T&B Depletion Non Malignant

Study Overview
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Brief Summary
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• The primary aim of the present trial is to assess in a randomized fashion the benefit on standard graft-versus-host disease (GVHD) prophylaxis of the addition of ATG-Fresenius S ® in transplants from matched related donors (MRD) and of anti-CD20 rituximab in transplants from matched unrelated donors (MUD). Both safety and efficacy of the treatment will be assessed, in particular in respect to the clinical status of the patient, i.e. prevention of graft failure and chronic GvHD and of Ebstein Barr virus (EBV) viremia for MUD patients. The conditioning proposed combines myeloablative drugs with a favorable safety profile such as treosulfan, thiotepa (Tepadina®) and fludarabine with the intent to reduce the traditional immediate and late toxicity of busulfan and cyclophosphamide.

Detailed Description
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For patients transplanted from a MRD The primary end-point is the cumulative incidence of a combined end-point defined as the time from randomization to: primary and secondary graft failure, aGVHD II-IV, cGVHD, death, whichever occurs first. For patients transplanted from a MUD The primary end-point is the cumulative incidence of a combined end-point defined as the time from randomization to: aGVHD II-IV, EBV viremia, whichever occurs first.

Official Title
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A Phase II Multicentre, Randomized, Controlled Open-label Study on the Use of Anti-thymocyte Globulin and Rituximab for Immunomodulation of Graft-versus-host Disease in Allogeneic Matched Transplants for Non Malignancies

Conditions
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Graft Versus Host Disease

Intervention / Treatment
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* Biological: polyclonal antibody
* Drug: Rituximab
* Drug: Treosulfan
* Drug: Fludarabine
* Drug: Thiotepa
* Drug: Cyclosporine A
* Drug: Methotrexate
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: non malignant haematological and inherited metabolic disorders benefiting from an allogeneic HSCT conditioned with a myeloablative regimen Availability of a matched related donor (MRD) or Matched Unrelated Donor (MUD) Lansky or Karnofsky Index ≥ 60 Inherited metabolic disorders: DQ ≥ 70 (+ MRI Loes score ≤ 9 for adrenoleukodystrophy) Adequate cardiac, renal, hepatic and pulmonary functions as evidenced by: Serum creatinine ≤ 1.5 × upper limit of normal (ULN) Heart shortening fraction (left-ventricle) > 28 % or LVEF > 55% Serum bilirubin ≤ 1.5 × ULN (except for Wolman disease), AST and ALT ≤ 2.5 × ULN (except for thalassemic syndromes and Wolman disease) Pulmonary function: if cooperative: FEV1 and FVC on pulmonary function testing > 60 %; if non cooperative: pulse oximetry > 95 % in room air Availability of autologous back up marrow (> 2 x 108 TNC+ cells/kg or > 2 x 106 CD34+ cells/kg) for MUD Adequate contraception in female patients of child-bearing potential Signed informed consent Exclusion Criteria: Any malignancy Liver cirrhosis evidenced on liver histology (performed in suspicious cases or in case of Wolman disease) HIV- positivity Clinically significant pleural effusion or ascites Pregnancy or lactation Known hypersensitivity to trial drugs Participation in another experimental drug trial in the 2 months preceding enrollment Non-cooperative behaviour or non-compliance Previous HSCT

Ages Eligible for Study
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Minimum Age: 28 Days
Maximum Age: 64 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MRD-Regimen&Polyclonal antibody<br>Patients MRD will be randomized to receive Treosulfan iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 + Fludarabine iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan + Thiotepa iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals + Cyclosporine A iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL + Methotrexate iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 & ATG-Fresenius S® iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2 | Biological: polyclonal antibody<br>* iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2 (total dose 15 mg/kg)<br>* Other names: ATG S Fresenius;Drug: Treosulfan<br>* iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 (total dose of 42 g/m²)<br>* Other names: Medac;Drug: Fludarabine<br>* iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan<br>* Other names: Fludara;Drug: Thiotepa<br>* iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals<br>* Other names: Tepadina;Drug: Cyclosporine A<br>* iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL<br>* Other names: Neoral;Drug: Methotrexate<br>* iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6<br>|
| Sham Comparator: MRD-Regimen<br>Patients receiving stem cell transplantation from a matched related donors (MRD) will be randomized to receive only Treosulfan iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 (total dose of 42 g/m²) + Fludarabine iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 (total dose of 150 mg/m²) after treosulfan + Thiotepa iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals (total dose of 8 mg/kg)+ Cyclosporine A iv at a starting dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL (In the absence of GvHD CSA will be tapered after day + 180 and stopped at 9-12 months) + Methotrexate iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 | Drug: Treosulfan<br>* iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 (total dose of 42 g/m²)<br>* Other names: Medac;Drug: Fludarabine<br>* iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan<br>* Other names: Fludara;Drug: Thiotepa<br>* iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals<br>* Other names: Tepadina;Drug: Cyclosporine A<br>* iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL<br>* Other names: Neoral;Drug: Methotrexate<br>* iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6<br>|
| Experimental: MUD-Regimen & Rituximab<br>Patients MUD will be randomized to receive Treosulfan iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 + Fludarabine iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan + Thiotepa iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals + Cyclosporine A iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL + Methotrexate iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 and at a dose of 10 mg/m2 on day +11 + ATG-Fresenius S ® iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2 & Rituximab in a single infusion of 200 mg/m2 on day -1 | Biological: polyclonal antibody<br>* iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2 (total dose 15 mg/kg)<br>* Other names: ATG S Fresenius;Drug: Rituximab<br>* single infusion of200 mg/m2 on day -1<br>* Other names: Mabthera;Drug: Treosulfan<br>* iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 (total dose of 42 g/m²)<br>* Other names: Medac;Drug: Fludarabine<br>* iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan<br>* Other names: Fludara;Drug: Thiotepa<br>* iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals<br>* Other names: Tepadina;Drug: Cyclosporine A<br>* iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL<br>* Other names: Neoral;Drug: Methotrexate<br>* iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 and at a dose of 10 mg/m2 on day +11<br>|
| Sham Comparator: MUD-Regimen<br>Patients MUD will be randomized to receive only Treosulfan iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 + Fludarabine iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan + Thiotepa iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals + Cyclosporine A iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL + Methotrexate iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 and at a dose of 10 mg/m2 on day +11 + ATG-Fresenius S ® iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2 | Biological: polyclonal antibody<br>* iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2 (total dose 15 mg/kg)<br>* Other names: ATG S Fresenius;Drug: Treosulfan<br>* iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 (total dose of 42 g/m²)<br>* Other names: Medac;Drug: Fludarabine<br>* iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan<br>* Other names: Fludara;Drug: Thiotepa<br>* iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals<br>* Other names: Tepadina;Drug: Cyclosporine A<br>* iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL<br>* Other names: Neoral;Drug: Methotrexate<br>* iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 and at a dose of 10 mg/m2 on day +11<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute graft-versus-host disease (aGVHD) II-IV and chronic GvHD | For patients transplanted from a MRD The cumulative incidence of a combined end-point defined as the time from randomization to: primary and secondary graft failure, aGVHD II-IV, cGVHD, death, whichever occurs first. For patients transplanted from a MUD The cumulative incidence of a combined end-point defined as the time from randomization to: aGVHD II-IV, EBV viremia, whichever occurs first. | From date of randomization assessed up to 100 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Chronic graft-versus-host disease (cGVHD) | The cumulative incidence and severity of cGVHD | From date of randomization assessed up to 100 months | 
| Treatment related mortality (TRM) | The incidence of TRM | From date of randomization assessed up to 100 months | 
| Overall survival (OS) | The overall survival probability | From date of randomization assessed up to 100 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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indication for HSCT, matched related donor, MRD, Matched Unrelated Donor, MUD