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

• ClinicalTrials.gov Identifier: NCT02500550
• Recruitment Status: Completed
• First Posted: July 16, 2015
• Results First Posted: January 12, 2021
• Last Update Posted: January 12, 2021
• Sponsor: Kiadis Pharma
• Information provided by (Responsible Party): Kiadis Pharma

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.

Condition or disease	Intervention/treatment	Phase
Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia; Myelodysplastic Syndrome	Biological: ATIR101; Procedure: Haploidentical hematopoietic stem cell transplantation (HSCT); Procedure: TBI regime; Procedure: Non-TBI regime	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• 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
• Actual Study Start Date: October 9, 2015
• Actual Primary Completion Date: July 2018
• Actual Study Completion Date: December 17, 2018

Arms and Interventions

Arm

Intervention/treatment

Experimental: ATIR101

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: Totol Body Irradiation (TBI) regime; Non-TBI regime (See below for details); Procedure: 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.; Procedure: 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.

Outcome Measures

Primary Outcome Measures :

1. Incidence of Acute Graft Versus Host Disease (GvHD) Grade III/IV [ Time Frame: 180 days post HSCT ]

Secondary Outcome Measures :

1. Incidence of Acute and Chronic GvHD [ Time Frame: 12 months post HSCT ]
2. Severity of Acute and Chronic GvHD [ Time Frame: 12 months post HSCT ]
3. Time to T-cell Reconstitution, [ Time Frame: 12 months post HSCT ]
   Defined as the time to CD3+ in peripheral blood higher than 0.2×10E9/L (at two consecutive measurements; time to first measurement)
4. Incidence of Viral, Fungal, and Bacterial Infections [ Time Frame: 12 months post HSCT ]
5. Severity of Viral, Fungal, and Bacterial Infections [ Time Frame: 12 months post HSCT ]
6. Transplant-related Mortality (TRM) [ Time Frame: 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)
7. Relapse-related Mortality (RRM) [ Time Frame: 12 months post HSCT ]
   Defined as death due to disease relapse or disease progression
8. Overall Survival (OS) [ Time Frame: 12 months post HSCT ]
   Defined as the time from HSCT until death from any cause
9. Progression-free Survival (PFS) [ Time Frame: 12 months post HSCT ]
   Defined as the time from HSCT until relapse, disease progression, or death, whichever occurs first
10. GvHD-free, Relapse-free Survival (GRFS) [ Time Frame: 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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

Belgium

Algemeen Ziekenhuis Sint-Jan

Brugge, Belgium, 8000

Institut Jules Bordet

Brussels, Belgium, 1000

Universitair Ziekenhuis Gasthuisberg

Leuven, Belgium, 3000

Centre Hospitalier Universitaire de Liège

Liège, Belgium, 4000

Canada, Ontario

Juravinski Hospital and Cancer Centre

Hamilton, Ontario, Canada, L8V 1C3

Canada, Quebec

Maisonneuve-Rosemont Hospital

Montreal, Quebec, Canada, H1T 2M4

Croatia

University Hospital Centre Zagreb

Zagreb, Croatia, 10000

Germany

University Medical Center Mainz

Mainz, Germany, 55131

Portugal

Hospital de Santa Maria, Clinica Universitaria Hematologia

Lisboa, Portugal, 1649-028

United Kingdom

Heartlands Hospital

Birmingham, United Kingdom, B9 5SS

Hammersmith Hospital

London, United Kingdom, W12 ONN

Sponsors and Collaborators

Kiadis Pharma

Investigators

• Principal Investigator: Denis Claude Roy, Prof MD; Maisonneuve-Rosemont Hospital (Montreal, Canada)
• Principal Investigator: Stephan Mielke, Prof MD; Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital (Stockholm, Sweden)

  Study Documents (Full-Text)

Documents provided by Kiadis Pharma:

Study Protocol  [PDF] November 20, 2015

Statistical Analysis Plan  [PDF] December 13, 2018

More Information

• Responsible Party: Kiadis Pharma
• ClinicalTrials.gov Identifier: NCT02500550
• Other Study ID Numbers: CR-AIR-008
• First Posted: July 16, 2015
• Results First Posted: January 12, 2021
• Last Update Posted: January 12, 2021
• Last Verified: December 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Kiadis Pharma:

Haploidentical stem cell transplantation; Graft versus host disease; Immune reconstitution; Alloreactive T-cells; Photodynamic treatment; Hematologic malignancy; Transplant-related mortality

Additional relevant MeSH terms:

Leukemia; Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hematologic Neoplasms; Myelodysplastic Syndromes; Neoplasms by Histologic Type; Bone Marrow Diseases; Hematologic Diseases; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Neoplasms by Site