Clinical Trial to Evaluate the Safety and Efficacy of Treosulfan Based Conditioning Prior to Allogeneic Haematopoietic Stem Cell Transplantation (HSCT)

Study Overview
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Brief Summary
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This is a multicentric, non-randomized, non-controlled open-label phase II trial to evaluate the safety and efficacy of treosulfan in a combination regimen with fludarabine as conditioning therapy prior to allogeneic stem cell transplantation (SCT) in patients with haematological malignancies. The aim is to demonstrate a clinical benefit compared with historical data on intravenous busulfan (BusulfexTM, BusilvexTM), the only drug so far registered in the indication conditioning before allogeneic stem cell transplantation.

Official Title
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Clinical Phase II Trial to Evaluate the Safety and Efficacy of Treosulfan Based Conditioning Prior to Allogeneic Haematopoietic Stem Cell Transplantation in Patients With Haematological Malignancies

Conditions
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Leukemia, Chronic Myeloid Leukemia, Myelodysplastic Syndrome, Diffuse Large Cell Lymphoma, Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, Multiple Myeloma

Intervention / Treatment
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* Drug: Treosulfan IV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with haematological malignancies, according to WHO classification, such as: acute myeloid leukaemia -AML- in CR1 except low-risk cases defined by t(15;17), t(8;21), inv 16 or normal cytogenetics at diagnosis with FLT3-ITD negative and NPM-1 positive, with no high risk clinical criteria any AML beyond CR1 acute lymphoblast leukaemia -ALL- in CR1 only if at high risk defined by cytogenetics as t(9;22), t(4;11) or for persistence of minimal residual disease (MRD) any ALL beyond CR1 chronic myeloid leukaemia -CML- in chronic phase (CP) or accelerated phase (AP) intolerant/not responsive to TK-inhibitors myeloproliferative disorders -MPD- myelodysplastic syndrome -MDS- with intermediate or high risk International Prognostic Scoring System (IPSS) diffuse large cell lymphoma -DLCL- with a chemosensitive relapse or beyond CR1 lymphoblastic and Burkitt lymphoma with a chemosensitive relapse or beyond CR1 mantle cell lymphoma -MCL- with a chemosensitive relapse or beyond CR1 follicular lymphoma -FCL- with a chemosensitive relapse or beyond CR2 Hodgkin lymphoma -HD- with a chemosensitive relapse or beyond CR1 chronic lymphocytic leukaemia -CLL- at poor risk in CR1 or with a chemosensitive relapse CLL relapsing after high dose chemotherapy T-cell non Hodgkin lymphoma -T-NHL- in CR1 or beyond multiple myeloma -MM- at high risk for cytogenetics or ISS stage 3 in CR1 following high dose chemotherapy MM at any relapse/progression except refractory disease Availability of an HLA-identical sibling donor (MRD) or HLA-identical unrelated donor (MUD) HLA-identity defined by the following markers: A, B, DRB1, DQB1 or a single or double Cord Blood unit (CB) with at least a 4 out of 6 HLA-matching by the following markers: A, B and DRB. A) identity between the 2 CB units and the recipient; B) Two identical CB units with one or two mismatches with the recipient; C) Two CB units with one mismatch between them and two mismatches with the recipient. We will prefer mismatches either for class I or for class II antigens; we will avoid mismatches concerning both classes I and II together. Target graft size (unmanipulated, preferably not cryopreserved) bone marrow: 2 to 10 x 106 CD34+ cells/kg BW recipient or > 2 x 108 nucleated cells/kg BW recipient or peripheral blood: 4 to 10 x 106 CD34+ cells/kg BW recipient Age > 18 and < 70 years Karnofsky Index > 80 % Adequate contraception in female patients of child-bearing potential Written informed consent Exclusion Criteria: Secondary malignancies Previous allogeneic transplantation Hematopoietic cell transplantation-specific comorbidity index > 4 (HCT-CI Sorror et al, Appendix M) Known and manifested malignant involvement of the CNS Active infectious disease HIV- positivity or active hepatitis infection Impaired liver function (Bilirubin > upper normal limit; Transaminases > 3.0 x upper normal limit) Impaired renal function (Creatinine-clearance < 60 ml/min; Serum Creatinine > 1.5 x upper normal limit). Pleural effusion or ascites > 1.0 L Pregnancy or lactation Known hypersensitivity to treosulfan and/or fludarabine Participation in another experimental drug trial within 4 weeks before day -6 Non-co-operative behaviour or non-compliance Psychiatric diseases or conditions that might impair the ability to give informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br> | Drug: Treosulfan IV<br>* Treosulfan i.v.: 14 g/m²/d from day -6 to day -4<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: Evaluation of engraftment |  | 28 days | 
| Safety: Evaluation of the incidence of CTC grade 3 and 4 adverse events |  | between day -6 and day +28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: Evaluation of disease free survival (DFS) |  | 1 year | 
| Efficacy: Evaluation of overall survival (OS) |  | 1 year | 
| Efficacy: Evaluation of relapse incidence (RI) |  | 1 year | 
| Efficacy: Documentation of donor chimerism |  | on day +28, +56 and +100 | 
| Safety: Evaluation of incidence of non-relapse mortality (NRM) |  | on day +28 and day +100 | 
| Safety: cumulative incidence of NRM |  | 1 year | 
| Safety: Evaluation of cumulative incidence and severity of acute and chronic graft vs. host disease (GvHD) |  | 1 year | 
| Safety: EBV reactivation |  | 1 year |