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

NCT ID: NCT00822393

Last Updated: 2020-07-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 570 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-11-24
• Study Completion Date: 2018-01-25

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.

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

1

Busulfan

Group Type: ACTIVE_COMPARATOR

Busulfan

Intervention Type: DRUG

4 x 0.8 mg/kg/d Intravenous Day -4 and -3

2

Treosulfan

Group Type: EXPERIMENTAL

Treosulfan

Intervention Type: DRUG

10 g/m2/d Intravenous Day -4, -3, -2

Interventions

Busulfan

4 x 0.8 mg/kg/d Intravenous Day -4 and -3

Intervention Type: DRUG

Treosulfan

10 g/m2/d Intravenous Day -4, -3, -2

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

medac GmbH

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Dietrich W. Beelen, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Essen

Locations

Helsinki University Central Hospital, Dept. of Medicine

Helsinki, , Finland

Centre Hospitalier Lyon Sud

Lyon, , France

Hopital Saint-Louis

Paris, , France

Universitätsklinikum Koeln, Stammzelltransplantation

Cologne, , Germany

Universitätsklinikum Carl Gustav Carus Dresden, Med. Klinik I

Dresden, , Germany

Klinik für Knochenmarktransplantation

Essen, , Germany

Malteser Krankenhaus St. Franziskus-Hospital

Flensburg, , Germany

Universitätsklinikum Freiburg

Freiburg im Breisgau, , Germany

Universitätsmedizin Goettingen, Haematolgie und Onkologie

Göttingen, , Germany

Asklepios Kliniken Hamburg GmbH

Hamburg, , Germany

Universitätsklinikum Heidelberg

Heidelberg, , Germany

Friedrich-Schiller-Universität Jena

Jena, , Germany

Universitätsklinikum Leipzig, Haematologie, internistische Onkologie

Leipzig, , Germany

Johannes-Gutenberg-Universität Mainz, III. Medizinische Klinik

Mainz, , Germany

Klinikum Rechts der Isar der TU München, III. Med. Klinik

München, , Germany

Universitätsklinikum Münster

Münster, , Germany

Klinikum Nürnberg, 5. Medizinische Klinik

Nuremberg, , Germany

Klinikum Oldenburg gGmbH

Oldenburg, , Germany

Klinikum der Universität Regensburg

Regensburg, , Germany

Universität Rostock

Rostock, , Germany

Universität Tübingen

Tübingen, , Germany

Stiftung Deutsche Klinik für Diagnostik

Wiesbaden, , Germany

Klinikum der Universität Würzburg

Würzburg, , Germany

St. Istvan and St. Laszlo Hospital of Budapest

Budapest, , Hungary

Azienda Ospedaliera Papa Giovanni XXIII

Bergamo, , Italy

Hematology University of Brescia

Brescia, , Italy

Scientific Institute H. San Raffaele

Milan, , Italy

Ospedale Civile Pescara

Pescara, , Italy

Policlinico Umberto I Univ. La Sapienza

Rome, , Italy

Clinica Ematologica ed Unita di Terapie Cellulari 'Carlo Melzi'

Udine, , Italy

Policlinico GB Rossi (Borgo Roma), Div. di Ematologia

Verona, , Italy

Medical University of Gdansk

Gdansk, , Poland

Silesian Medical University

Katowice, , Poland

Countries

Finland; France; Germany; Hungary; Italy; Poland

References

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.

Reference Type: DERIVED

PMID: 31606445 (View on PubMed)

Related Links

http://www.medac.de

Sponsor's homepage

Other Identifiers

EudraCT-No.: 2008-002356-18

Identifier Type: -

Identifier Source: secondary_id

MC-FludT.14/L

Identifier Type: -

Identifier Source: org_study_id