Safety and Efficacy of ATIR101 as Adjunctive Treatment to Blood Stem Cell Transplantation From a Haploidentical Family Donor Compared to Post-transplant Cyclophosphamide in Patients With Blood Cancer

Study Overview
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Brief Summary
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The primary objective of this study is to compare safety and efficacy of a haploidentical T-cell depleted HSCT and adjunctive treatment with ATIR101 versus a haploidentical T cell replete HSCT with post-transplant administration of high dose cyclophosphamide (PTCy) in patients with a hematologic malignancy. An additional objective of the study is to compare the effect of the two treatments on quality of life.

Detailed Description
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Study CR-AIR-009 is a Phase III randomized controlled multicenter open-label study comparing two parallel groups. After signing informed consent, a total of 250 patients will be randomized in a 1:1 fashion to receive either a T-cell depleted hematopoietic stem cell transplantation (HSCT; CD34 selection) from a related, haploidentical donor, followed by ATIR101 infusion, or a T-cell replete HSCT, followed by a high dose of post-transplant cyclophosphamide (PTCy). Randomization will use minimization to balance treatment groups with respect to underlying disease (AML, ALL, or MDS), Disease Risk Index (DRI; intermediate risk, high risk, or very high risk) and center. A stochastic treatment allocation procedure will be used so that the treatment assignment is random for all patients entered in the study. Patients randomized in the ATIR101 group will receive a single ATIR101 dose of 2×10E6 viable T-cells/kg between 28 and 32 days after the HSCT. Patients randomized in the PTCy group will receive cyclophosphamide 50 mg/kg/day at 3 and 4/5 days after the HSCT. All patients will be followed up for at least 24 months post HSCT.

Official Title
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A Phase III, Multicenter, Randomized Controlled Study to Compare Safety and Efficacy of a Haploidentical HSCT and Adjunctive Treatment With ATIR101, a T-lymphocyte Enriched Leukocyte Preparation Depleted ex Vivo of Host Alloreactive T-cells, Versus a Haploidentical HSCT With Post-transplant Cyclophosphamide in Patients With a Hematologic Malignancy

Conditions
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Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndrome

Intervention / Treatment
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* Biological: ATIR101
* Drug: Cyclophosphamide
* Procedure: T-cell depleted HSCT from a related, haploidentical donor
* Procedure: T-cell replete HSCT from a related, haploidentical donor


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 cytomorphological remission (with < 5% blasts in the bone marrow) with Disease Risk Index (DRI) intermediate or above, or in second or higher cytomorphological remission (with < 5% blasts in the bone marrow) Acute lymphoblastic leukemia (ALL) in first or higher remission (with < 5% blasts in the bone marrow) Myelodysplastic syndrome (MDS): transfusion-dependent (requiring at least one transfusion per month), or intermediate or higher Revised International Prognostic Scoring System (IPSS-R) risk group Clinical justification of allogeneic stem cell transplantation where a suitable HLA matched sibling or unrelated donor is unavailable in a timely manner Availability of a related haploidentical donor with one fully shared haplotype and 2 to 4 mismatches at the HLA-A, -B, -C, and -DRB1 loci of the unshared haplotype, as determined by high resolution human leukocyte antigen (HLA)-typing Karnofsky Performance Status (KPS) ≥ 70% Male or female, age ≥ 18 years and ≤ 70 years. Patients aged ≥ 65 years must have a Sorror score ≤ 3 Patient weight ≥ 25 kg and ≤ 130 kg Availability of a donor aged ≥ 16 years and ≤ 75 years who is eligible according to local requirements and regulations. Donors aged < 16 years are allowed if they are the only option for an HSCT, if they are permitted by local regulations, and if the IRB/IEC approves participation in the study. For females of childbearing potential who are sexually active and males who have sexual contact with a female of childbearing potential: willingness to use of reliable methods of contraception (oral contraceptives, intrauterine device, hormone implants, contraceptive injection or abstinence) during study participation Given written informed consent (patient and donor) Exclusion Criteria: Diagnosis of chronic myelomonocytic leukemia (CMML) Availability of a suitable HLA-matched sibling or unrelated donor in a donor search Prior allogeneic hematopoietic stem cell transplantation Diffusing capacity for carbon monoxide (hemoglobin corrected DLCO) < 50% predicted Left ventricular ejection fraction < 45% (evaluated by echocardiogram or MUGA scan) Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 2.5 × upper limit of normal (CTCAE grade 2) Creatinine clearance < 50 ml/min (calculated or measured) Positive pregnancy test or breastfeeding of patient or donor (women of childbearing age only) Estimated probability of surviving less than 3 months Known allergy to any of the components of ATIR101 (e.g., dimethyl sulfoxide) Known hypersensitivity to cyclophosphamide or any of its metabolites Any contraindication for GVHD prophylaxis with mycophenolate mofetil, cyclosporine A, or tacrolimus Known presence of HLA antibodies against the non-shared donor haplotype Positive viral test of the patient or donor for human immunodeficiency virus (HIV)-1, HIV-2, hepatitis B virus (HBV), hepatitis C virus (HCV), Treponema pallidum, human T-lymphotropic virus (HTLV)-1 (if tested), HTLV-2 (if tested), West Nile virus (WNV; if tested), or Zika virus (if tested) Any other condition that, in the opinion of the investigator, makes the patient or donor ineligible for the study

Ages Eligible for Study
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Minimum Age: 18 Years
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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ATIR101<br>T-cell depleted HSCT from a related, haploidentical donor, followed by IV infusion with ATIR101 at a single dose of 2×10E6 viable T-cells/kg body weight between 28 and 32 days after the HSCT | Biological: ATIR101<br>* ATIR101 is a T-lymphocyte enriched leukocyte preparation depleted ex vivo of host alloreactive T-cells using photodynamic treatment; single dose of 2×10E6 viable T-cells/kg body weight between 28 and 32 days after the HSCT (intravenous infusion)<br>Procedure: T-cell depleted HSCT from a related, haploidentical donor<br>* T-cell depleted graft prepared from peripheral blood stem cells using the CD34+ cell selection method; infused after a total body irradiation (TBI) or non-TBI conditioning regimen<br>|
| Active Comparator: PTCy<br>T-cell replete HSCT from a related, haploidentical donor, followed by IV infusion of post-transplant cyclophosphamide (PTCy) 50 mg/kg/day at 3 and 4/5 days after the HSCT | Drug: Cyclophosphamide<br>* High dose post-transplant cyclophosphamide 50 mg/kg/day at 3 and 4/5 days after the HSCT (powder for intravenous infusion)<br>Procedure: T-cell replete HSCT from a related, haploidentical donor<br>* T-cell replete (full, non-manipulated) graft prepared from either bone marrow or peripheral blood stem cells; infused after a total body irradiation (TBI) or non-TBI conditioning regimen<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Graft-versus-host Disease-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. Kaplan-Meier estimates (percentage of participants) of GRFS were calculated at 24 months post HSCT. | 24 months post-HSCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from HSCT until death from any cause. Kaplan-Meier estimates (percentage of participants) of OS were calculated at 24 months post HSCT. | 24 months post-HSCT | 
| Progression-free Survival (PFS) | Defined as the time from HSCT until relapse, disease progression, or death, whichever occurs first. Kaplan-Meier estimates (percentage of participants) of PFS were calculated at 24 months post HSCT. | 24 months post-HSCT | 
| Relapse-related Mortality (RRM) | Time from randomization to death due to disease relapse or disease progression | Through study completion, at least two years post 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). Kaplan-Meier estimates (percentage of participants) of PFS were calculated at 24 months post HSCT. | 24 months post-HSCT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alloreactive T-cells, Haploidentical stem cell transplantation, Graft-versus-host disease, Immune reconstitution, Photodynamic treatment, Hematologic malignancy, Transplant-related mortality, Overall survival, GRFS, GVHD