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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

Primary Purpose

Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndrome

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
ATIR101
Haploidentical hematopoietic stem cell transplantation (HSCT)
TBI regime
Non-TBI regime
Sponsored by
Kiadis Pharma
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Acute Myeloid Leukemia focused on measuring Haploidentical stem cell transplantation, Graft versus host disease, Immune reconstitution, Alloreactive T-cells, Photodynamic treatment, Hematologic malignancy, Transplant-related mortality

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Algemeen Ziekenhuis Sint-Jan
  • Institut Jules Bordet
  • Universitair Ziekenhuis Gasthuisberg
  • Centre Hospitalier Universitaire de Liège
  • Juravinski Hospital and Cancer Centre
  • Maisonneuve-Rosemont Hospital
  • University Hospital Centre Zagreb
  • University Medical Center Mainz
  • Hospital de Santa Maria, Clinica Universitaria Hematologia
  • Heartlands Hospital
  • Hammersmith Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

ATIR101

Arm Description

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Incidence and Severity of Acute and Chronic GVHD
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.
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
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)
Relapse-related Mortality (RRM)
Defined as death due to disease relapse or disease progression
Overall Survival (OS)
Defined as the time from HSCT until death from any cause
Progression-free Survival (PFS)
Defined as the time from HSCT until relapse, disease progression, or death, whichever occurs first
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

Full Information

First Posted
July 14, 2015
Last Updated
May 17, 2021
Sponsor
Kiadis Pharma
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1. Study Identification

Unique Protocol Identification Number
NCT02500550
Brief Title
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
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2021
Overall Recruitment Status
Completed
Study Start Date
October 9, 2015 (Actual)
Primary Completion Date
July 2018 (Actual)
Study Completion Date
December 17, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Kiadis Pharma

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndrome
Keywords
Haploidentical stem cell transplantation, Graft versus host disease, Immune reconstitution, Alloreactive T-cells, Photodynamic treatment, Hematologic malignancy, Transplant-related mortality

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ATIR101
Arm Type
Experimental
Intervention Type
Biological
Intervention Name(s)
ATIR101
Intervention Description
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).
Intervention Type
Procedure
Intervention Name(s)
Haploidentical hematopoietic stem cell transplantation (HSCT)
Intervention Description
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)
Intervention Type
Procedure
Intervention Name(s)
TBI regime
Intervention Description
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.
Intervention Type
Procedure
Intervention Name(s)
Non-TBI regime
Intervention Description
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.
Primary Outcome Measure Information:
Title
Incidence of Acute Graft Versus Host Disease (GVHD) Grade III/IV
Time Frame
180 days post HSCT
Secondary Outcome Measure Information:
Title
Incidence and Severity of Acute and Chronic GVHD
Time Frame
Between 6 and 12 months after HSCT
Title
Percentage of Participants Who Achieved T-Cell Reconstitution at 6 and 12 Months Post HSCT
Description
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
Title
Viral, Fungal, and Bacterial Infections
Description
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
Title
Transplant-related Mortality (TRM)
Description
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)
Time Frame
12 months post HSCT
Title
Relapse-related Mortality (RRM)
Description
Defined as death due to disease relapse or disease progression
Time Frame
12 months post HSCT
Title
Overall Survival (OS)
Description
Defined as the time from HSCT until death from any cause
Time Frame
12 months post HSCT
Title
Progression-free Survival (PFS)
Description
Defined as the time from HSCT until relapse, disease progression, or death, whichever occurs first
Time Frame
12 months post HSCT
Title
GVHD-free, Relapse-free Survival (GRFS)
Description
Defined as the time until acute GVHD grade III/IV, chronic GVHD requiring systemic treatment, relapse, or death, whichever occurs first
Time Frame
12 months post HSCT

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Denis Claude Roy, Prof MD
Organizational Affiliation
Maisonneuve-Rosemont Hospital (Montreal, Canada)
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Stephan Mielke, Prof MD
Organizational Affiliation
Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital (Stockholm, Sweden)
Official's Role
Principal Investigator
Facility Information:
Facility Name
Algemeen Ziekenhuis Sint-Jan
City
Brugge
ZIP/Postal Code
8000
Country
Belgium
Facility Name
Institut Jules Bordet
City
Brussels
ZIP/Postal Code
1000
Country
Belgium
Facility Name
Universitair Ziekenhuis Gasthuisberg
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
Centre Hospitalier Universitaire de Liège
City
Liège
ZIP/Postal Code
4000
Country
Belgium
Facility Name
Juravinski Hospital and Cancer Centre
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8V 1C3
Country
Canada
Facility Name
Maisonneuve-Rosemont Hospital
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H1T 2M4
Country
Canada
Facility Name
University Hospital Centre Zagreb
City
Zagreb
ZIP/Postal Code
10000
Country
Croatia
Facility Name
University Medical Center Mainz
City
Mainz
ZIP/Postal Code
55131
Country
Germany
Facility Name
Hospital de Santa Maria, Clinica Universitaria Hematologia
City
Lisboa
ZIP/Postal Code
1649-028
Country
Portugal
Facility Name
Heartlands Hospital
City
Birmingham
ZIP/Postal Code
B9 5SS
Country
United Kingdom
Facility Name
Hammersmith Hospital
City
London
ZIP/Postal Code
W12 ONN
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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