Clinical trial NCT00822393: Clinical Phase III Trial Treosulfan-based Conditioning Versus Reduced-intensity Conditioning (RIC)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Myeloid Leukemia
Myelodysplastic Syndrome
Keywords: Treosulfan
Busulfan
Conditioning
Allogeneic
Transplantation
Lead sponsor: medac GmbH
Sponsor class: INDUSTRY
First posted: 2009-01-14
Enrollment: 570
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Event-free survival (EFS)
timeFrame: 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
timeFrame: between day -6 and day +28
Other outcomes:
Locations:
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital, Dept. of Medicine
city: Lyon
country: France
facility: Centre Hospitalier Lyon Sud
city: Paris
country: France
facility: Hopital Saint-Louis
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus Dresden, Med. Klinik I
city: Essen
country: Germany
facility: Klinik für Knochenmarktransplantation
city: Flensburg
country: Germany
facility: Malteser Krankenhaus St. Franziskus-Hospital
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Göttingen
country: Germany
facility: Universitätsmedizin Goettingen, Haematolgie und Onkologie
city: Hamburg
country: Germany
facility: Asklepios Kliniken Hamburg GmbH
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Jena
country: Germany
facility: Friedrich-Schiller-Universität Jena
city: Koeln
country: Germany
facility: Universitätsklinikum Koeln, Stammzelltransplantation
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig, Haematologie, internistische Onkologie
city: Mainz
country: Germany
facility: Johannes-Gutenberg-Universität Mainz, III. Medizinische Klinik
city: Muenchen
country: Germany
facility: Klinikum Rechts der Isar der TU München, III. Med. Klinik
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Nürnberg
country: Germany
facility: Klinikum Nürnberg, 5. Medizinische Klinik
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg gGmbH
city: Regensburg
country: Germany
facility: Klinikum der Universität Regensburg
city: Rostock
country: Germany
facility: Universität Rostock
city: Tübingen
country: Germany
facility: Universität Tübingen
city: Wiesbaden
country: Germany
facility: Stiftung Deutsche Klinik für Diagnostik
city: Würzburg
country: Germany
facility: Klinikum der Universität Würzburg
city: Budapest
country: Hungary
facility: St. Istvan and St. Laszlo Hospital of Budapest
city: Bergamo
country: Italy
facility: Azienda Ospedaliera Papa Giovanni XXIII
city: Brescia
country: Italy
facility: Hematology University of Brescia
city: Milan
country: Italy
facility: Scientific Institute H. San Raffaele
city: Pescara
country: Italy
facility: Ospedale Civile Pescara
city: Rome
country: Italy
facility: Policlinico Umberto I Univ. La Sapienza
city: Udine
country: Italy
facility: Clinica Ematologica ed Unita di Terapie Cellulari 'Carlo Melzi'
city: Verona
country: Italy
facility: Policlinico GB Rossi (Borgo Roma), Div. di Ematologia
city: Gdansk
country: Poland
facility: Medical University of Gdansk
city: Katowice
country: Poland
facility: Silesian Medical University
Study officials:
affiliation: University Hospital, Essen
name: Dietrich W. Beelen, MD
role: PRINCIPAL_INVESTIGATOR
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.