Acute Graft-Versus-Host Disease (aGvHD) Prophylaxis With ATG-Fresenius in Matched Unrelated Donor-Stem Cell Transplantation (MUD-SCT)

Study Overview
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Brief Summary
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The study aim is to evaluate the influence of the anti-T-lymphocyte globulin ATG-Fresenius S given pre-transplant in addition to standard GvHD prophylaxis with cyclosporine A and a short course of methotrexate with respect to efficacy and safety.

Detailed Description
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To assess the efficacy of ATG-FRESENIUS S in addition to standard therapy (cyclosporine A / methotrexate) with respect to early treatment failure defined by the occurrence of severe acute GvHD grade III-IV or early mortality within 100 days post transplantation compared to standard therapy alone. All patients receive myeloablative therapy. Recommended regimens: For patients with ALL: fractionated TBI (8-12 Gy) plus cyclophosphamide (1-2 x 60 mg/kg) [etoposide/melfalan are also allowed]. For all other indications: either TBI (8-12 Gy) or busulfan (per os 14-16 mg/kg b.w. or equivalent for IV administration) plus cyclophosphamide (1-2 x 60 mg/kg) or thiotepa ≥ 15 mg/kg or BCNU ≥ 300 mg/m2. Conditioning regimens may differ from centre to centre; each centre decides for constant (disease specific) regimen(s) throughout the whole study period. Standard GvHD prophylaxis consists of cyclosporine A (target trough level ≥ 200 ng/ml starting from day -1 until day +100) and short course methotrexate (15 mg/m2 at day +1, 10 mg/m2 at days +3, +6 and +11).

Official Title
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GvHD Prophylaxis With ATG-Fresenius S in Allogeneic Stem Cell Transplantation From Matched Unrelated Donors: A Randomized Phase III Multicenter Trial Comparing a Standard GvHD Prophylaxis With Cyclosporine A and Methotrexate With Additional Pretransplant ATG-Fresenius S

Conditions
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Graft vs Host Disease

Intervention / Treatment
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* Drug: ATG-Fresenius S


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participation of patients in simultaneous diagnostic and comprehensive therapeutical trials for certain entities is allowed. Patients 18-60 years of age; Patients suffering from one of the following diseases: AML: 1st complete remission (CR1) or beyond 1st remission (CR2, CR3), in relapse, not in remission (primary refractory, induction failure); ALL: 1st complete remission (CR1) or beyond 1st remission (CR2, CR3), in relapse, not in remission (primary refractory, induction failure); MDS, if transplantation is medically indicated: RA (with poor risk factors as classified by the International Prognostic Scoring System of MDS), RARS, RAEB, RAEB-t, CMML; CML: beyond 1st chronic phase (CP1): accelerated phase, blast crisis, chronic phase (CP2, CP3); OMF, if transplantation is medically indicated: Osteomyelofibrosis; Patients designated to undergo allogeneic bone marrow transplantation or allogeneic peripheral blood stem cell transplantation; Patients with a HLA-A, -B (DNA-based, 2 digits), HLA-DRB1, -DQB1 (DNA-based 4 digits) matched (8 out of 8 alleles) unrelated donor; serological typing is not required Patients with a Karnofsky Performance Score (KPS): > 60%; Patients who underwent all obligatory screening examinations (special examinations within the last 4 weeks); Patients who have given their written informed consent to participate in the study. Exclusion Criteria: Patients with significant cardiac (e.g. ejection fraction <50%), pulmonary (e.g. FEV1 <50%), renal (e.g. creatinine > 1.5 mg/dl), metabolic (e.g. bilirubin > 2.0 mg/dl) and/or CNS disease, currently uncontrolled by treatment, which may interfere with the completion of the study; Patients with any bacterial, viral, or fungal infections not under adequate antimicrobial control; Patients who are known to have serum hepatitis or who are carriers of the Hepatitis B surface antigen (HBs-Ag), or Hepatitis C antibody, or who are known to have a positive result to the test of HIV antibodies; Patients with any additional concurrent or previous malignant disease; Patients with known hypersensitivity to rabbit immunoglobulin antibodies in past patient history or with known allergy to any substance chemically related to the study medication; Pregnant (β-HCG test) or lactating women; Patients who formerly underwent transplantation including previous autologous transplants; Patients who cannot communicate reliably with the investigator or who are not likely to cope with the requirements of the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: ATG-F<br>ATG-Fresenius S (20 mg/kg body weight at days -3 to -1 (total dose: 60 mg/kg) cyclosporine A (target trough level > 200ng/ml (day -1 until day +100) methotrexate: 15mg/m2 at day +1, 10mg/m2 at days +3, +6, and +11 | Drug: ATG-Fresenius S<br>* 20 mg rabbit immunoglobulin (IgG) in 1 ml of sterile solution 20 mg/kg body weight per day diluted in 500 ml physiological saline, slow intravenous infusion at days -3, -2, -1 prior to transplantation<br>* Other names: Anti-T-Lymphocyte globulin;|
| No Intervention: non-ATG-F<br>cyclosporine A (target trough level > 200ng/ml (day -1 until day +100) methotrexate: 15mg/m2 at day +1, 10mg/m2 at days +3, +6, and +11 | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary: Early treatment failure defined by the occurrence of severe acute GvHD (°III-°IV) or early mortality within 100 days post transplantation. |  | 100 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to onset of acute GvHD, incidence and severity of infections until day +100, time to engraftment, incidence of cGvHD, disease free survival, relapse, death without relapse, overall survival, safety, tolerability. |  | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ATG, GvHD, aGvHD prophylaxis, Matched unrelated donor, SCT, BMT, polyclonal antibody, GvHD prophylaxis for patients with ALL, AML, CML, MDS, OMF, Patients with allogeneic BM or PBSC transplantation, Patients with a matched unrelated donor