Efficacy and Safety of a Donor Lymphocyte Preparation Depleted of Functional Host Alloreactive T-cells (ATIR) in Patients Undergoing a Peripheral Blood Stem Cell Transplant From a Related, Haploidentical Donor

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the administration of a donor lymphocyte preparation depleted of functional host alloreactive T-cells (ATIR) after a T-cell depleted stem cell transplant from a related, haploidentical donor enhances survival by improving the immune effect against infections while preventing graft-versus-host disease .

Detailed Description
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Allogeneic stem cell transplantation is the treatment of choice for many patients with leukemia and other hematologic malignancies. However, a major limitation of this therapy is that for a significant number of patients no fully HLA-matched donor can be found. The application of partially HLA-matched (haploidentical) family donors, who are virtually always available, has some complications. If there is no T-cell add-back it increases the risk for life-threatening infections and disease relapse, while in case of T-cell add-back the risk for graft-versus-host disease is raised. Kiadis Pharma has developed a method to selectively deplete host alloreactive T-cells through photodynamic therapy, using TH9402 ex vivo. The donor lymphocyte preparation depleted of functional host alloreactive T-cells (ATIR) is administered to the patient 28-42 days after the stem cell transplant.

Official Title
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An Open-label, Uncontrolled, Multicenter, Multinational Study on the Efficacy and Safety of Administration of Donor Lymphocytes Depleted of Alloreactive T-cells (ATIR), Through the Use of TH9402 and Light Treatment in an ex Vivo Process, in Patients Receiving a CD34-selected Peripheral Blood Stem Cell Graft From a Related, Haploidentical Donor

Conditions
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Myeloid Leukemia, Lymphoblastic Leukemia, Lymphoma, Multiple Myeloma, Myelodysplastic Syndrome, Myeloproliferative Disorders

Intervention / Treatment
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* Biological: Donor lymphocyte preparation depleted of host functional alloreactive T-cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: One of the following hematological malignancies: Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Myelodysplastic Syndrome (MDS) Ph-positive chronic myeloid leukemia (CML) Non-Hodgkin Lymphoma (NHL) Myelodysplastic Syndrome (MDS) Chronic Myeloid Leukemia (CML) Multiple Myeloma (MM) Chronic Lymphocytic Leukemia (CLL) Myeloproliferative Syndrome (MPS) Exclusion Criteria: AML in 1st complete remission with good risk karyotypes MM featuring concurrent extramedullar disease or being non-responsive to prior therapy CML in blast crisis CLL concurrently transformed into high-grade lymphoma and failing to demonstrate at least partial remission NHL with concurrent bulky disease (≥ 5 cm) Diffusing Capacity for Carbon Monoxide (DLCO) < 40% predicted Left ventricular ejection fraction < 40% AST/SGOT > 2.5 x ULN Bilirubin > 1.5 x ULN Creatinine > 1.5 x ULN HIV positive Positive pregnancy test for women of childbearing age Prior haploidentical peripheral blood stem cell or cord blood transplantation Less than 2 years from a prior allogeneic stem cell transplantation Estimated probability of surviving less than three months Major anticipated illness or organ failure incompatible with survival from transplant Severe psychiatric illness or mental deficiency sufficiently severe as to make compliance with the transplant treatment unlikely and informed consent impossible Known allergy to any of the components of ATIR Any other condition which, in the opinion of the investigator, makes the patient ineligible for the study Donor Inclusion Criteria: Haploidentical family donor with 2 to 3 mismatches at the HLA-A, -B and/or DR loci of the unshared haplotype. Male or female, age ≥ 16, ≤ 75 years. Donors must be fit to receive G-CSF and undergo apheresis (normal blood count, normotensive and no history of stroke). Donor must have Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Donor must provide written informed consent. Donor Exclusion Criteria: Medically uncontrolled coronary heart disease. Myocardial infarction within the last 3 months. History of uncontrolled seizures. History of malignancy (except basal cell or squamous carcinoma of the skin, positive PAP smear and subsequent negative follow up). Positive test result for any of the mandatory viral tests in the applicable region, except for a positive cytomegalovirus (CMV) result, which does not lead to exclusion. Presence of a transmissible disease (such as HIV positive), a major illness, a suspected systemic dysfunction and/or an active inflammatory or autoimmune disorder. Female donors who are pregnant or nursing.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ATIR<br> | Biological: Donor lymphocyte preparation depleted of host functional alloreactive T-cells<br>* Single intravenous infusion with 2x10E6 T-cells/kg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transplant Related Mortality | TRM is defined as death due to causes other than disease relapse or progression, or other causes which are unrelated to the transplantation procedure (e.g. accident, suicide) | 6, 12 and 24 months after the transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and Severity Graft-versus-host Disease (GVHD) | GVHD was graded according to standard criteria as referred to in the reference module (Filipovich et al. 2005; Przepiorka et al. 1995). | Up to 24 months after the transplantation | 
| Progression Free Survival |  | Up to 24 months after the transplantation | 
| Incidence and Severity of Bacterial, Viral or Fungal Infection |  | Up to 24 months after the transplantation | 
| Immune Reconstitution |  | Up to 24 months after the transplantation | 
| Health Status (Including Quality of Life) |  | Up to 24 months after the transplantation | 
| Overall Survival |  | 6, 12, and 24 months after the transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Haploidentical stem cell transplantation, Graft-versus-host disease, Immune reconstitution, Alloreactive T-cells, Photodepletion, TH9402, Transplant related mortality, Hematologic malignancy