège

Sweden · 4 centers

• Queen Silvia Children's Hospital, Sahlgrenska University Hospital — Gothenburg
• Barncancercentrum, avdelning 64, Skane University Hospital — Lund
• Pediatric Hematology immunology and stem cell transplantation Astrid Lindgren children's H — Stockholm
• Childrens department for Blood and tumor diseases Uppsala University Hospital — Uppsala

Denmark · 1 center

• Paediatric Stem Cell Transplant and Immune Deficiency, Department of Pediatric and Adolesc — Copenhagen

Finland · 1 center

• Division of Hematology, Oncology, and Stem Cell Transplantation, The New Children's Hospit — Helsinki

Hong Kong · 1 center

• Department of Pediatrics and Adolescent Medicine, Hong King Children's Hospital — Hong Kong

Israel · 1 center

• Schneider Children's Medical Center of Israel — Petah Tikva

Lithuania · 1 center

• Vilnius University Hospital Santaros Klinikos Center for Pediatric Oncology and Hematology — Vilnius

Netherlands · 1 center

• Princess Máxima Center for Pediatric Oncology — Utrecht

Norway · 1 center

• Department of Pediatric Hematology and Oncology, Oslo University HospitalOslo University H — Oslo

Spain · 1 center

• Stemcelltransplant unit Hospital Niño Jesús — Madrid

Identifiers

NCT: NCT05477589 · 2021-003282-36

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗