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

Phase 2

Completed

Conditions: Acute Lymphoblastic Leukemia
Acute Myeloid Leukemia
Myelodysplastic Syndrome

Interventions: Biological: ATIR101
Procedure: Haploidentical hematopoietic stem cell transplantation (HSCT)
Procedure: TBI regime
Procedure: Non-TBI regime

Registration Number: NCT02500550

Lead Sponsor: Kiadis Pharma

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 15

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
ATIR101	Haploidentical hematopoietic stem cell transplantation (HSCT)	-
ATIR101	Non-TBI regime	-
ATIR101	ATIR101	-
ATIR101	TBI regime	-

Primary Outcome Measures

Name	Time	Method
Incidence of Acute Graft Versus Host Disease (GVHD) Grade III/IV	180 days post HSCT

Secondary Outcome Measures

Name	Time	Method
Relapse-related Mortality (RRM)	12 months post HSCT	Defined as death due to disease relapse or disease progression
Percentage of Participants Who Achieved T-Cell Reconstitution at 6 and 12 Months Post HSCT	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.
Viral, Fungal, and Bacterial Infections	From 6 months to 1 year after HSCT	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
Transplant-related Mortality (TRM)	12 months post HSCT	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)
Overall Survival (OS)	12 months post HSCT	Defined as the time from HSCT until death from any cause
Incidence and Severity of Acute and Chronic GVHD	Between 6 and 12 months after HSCT
Progression-free Survival (PFS)	12 months post HSCT	Defined as the time from HSCT until relapse, disease progression, or death, whichever occurs first
GVHD-free, Relapse-free Survival (GRFS)	12 months post HSCT	Defined as the time until acute GVHD grade III/IV, chronic GVHD requiring systemic treatment, relapse, or death, whichever occurs first

Trial Locations

Locations (11): Universitair Ziekenhuis Gasthuisberg
🇧🇪
Leuven, Belgium
Maisonneuve-Rosemont Hospital
🇨🇦
Montreal, Quebec, Canada
Algemeen Ziekenhuis Sint-Jan
🇧🇪
Brugge, Belgium
Juravinski Hospital and Cancer Centre
🇨🇦
Hamilton, Ontario, Canada
Institut Jules Bordet
🇧🇪
Brussels, Belgium
Heartlands Hospital
🇬🇧
Birmingham, United Kingdom
Hammersmith Hospital
🇬🇧
London, United Kingdom
University Hospital Centre Zagreb
🇭🇷
Zagreb, Croatia
University Medical Center Mainz
🇩🇪
Mainz, Germany
Centre Hospitalier Universitaire de Liège
🇧🇪
Liège, Belgium
Hospital de Santa Maria, Clinica Universitaria Hematologia
🇵🇹
Lisboa, Portugal