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

Kiadis Pharma15 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

PREVENTION

Masking

Interventions

ATIR101BIOLOGICAL

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).

Haploidentical hematopoietic stem cell transplantation (HSCT)PROCEDURE

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)

TBI regimePROCEDURE

* 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.

Non-TBI regimePROCEDURE

* 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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

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)

Locations (11)

Algemeen Ziekenhuis Sint-Jan

Bruges, Belgium

Institut Jules Bordet

Brussels, Belgium

Universitair Ziekenhuis Gasthuisberg

Leuven, Belgium

Centre Hospitalier Universitaire de Liège

Liège, Belgium

Juravinski Hospital and Cancer Centre

Hamilton, Ontario, Canada

Maisonneuve-Rosemont Hospital

Montreal, Quebec, Canada

University Hospital Centre Zagreb

Zagreb, Croatia

University Medical Center Mainz

Mainz, Germany

Hospital de Santa Maria, Clinica Universitaria Hematologia

Lisbon, Portugal

Heartlands Hospital

Birmingham, United Kingdom

...and 1 more locations

Outcomes

Primary Outcomes

Incidence of Acute Graft Versus Host Disease (GVHD) Grade III/IV

Time frame: 180 days post HSCT

Secondary Outcomes

Incidence and Severity of Acute and Chronic GVHD

Time frame: 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.

Time frame: 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

Time frame: 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)