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

Sponsor

medac GmbH (Industry)

Overall Status

Completed

CT.gov ID

NCT00822393

Collaborator

(none)

570

Enrollment

Locations

Arms

110

Actual Duration (Months)

17.3

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

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.

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).

Comparative evaluation of incidence of CTC grade III/IV mucositis/stomatitis between day -6 and day +28
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
Comparative evaluation of day +28 conditional cumulative incidence of engraftment
Comparative evaluation of day +28 and day +100 incidence of complete donor-type chimerism
Comparative evaluation of cumulative incidence of acute and chronic GvHD within 2 years after transplantation
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.

Study Design

Study Type:

Interventional

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 :

Nov 24, 2008

Actual Primary Completion Date :

Jan 25, 2018

Actual Study Completion Date :

Jan 25, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 Busulfan	Drug: Busulfan 4 x 0.8 mg/kg/d Intravenous Day -4 and -3
Experimental: 2 Treosulfan	Drug: Treosulfan 10 g/m2/d Intravenous Day -4, -3, -2

Arm

Intervention/Treatment

Active Comparator: 1

Busulfan

Drug: Busulfan

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

Experimental: 2

Treosulfan

Drug: Treosulfan

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

Outcome Measures

Primary Outcome Measures

Event-free survival (EFS) [within 2 years after transplantation]

Secondary Outcome Measures

Comparative evaluation of incidence of CTC grade III/IV mucositis/stomatitis between day -6 and day +28 [between day -6 and day +28]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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]

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.
Adult patients of both gender, age 18 - 70 years
Karnofsky Index ≥ 60 %
Written informed consent
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:

Patients with acute promyelocytic leukaemia with t(15;17)(q22;q12) and in CR1
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

Active malignant involvement of the CNS
HIV-positivity, active non-controlled infectious disease under treatment (no decrease of CRP or PCT) including active viral liver infection
Previous allogeneic HSCT
Pleural effusion or ascites > 1.0 L
Pregnancy or lactation
Known hypersensitivity to treosulfan, busulfan and/or related ingredients
Participation in another experimental drug trial within 4 weeks prior to day -6 of the protocol
Non-cooperative behaviour or non-compliance
Psychiatric diseases or conditions that might compromise the ability to give informed consent

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Helsinki University Central Hospital, Dept. of Medicine	Helsinki	Finland	00290
2	Centre Hospitalier Lyon Sud	Lyon	France	69495
3	Hopital Saint-Louis	Paris	France	75475
4	Universitätsklinikum Carl Gustav Carus Dresden, Med. Klinik I	Dresden	Germany	01307
5	Klinik für Knochenmarktransplantation	Essen	Germany	45122
6	Malteser Krankenhaus St. Franziskus-Hospital	Flensburg	Germany	24939
7	Universitätsklinikum Freiburg	Freiburg	Germany	79106
8	Universitätsmedizin Goettingen, Haematolgie und Onkologie	Göttingen	Germany	37075
9	Asklepios Kliniken Hamburg GmbH	Hamburg	Germany	20099
10	Universitätsklinikum Heidelberg	Heidelberg	Germany	69120
11	Friedrich-Schiller-Universität Jena	Jena	Germany	07747
12	Universitätsklinikum Koeln, Stammzelltransplantation	Koeln	Germany	50937
13	Universitätsklinikum Leipzig, Haematologie, internistische Onkologie	Leipzig	Germany	04109
14	Johannes-Gutenberg-Universität Mainz, III. Medizinische Klinik	Mainz	Germany	55131
15	Klinikum Rechts der Isar der TU München, III. Med. Klinik	Muenchen	Germany	81675
16	Universitätsklinikum Münster	Münster	Germany	48129
17	Klinikum Nürnberg, 5. Medizinische Klinik	Nürnberg	Germany	90419
18	Klinikum Oldenburg gGmbH	Oldenburg	Germany	26133
19	Klinikum der Universität Regensburg	Regensburg	Germany	93053
20	Universität Rostock	Rostock	Germany	18057
21	Universität Tübingen	Tübingen	Germany	72076
22	Stiftung Deutsche Klinik für Diagnostik	Wiesbaden	Germany	65191
23	Klinikum der Universität Würzburg	Würzburg	Germany	97070
24	St. Istvan and St. Laszlo Hospital of Budapest	Budapest	Hungary	1097
25	Azienda Ospedaliera Papa Giovanni XXIII	Bergamo	Italy	24127
26	Hematology University of Brescia	Brescia	Italy	1-25123
27	Scientific Institute H. San Raffaele	Milan	Italy	20132
28	Ospedale Civile Pescara	Pescara	Italy	65123
29	Policlinico Umberto I Univ. La Sapienza	Rome	Italy	00161
30	Clinica Ematologica ed Unita di Terapie Cellulari 'Carlo Melzi'	Udine	Italy	33100
31	Policlinico GB Rossi (Borgo Roma), Div. di Ematologia	Verona	Italy	37134
32	Medical University of Gdansk	Gdansk	Poland	80-952
33	Silesian Medical University	Katowice	Poland	40-032