NCT00822393 · CITED IN SOURCE DOCUMENTS

Clinical Phase III Trial Treosulfan-based Conditioning Versus Reduced-intensity Conditioning (RIC)

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2020-07-30

This randomized allogeneic transplantation protocol compares i.v. Treosulfan-based conditioning therapy with reduced intensity i.v. Busulfan-based conditioning in adult AML and MDS patients at increased risk for standard conditioning therapies. The protocol is based on results of previous phase I/II trials evaluating Treosulfan/Fludarabine conditioning prior to allogeneic haematopoietic stem cell transplantation. The reference arm (reduced intensity i.v. Busulfan/Fludarabine) is considered to be accepted medical practice for the study patient population.

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What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part

eligibility Criteria: Inclusion Criteria: 1. Patients with acute myeloid leukaemia acc. to WHO, 2008 (AML in complete remission at transplant, i.e. blast counts \< 5 % in bone marrow) or myelodysplastic syndrome acc. to WHO, 2008 (MDS with blast counts \< 20 % in bone marrow during disease history) indicated for allogeneic haematopoietic progenitor cell transplantation but considered to be at increased risk for standard conditioning therapies according to the following criteria: * patients aged ≥ 50 years at transplant and / or * patients with a HCT-CI score \> 2 \[acc. to Sorror et al., 2005\] 2. Availability of an HLA-identical sibling donor (MRD) or HLA-identical unrelated donor (MUD). Donor selection is based on molecular high resolution typing (4 digits) of class II alleles of the DRB1 and DQB1 gene loci and molecular (at least) low resolution typing (2 digits) of class I alleles (i.e., antigens) of the HLA- A, B, and C gene loci. In case, no class I and class II completely identical donor (10 out of 10 gene loci) can be identified, one antigen disparity (class I) and/or one allele disparity (class II) between patient and donor are acceptable. Conversely, disparity of two antigens (irrespective of the involved gene loci) cannot be accepted. These definitions for the required degree of histocompatibility apply to the selection of related as well as of unrelated donors. 3. Adult patients of both gender, age 18 - 70 years 4. Karnofsky Index ≥ 60 % 5. Written informed consent 6. Men capable of reproduction and women of childbearing potential must be willing to consent to using a highly effective method of birth control such as condoms, implants, injectables, combined oral contraceptives, IUDs, sexual abstinence or vasectomised partner while on treatment and for at least 6 months thereafter Exclusion Criteria: 1. Patients with acute promyelocytic leukaemia with t(15;17)(q22;q12) and in CR1 2. Patients considered contra-indicated for allogeneic HSCT due to severe concomitant illness (within three weeks prior to scheduled day -6): * patients with severe renal impairment like patients on dialysis or prior renal transplantation or S-creatinine \> 3.0 x ULN or calculated creatinine-clearance \< 60 ml/min * patients with severe pulmonary impairment, DLCOsb (Hb-adjusted)/or FEV1 \< 50 % or severe dyspnoea at rest or requiring oxygen supply * patients with severe cardiac impairment diagnosed by echocardiography and LVEF \< 40 % * patients with severe hepatic impairment indicated by hyperbilirubinaemia \> 3 x ULN or ALT / AST \> 5 x ULN 3. Active malignant involvement of the CNS 4. HIV-positivity, active non-controlled infectious disease under treatment (no decrease of CRP or PCT) including active viral liver infection 5. Previous allogeneic HSCT 6. Pleural effusion or ascites \> 1.0 L 7. Pregnancy or lactation 8. Known hypersensitivity to treosulfan, busulfan and/or related ingredients 9. Participation in another experimental drug trial within 4 weeks prior to day -6 of the protocol 10. Non-cooperative behaviour or non-compliance 11. Psychiatric diseases or conditions that might compromise the ability to give informed consent
healthy Volunteers: false
maximum Age: 70 Years
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
Busulfan
intervention Names
Drug: Busulfan
label
1
type
ACTIVE_COMPARATOR
description
Treosulfan
intervention Names
Drug: Treosulfan
label
2
type
EXPERIMENTAL

interventions

arm Group Labels
1
description
4 x 0.8 mg/kg/d Intravenous Day -4 and -3
name
Busulfan
type
DRUG
arm Group Labels
2
description
10 g/m2/d Intravenous Day -4, -3, -2
name
Treosulfan
type
DRUG

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 570
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

measure
Event-free survival (EFS)
time Frame
within 2 years after transplantation

secondary Outcomes

measure
Comparative evaluation of incidence of CTC grade III/IV mucositis/stomatitis between day -6 and day +28
time Frame
between day -6 and day +28

Full study description

brief Summary: This randomized allogeneic transplantation protocol compares i.v. Treosulfan-based conditioning therapy with reduced intensity i.v. Busulfan-based conditioning in adult AML and MDS patients at increased risk for standard conditioning therapies. The protocol is based on results of previous phase I/II trials evaluating Treosulfan/Fludarabine conditioning prior to allogeneic haematopoietic stem cell transplantation. The reference arm (reduced intensity i.v. Busulfan/Fludarabine) is considered to be accepted medical practice for the study patient population.
detailed Description: To compare efficacy and safety of Treosulfan-based conditioning (test) with i.v. Busulfan-based reduced intensity conditioning (reference). The statistical aim of the study is to show non-inferiority with respect to: Event-free survival (EFS) within 2 years after transplantation. Events are defined as relapse of disease, graft failure or death (whatever occurs first). 1. Comparative evaluation of incidence of CTC grade III/IV mucositis/stomatitis between day -6 and day +28 2. Comparative evaluation of overall survival (OS) and cumulative incidence of relapse (RI) as well as non-relapse mortality (NRM) and transplantation-related mortality (TRM)within 2 years after transplantation 3. Comparative evaluation of day +28 conditional cumulative incidence of engraftment 4. Comparative evaluation of day +28 and day +100 incidence of complete donor-type chimerism 5. Comparative evaluation of cumulative incidence of acute and chronic GvHD within 2 years after transplantation 6. Comparative evaluation of incidence of other CTC grade III/IV adverse events between day -6 and day +28 Individual patients will be followed-up for at most 2 years after transplantation. Three confirmatory interim evaluations and one final analysis are planned, which allow to stop the trial as soon as the question of non-inferiority is answered (as outlined below). In addition, post-surveillance with respect to OS and EFS will be conducted one year after transplantation of the last randomised patient.

Source references

references

citation
Beelen DW, Trenschel R, Stelljes M, Groth C, Masszi T, Remenyi P, Wagner-Drouet EM, Hauptrock B, Dreger P, Luft T, Bethge W, Vogel W, Ciceri F, Peccatori J, Stolzel F, Schetelig J, Junghanss C, Grosse-Thie C, Michallet M, Labussiere-Wallet H, Schaefer-Eckart K, Dressler S, Grigoleit GU, Mielke S, Scheid C, Holtick U, Patriarca F, Medeot M, Rambaldi A, Mico MC, Niederwieser D, Franke GN, Hilgendorf I, Winkelmann NR, Russo D, Socie G, Peffault de Latour R, Holler E, Wolff D, Glass B, Casper J, Wulf G, Menzel H, Basara N, Bieniaszewska M, Stuhler G, Verbeek M, Grass S, Iori AP, Finke J, Benedetti F, Pichlmeier U, Hemmelmann C, Tribanek M, Klein A, Mylius HA, Baumgart J, Dzierzak-Mietla M, Markiewicz M. Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial. Lancet Haematol. 2020 Jan;7(1):e28-e39. doi: 10.1016/S2352-3026(19)30157-7. Epub 2019 Oct 9.
pmid
31606445
type
DERIVED