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

Conditions: Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia; Myelodysplastic Syndrome

Summary: 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.

Eligibility criteria:
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

Keywords: haploidentical stem cell transplantation graft-versus-host disease immune reconstitution alloreactive t-cells photodynamic treatment hematologic malignancy transplant-related mortality overall survival grfs gvhd