Safety and Efficacy of Two Doses of ATIR101, a T-lymphocyte Enriched Leukocyte Preparation Depleted of Host Alloreactive T-cells, in Patients With a Hematologic Malignancy Who Received a Hematopoietic Stem Cell Transplantation From a Haploidentical Donor

Study Overview
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Brief Summary
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The purpose of this study is to determine whether a repeat dose administration of ATIR101 is safe and effective when infused in patients with a hematologic malignancy following a T-cell depleted stem cell graft from a related haploidentical donor. All patients are planned to receive two ATIR101 doses of 2×10E6 viable T-cells/kg, unless the second dose is reduced or halted for safety reasons.

Detailed Description
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Study CR-AIR-008 is an exploratory, open-label, multicenter study. After signing informed consent, patients will receive a hematopoietic stem cell transplantation (HSCT) from a related, haploidentical donor, followed by a first ATIR101 infusion at a dose of 2×10E6 viable T-cells/kg between 28 and 32 days after the HSCT. Patients will receive a second ATIR101 infusion at a dose of 2×10E6 viable T-cells/kg between 70 and 74 days after the HSCT. To evaluate safety of the second dose administration, the first 6 patients treated will be evaluated for the occurrence of dose limiting toxicity (DLT), defined as acute GvHD grade III/IV within 120 days post HSCT (or within 42 days after the second ATIR101 infusion in case of prior dose delays). If within the first 6 patients no DLT is observed, treatment of the remaining 9 patients will continue with two ATIR101 doses of 2×10E6 viable T cells/kg. If within the first 6 patients at least 2 patients show DLT, the second ATIR101 infusion will be adjusted to a dose of 1×10E6 viable T cells/kg. If in one of the next 3 patients treated at this lower dose again DLT is observed, the second ATIR101 infusion will be halted and the remaining patients will be given only a single dose of ATIR101. All patients treated with ATIR101 will be followed up until 12 months after the HSCT. Assessments will be performed at weekly visits from the day of the first ATIR101 infusion (Week 4) until 6 weeks after the second ATIR101 infusion (Week 16), at monthly visits from 4 until 6 months after the HSCT, and every 3 months from 6 until 12 months after the HSCT.

Official Title
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An Exploratory, Open-label, Multicenter Study to Evaluate the Safety and Efficacy of a Two-dose Regimen of ATIR101, a T-lymphocyte Enriched Leukocyte Preparation Depleted ex Vivo of Host Alloreactive T-cells (Using Photodynamic Treatment), in Patients With a Hematologic Malignancy, Who Received a CD34-selected Hematopoietic Stem Cell Transplantation From a Haploidentical Donor

Conditions
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Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndrome

Intervention / Treatment
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* Biological: ATIR101
* Procedure: Haploidentical hematopoietic stem cell transplantation (HSCT)
* Procedure: TBI regime
* Procedure: Non-TBI regime


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any of the following hematologic malignancies: Acute myeloid leukemia (AML) in first remission with high-risk features or in second or higher remission Acute lymphoblastic leukemia (ALL) in first remission with high-risk features or in second or higher remission Myelodysplastic syndrome (MDS): transfusion-dependent, or intermediate or higher IPSS-R risk group Karnofsky performance status ≥ 70% Eligible for haploidentical stem cell transplantation according to the investigator Male or female, age ≥ 18 years and ≤ 65 years Exclusion Criteria: Availability of a fully matched related or unrelated donor following a donor search Diffusing capacity for carbon monoxide (DLCO) < 50% predicted Left ventricular ejection fraction < 50% (evaluated by echocardiogram or MUGA) AST > 2.5 x ULN (CTCAE grade 2) Bilirubin > 1.5 x ULN (CTCAE grade 2) Creatinine clearance < 50 mL/min (calculated or measured) Positive HIV test Positive pregnancy test (women of childbearing age only) Prior allogeneic HSCT Estimated probability of surviving less than 3 months Known allergy to any of the components of ATIR101 (e.g., dimethyl sulfoxide) Known presence of HLA antibodies against the non-shared donor haplotype Any other condition which, in the opinion of the investigator, makes the patient ineligible for the study Inclusion Criteria Donor: 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 and ≤ 75 years (If applicable, local legal requirements for donors under the age of 18 will be followed) Eligible for donations of human blood and blood components according to local requirements and regulations Eligible for donation according to the transplantation center Exclusion Criteria Donor: Positive pregnancy test or nursing (women of childbearing age only) Positive viral test for HIV-1, HIV-2, HBV, HCV, Treponema pallidum, HTLV 1 (if tested), HTLV-2 (if tested), or WNV (if tested)

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: ATIR101<br> | Biological: ATIR101<br>* T-lymphocyte enriched leukocyte preparation depleted ex vivo of host alloreactive T-cells (using photodynamic treatment). Two intravenous infusions with 2x10E6 viable T-cells/kg approximately 42 days apart (unless the second dose is reduced or halted for safety reasons).<br>Procedure: Haploidentical hematopoietic stem cell transplantation (HSCT)<br>* CD34-selected HSCT from a haploidentical donor. In order to prepare the patient for the HSCT one of the following myeloablative conditioning regimens is recommended: Total Body Irradiation (TBI) regime Non-TBI regime (See below for details)<br>Procedure: TBI regime<br>* Fractionated TBI 200 cGy twice daily for 3 days on Day -10 to -8 (1200 cGy in 6 fractions) Fludarabine 30 mg/m2 IV once daily for 5 days on Day -7 to -3 Thiotepa; 5 mg/kg IV twice daily for 1 day on Day -7 Anti-thymocyte globulin (ATG; Thymoglobulin®); 2.5 mg/kg once daily for 4 days on Day -5 to -2, as a continuous IV infusion for 8 hours. During the course of ATG, patients will receive methylprednisolone 2 mg/kg/day IV.<br>Procedure: Non-TBI regime<br>* Fludarabine; 30 mg/m2 IV once daily for 5 days on Day -8 to -4 Thiotepa; 5 mg/kg IV twice daily for 1 day on Day -7 Melphalan; 60 mg/m2 IV once daily for 2 days on Day -2 and -1 ATG (Thymoglobulin®); 2.5 mg/kg once daily for 4 days on Day -5 to -2, as a continuous IV infusion for 8 hours. During the course of ATG, patients will receive methylprednisolone 2 mg/kg/day IV.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Acute Graft Versus Host Disease (GVHD) Grade III/IV |  | 180 days post HSCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and Severity of Acute and Chronic GVHD |  | Between 6 and 12 months after HSCT | 
| Percentage of Participants Who Achieved T-Cell Reconstitution at 6 and 12 Months Post HSCT | Defined as CD3+ in peripheral blood higher than 0.2×10E9/L at 6 and 12 months post HSCT. | 6 and 12 months post HSCT | 
| Viral, Fungal, and Bacterial Infections | Infection was defined as (1) a clinically apparent infectious disease with symptoms or (2) a viral reactivation. Severity was graded according to CTCAE vs. 4.0 | From 6 months to 1 year after HSCT | 
| Transplant-related Mortality (TRM) | 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) | 12 months post HSCT | 
| Relapse-related Mortality (RRM) | Defined as death due to disease relapse or disease progression | 12 months post HSCT | 
| Overall Survival (OS) | Defined as the time from HSCT until death from any cause | 12 months post HSCT | 
| Progression-free Survival (PFS) | Defined as the time from HSCT until relapse, disease progression, or death, whichever occurs first | 12 months post HSCT | 
| GVHD-free, Relapse-free Survival (GRFS) | Defined as the time until acute GVHD grade III/IV, chronic GVHD requiring systemic treatment, relapse, or death, whichever occurs first | 12 months post HSCT | 

 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, Photodynamic treatment, Hematologic malignancy, Transplant-related mortality