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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00822393
Recruitment Status : Completed
First Posted : January 14, 2009
Last Update Posted : July 30, 2020
Information provided by (Responsible Party):
medac GmbH

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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Myelodysplastic Syndrome Drug: Busulfan Drug: Treosulfan Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 570 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Clinical Phase III Trial to Compare Treosulfan-based Conditioning Therapy With Busulfan-based Reduced-intensity Conditioning (RIC) Prior to Allogeneic Haematopoietic Stem Cell Transplantation in Patients With AML or MDS Considered Ineligible to Standard Conditioning Regimens
Actual Study Start Date : November 24, 2008
Actual Primary Completion Date : January 25, 2018
Actual Study Completion Date : January 25, 2018

Arm Intervention/treatment
Active Comparator: 1
Drug: Busulfan
4 x 0.8 mg/kg/d Intravenous Day -4 and -3

Experimental: 2
Drug: Treosulfan
10 g/m2/d Intravenous Day -4, -3, -2

Primary Outcome Measures :
  1. Event-free survival (EFS) [ Time Frame: within 2 years after transplantation ]

Secondary Outcome Measures :
  1. 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 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00822393

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Sponsors and Collaborators
medac GmbH
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Principal Investigator: Dietrich W. Beelen, MD University Hospital, Essen
Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: medac GmbH Identifier: NCT00822393    
Other Study ID Numbers: MC-FludT.14/L
EudraCT-No.: 2008-002356-18
First Posted: January 14, 2009    Key Record Dates
Last Update Posted: July 30, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by medac GmbH:
Additional relevant MeSH terms:
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Myelodysplastic Syndromes
Bone Marrow Diseases
Hematologic Diseases
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Antineoplastic Agents
Myeloablative Agonists