This study has been transitioned to CTIS with ID 2023-505512-37-00 check the CTIS register for the current data. The primary objective of the randomized part of the protocol is to investigate if a conditioning regimen containing one alkylator (Bu)…
ID
Source
Brief title
Condition
- Leukaemias
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary end-point is a comparison of the 2-year acute grade III to IV-free,
chronic nonlimited GVHD-free, relapse-free survival (GRFS) between the 2 arms
of the trial. GRFS is defined as the time from randomization to the first event
(acute GvHD III-IV, chronic nonlimited GvHD, relapse, death) or last follow-up.
Secondary outcome
Exploratory endpoints in both interventional and observational parts of the
study:
- Disease free Survival (DFS)
- Overall Survival (OS)
- Cumulative incidence of relapse (CIR)
- Transplant-related Mortality (TRM)
- Hematologic Recovery
- Graft Failure (GF)
- Immunereconstitution
- Acute GVHD
- Chronic GVHD
- Infections
- Toxicity
Background summary
The role of conditioning regimen in allogeneic hematopoietic stem cell
transplantation (HCT) of acute myeloid leukemia (AML) in pediatric patients is
not well studied. Donor choice, graft source, type of conditioning regimen and
intensity of GVHD prophylaxis can significantly impact both anti-leukemic
efficacy and transplant related mortality (TRM), and the benefit of reduced
incidence of relapse after HCT can be counterbalanced by an increased TRM rate.
Historically, there have been two standard conditioning regimens for leukemia,
namely regimens consisting of Busulfan and Cyclophosphamide or TBI and
Cyclophosphamide. Relapse after HCT was mainly regarded as conditioning regimen
failure. Therefore, the addition of a third alkylator (Melphalan) to a standard
BuCy regimen was investigated.
Escalation of the intensity of a standard conditioning regimen by the addition
of a third alkylating agent is associated with a high toxic burden for the
patients.To find a less toxic conditioning regimen with potent antileukemic
activity, the combination of Clofarabine, Fludarabine, and Busulfan (CloFluBu)
was investigated.
BuCyMel had proven to be an efficacious conditioning regimen in allo-HCT for
pediatric AML but comes with high toxicity. CloFluBu might be a less toxic
alternative, with good anti-leukemic properties. This prospective randomized
study will compare both conditioning regimens for the primary endpoint 2-year
acute grade III to IV-free, chronic nonlimited GVHD-free, relapse free (GRFS).
Study objective
This study has been transitioned to CTIS with ID 2023-505512-37-00 check the CTIS register for the current data.
The primary objective of the randomized part of the protocol 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-mild GVHD-free, relapse-free survival than a conditioning
regimen combining three alkylating agents (BuCyMel).
Exploratory objectives:
1) To compare the following outcomes between the 2 arms of the trial:
• neutrophil and platelet engraftment
• rate of primary and secondary graft failure
• cumulative incidence of relapse
• cumulative incidence of transplant-related mortality
• disease-free and overall survival
• incidence of grade II-IV and III-IV acute GVHD
• incidence of chronic GVHD
• rates of Grade >= 3 toxicity according to the Common Terminology Criteria for
Adverse Events (CTCAE) Version 5.0, and specifically
o Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease (SOS/VOD)
o Engraftment Syndrome (ES)
o Transplant-associated thrombotic microangiopathy (TA-TMA)
o Hemorrhagic Cystitis (HC)
o Mucositis
• incidence of infections
• immunological recovery
• quality of life
• late effects
• nutritional status
2) To analyze the association between pre-HCT minimal residual disease in the
last bone marrow sample taken before start of conditioning, and incidence of
relapse, disease-free survival, and overall survival.
Study design
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 primary outcome of 2-year acute grade III to IV-free, chronic non-limited
GVHD-free, relapse-free survival (GRFS) will be compared between the two
conditioning regimens.
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.
Intervention
Randomisation between 2 conditioning regimens:
1) BuCyMel, standard arm
2) CloFluBu, experimental arm
Study burden and risks
This trial studies the conditioning in search of the least toxic effective
regimen. The additional burden on the participating patient is minimal, the
significance for patients in the future is great. The additional bone marrow
punctures are not perceived as a great burden by patients and parents. They
often ask for it, to be informed about the status of the leukemia even after
the transplantation, they are used to it during the leukemia treatment as well.
Behandlingsvägen 7
Göteborg 41650
NL
Behandlingsvägen 7
Göteborg 41650
NL
Listed location countries
Age
Inclusion 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
o < 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
o no evidence of extramedullary disease, including in CNS and
o 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
o HLA 10/10 allelic matched, identical, sibling BM donor or
o HLA 10/10 or 9/10 allelic matched related/unrelated BM or PBSC donor or
o HLA 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
Exclusion criteria for randomization part of the study:
• 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 observation/registration only:
• 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-505512-37-00 |
| EudraCT | EUCTR2021-003282-36-NL |
| CCMO | NL83430.041.23 |