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

Acute Myeloid Leukemia Clinical Trial

Official title:

An Exploratory, Open-label, Multicenter Study to Evaluate the Safety and Efficacy of a Two-dose Regimen of ATIR101, a T-lymphocyte Enriched Leukocyte Preparation Depleted ex Vivo of Host Alloreactive T-cells (Using Photodynamic Treatment), in Patients With a Hematologic Malignancy, Who Received a CD34-selected Hematopoietic Stem Cell Transplantation From a Haploidentical Donor

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02500550
• Other study ID #: CR-AIR-008
• Status: Completed
• Phase: Phase 2
• Start date: October 9, 2015
• Est. completion date: December 17, 2018

Study information

• Verified date: May 2021
• Source: Kiadis Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: December 17, 2018
• Est. primary completion date: July 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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)

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Acute Myeloid Leukemia
• Hematologic Neoplasms
• Leukemia
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Neoplasms
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Biological:
• ATIR101
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).

Procedure:
• Haploidentical hematopoietic stem cell transplantation (HSCT)
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 regime
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 regime
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.

Locations

Country	Name	City	State
Belgium	Algemeen Ziekenhuis Sint-Jan	Brugge
Belgium	Institut Jules Bordet	Brussels
Belgium	Universitair Ziekenhuis Gasthuisberg	Leuven
Belgium	Centre Hospitalier Universitaire de Liège	Liège
Canada	Juravinski Hospital and Cancer Centre	Hamilton	Ontario
Canada	Maisonneuve-Rosemont Hospital	Montreal	Quebec
Croatia	University Hospital Centre Zagreb	Zagreb
Germany	University Medical Center Mainz	Mainz
Portugal	Hospital de Santa Maria, Clinica Universitaria Hematologia	Lisboa
United Kingdom	Heartlands Hospital	Birmingham
United Kingdom	Hammersmith Hospital	London

Sponsors (1)

Lead Sponsor	Collaborator
Kiadis Pharma

Countries where clinical trial is conducted

Belgium,  Canada,  Croatia,  Germany,  Portugal,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of Acute Graft Versus Host Disease (GVHD) Grade III/IV		180 days post HSCT
Secondary	Incidence and Severity of Acute and Chronic GVHD		Between 6 and 12 months after HSCT
Secondary	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.	6 and 12 months post HSCT
Secondary	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	From 6 months to 1 year after HSCT
Secondary	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)	12 months post HSCT
Secondary	Relapse-related Mortality (RRM)	Defined as death due to disease relapse or disease progression	12 months post HSCT
Secondary	Overall Survival (OS)	Defined as the time from HSCT until death from any cause	12 months post HSCT
Secondary	Progression-free Survival (PFS)	Defined as the time from HSCT until relapse, disease progression, or death, whichever occurs first	12 months post HSCT
Secondary	GVHD-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	12 months post HSCT