Umbilical Cord Derived Mesenchymal Stromal Cells For The Treatment of Severe Steroid-resistant Graft Versus Host Disease

Study Overview
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Brief Summary
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MESENCHYMAL STROMAL CELLS (MSC) have shown promising albeit not always consistent therapeutic effects in the treatment of severe steroid-resistant acute Graf versus Host Disease. Remarkably, in all reported clinical studies the toxicity of Mesenchymal stromal cells administration has been found consistently negligible. The investigators believe that Umbilical Cord (UC) derived Mesenchymal stromal cells may represent a stronger immunosuppressive tool for such clinical emergency and no data suggest any change in the safety profile of these cells. For this reason, and in the best interest of the patient, the investigators plan to test the safety and activity of Umbilical Cord Mesenchymal stromal cells when given sequentially to another partially effective treatment of steroid resistant acute graf versus host disease such as Pentostatin.

Official Title
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UMBILICAL CORD DERIVED MESENCHYMAL STROMAL CELLS (UC-MSC) FOR THE TREATMENT OF SEVERE (GRADE III-IV) STEROID-RESISTANT GRAFT VERSUS HOST DISEASE (GvHD): A PHASE I/II TRIAL

Conditions
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Hematologic Malignancies

Intervention / Treatment
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* Biological: UMBILICAL CORD DERIVED MESENCHYMAL STROMAL CELLS (UC-MSC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients are required to meet the following inclusion criteria: Patients with steroid refractory grade III-IV classic acute graft versus host disease (GvHD)occurring within 100 days after transplant or induced by donor lymphocyte infusions (DLI) or T-cell add back. Steroid refractory graft versus host disease (GvHD)is defined according to Pidala and Anasetti10 as follows: a) progression of at least 1 overall grade within 3 days of optimal steroid treatment; b) failure to demonstrate any overall grade improvement over 5 to 7 days; c) incomplete response by 14 days of 2 mg/kg/day of steroid therapy. Patients with persistent, recurrent, or late acute graft versus host disease (GvHD) (features of acute graft versus host disease occurring beyond 100 days, often during withdrawal of immune suppression). Patients with an overlap syndrome in which diagnostic or distinctive features of chronic graft versus host disease (GvHD) and acute graft versus host disease (GvHD) appear together79. Exclusion Criteria: 1. Inability to obtain written informed consent

Ages Eligible for Study
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Maximum Age: 70 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Umbilical Cord Mesenchymal stromal cells (UC-MSC)<br>Pentostatin will be given by intravenous infusion at a dose of 1 mg/m2 for 3 consecutive days. Thereafter, three Umbilical Cord Mesenchymal stromal cells (UC-MSC) infusions will be given at weekly interval starting from day 5. We will follow a dose escalating programme with progressively increasing doses of cells until the maximally tolerated dose (MTD) is achieved. The dose escalating design will be characterised by the administration of 1x106 /kg UC-MSC per dose per three doses for the first three patients (total up to 3x106/kg). The second three patients will receive 2x106/kg UC-MSC per dose per three doses (total up to 6x106/kg). The third three patients will receive 3x106/kg UC-MSC per dose per three doses (total up to 9x106 cells/kg). Since three dosages of cells are programmed for each group of 3 patients, a minimum of 9 patients should be studied, unless unacceptable acute infusion related toxicity is observed. | Biological: UMBILICAL CORD DERIVED MESENCHYMAL STROMAL CELLS (UC-MSC)<br>* pentostatin, dose 1 mg/m2 § MSC doses: 3 patients → 3 infusions of 1x106 cells /kg 3 patients → 3 infusions of 2x106 cells /kg 3 patients → 3 infusions of 3x106 cells /kg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| vital parameters | Following infusion of UC-MSC, the patient will be monitored for acute infusion-related toxicity. Any toxicity will be treated at the discretion of the attending physician. Infusional toxicity is defined as any alteration of the vital parameters of the patient if they have appeared acutely and may be directly correlated to the UC-MSC infusion | one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| assessed of acute graft versus host disease (GvHD) | graft versus host disease will be assessed at day +7, +9, +12, +14, +16, +19, +21, +28, + 35, +42 e +49 and after 6 months and 1 year from the last UC-MSC infusion. Efficacy on acute graft versus host disease is defined as complete or partial resolution of acute GvHD evaluated according to conventional staging and grading score systems.The efficacy will be evaluated at day +30 after the third UC-MSC infusion or, if less, at day +30 after the last UC-MSC infusion. | one year |