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

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

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.

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.

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