Efficacy and Safety of a Donor Lymphocyte Preparation Depleted of Functional Host Alloreactive T-cells (ATIR) in Patients Undergoing a Peripheral Blood Stem Cell Transplant From a Related, Haploidentical Donor

An Open-label, Uncontrolled, Multicenter, Multinational Study on the Efficacy and Safety of Administration of Donor Lymphocytes Depleted of Alloreactive T-cells (ATIR), Through the Use of TH9402 and Light Treatment in an ex Vivo Process, in Patients Receiving a CD34-selected Peripheral Blood Stem Cell Graft From a Related, Haploidentical Donor

The purpose of this study is to determine whether the administration of a donor lymphocyte preparation depleted of functional host alloreactive T-cells (ATIR) after a T-cell depleted stem cell transplant from a related, haploidentical donor enhances survival by improving the immune effect against infections while preventing graft-versus-host disease .

Study Overview

• Status: Terminated
• Conditions: Lymphoma; Myeloid Leukemia; Myeloproliferative Disorders; Multiple Myeloma; Myelodysplastic Syndrome; Lymphoblastic Leukemia
• Intervention / Treatment: Biological: Donor lymphocyte preparation depleted of host functional alloreactive T-cells

Detailed Description

Allogeneic stem cell transplantation is the treatment of choice for many patients with leukemia and other hematologic malignancies. However, a major limitation of this therapy is that for a significant number of patients no fully HLA-matched donor can be found. The application of partially HLA-matched (haploidentical) family donors, who are virtually always available, has some complications. If there is no T-cell add-back it increases the risk for life-threatening infections and disease relapse, while in case of T-cell add-back the risk for graft-versus-host disease is raised.

Kiadis Pharma has developed a method to selectively deplete host alloreactive T-cells through photodynamic therapy, using TH9402 ex vivo. The donor lymphocyte preparation depleted of functional host alloreactive T-cells (ATIR) is administered to the patient 28-42 days after the stem cell transplant.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brugge, Belgium, 8000
    • Algemeen Ziekenhuis Sint-Jan
  • Brussels, Belgium, 1000
    • Université Libre de Bruxelles - Institute Jules Bordet
  • Leuven, Belgium, 3000
    • Universitair Ziekenhuis Gasthuisberg
  • Liege, Belgium, 4000
    • University of Liege - CHU Sart Tilman
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8V 1C3
      • HHSC, Henderson Hospital Site
    • Toronto, Ontario, Canada, M5G 2M9
      • Ontario Cancer Institute / Princess Margaret Hospital
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Maisonneuve-Rosemont Hospital
• Germany
  • Freiburg, Germany, 79106
    • Universitätsklinikum Freiburg, Medizinische UNI-Klinik
  • Kiel, Germany, 24105
    • Universitätsklinikums Schleswig-Holstein Campus Kiel
  • Mainz, Germany, 55101
    • Universitätsklinikum Mainz
  • Würzburg, Germany, 97080
    • Universitätsklinikum Würzburg
• Italy
  • Perugia, Italy, 06123
    • Perugia University
• Netherlands
  • Maastricht, Netherlands, 6229 HX
    • Academisch Ziekenhuis Maastricht
• United Kingdom
  • London, United Kingdom, W12 ONN
    • Hammersmith Hospital
• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University, Comprehesive Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

One of the following hematological malignancies:

• Acute Myeloid Leukemia (AML)
• Acute Lymphoblastic Leukemia (ALL)
• Myelodysplastic Syndrome (MDS)
• Ph-positive chronic myeloid leukemia (CML)
• Non-Hodgkin Lymphoma (NHL)
• Myelodysplastic Syndrome (MDS)
• Chronic Myeloid Leukemia (CML)
• Multiple Myeloma (MM)
• Chronic Lymphocytic Leukemia (CLL)
• Myeloproliferative Syndrome (MPS)

Exclusion Criteria:

• AML in 1st complete remission with good risk karyotypes
• MM featuring concurrent extramedullar disease or being non-responsive to prior therapy
• CML in blast crisis
• CLL concurrently transformed into high-grade lymphoma and failing to demonstrate at least partial remission
• NHL with concurrent bulky disease (≥ 5 cm)
• Diffusing Capacity for Carbon Monoxide (DLCO) < 40% predicted
• Left ventricular ejection fraction < 40%
• AST/SGOT > 2.5 x ULN
• Bilirubin > 1.5 x ULN
• Creatinine > 1.5 x ULN
• HIV positive
• Positive pregnancy test for women of childbearing age
• Prior haploidentical peripheral blood stem cell or cord blood transplantation
• Less than 2 years from a prior allogeneic stem cell transplantation
• Estimated probability of surviving less than three months
• Major anticipated illness or organ failure incompatible with survival from transplant
• Severe psychiatric illness or mental deficiency sufficiently severe as to make compliance with the transplant treatment unlikely and informed consent impossible
• Known allergy to any of the components of ATIR
• Any other condition which, in the opinion of the investigator, makes the patient ineligible for the study

Donor Inclusion Criteria:

• 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, ≤ 75 years.
• Donors must be fit to receive G-CSF and undergo apheresis (normal blood count, normotensive and no history of stroke).
• Donor must have Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less.
• Donor must provide written informed consent.

Donor Exclusion Criteria:

• Medically uncontrolled coronary heart disease.
• Myocardial infarction within the last 3 months.
• History of uncontrolled seizures.
• History of malignancy (except basal cell or squamous carcinoma of the skin, positive PAP smear and subsequent negative follow up).
• Positive test result for any of the mandatory viral tests in the applicable region, except for a positive cytomegalovirus (CMV) result, which does not lead to exclusion.
• Presence of a transmissible disease (such as HIV positive), a major illness, a suspected systemic dysfunction and/or an active inflammatory or autoimmune disorder.
• Female donors who are pregnant or nursing.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ATIR	Biological: Donor lymphocyte preparation depleted of host functional alloreactive T-cells; Single intravenous infusion with 2x10E6 T-cells/kg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Transplant Related Mortality	TRM is 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)	6, 12 and 24 months after the transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and Severity Graft-versus-host Disease (GVHD)	GVHD was graded according to standard criteria as referred to in the reference module (Filipovich et al. 2005; Przepiorka et al. 1995).	Up to 24 months after the transplantation
Progression Free Survival		Up to 24 months after the transplantation
Incidence and Severity of Bacterial, Viral or Fungal Infection		Up to 24 months after the transplantation
Immune Reconstitution		Up to 24 months after the transplantation
Health Status (Including Quality of Life)		Up to 24 months after the transplantation
Overall Survival		6, 12, and 24 months after the transplantation

Collaborators and Investigators

• Sponsor: Kiadis Pharma
• Investigators: Study Chair: Stephan Mielke, MD, Julius Maximilian University of Würzburg, Germany; Study Chair: Denis-Claude Roy, MD, Maisonneuve-Rosemont Hospital, Montréal, Canada; Principal Investigator: Andrea Velardi, MD, University of Perugia, Italy; Principal Investigator: Katy Rezvani, MD PhD, Hammersmith Hospital, London, United Kingdom

Publications and helpful links

General Publications

• Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56. doi: 10.1016/j.bbmt.2005.09.004.
• Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995 Jun;15(6):825-8.

Study record dates

Study Major Dates

• Study Start: August 1, 2009
• Primary Completion (Actual): February 1, 2012
• Study Completion (Actual): February 1, 2012

Study Registration Dates

• First Submitted: August 26, 2009
• First Submitted That Met QC Criteria: August 26, 2009
• First Posted (Estimate): August 27, 2009

Study Record Updates

• Last Update Posted (Actual): June 14, 2021
• Last Update Submitted That Met QC Criteria: May 19, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Transplant related mortality; Graft-versus-host disease; Hematologic malignancy; Immune reconstitution; Haploidentical stem cell transplantation; Alloreactive T-cells; Photodepletion; TH9402
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Myelodysplastic Syndromes; Multiple Myeloma; Leukemia; Myeloproliferative Disorders
• Other Study ID Numbers: CR-AIR-004; EudraCT no. 2008-008198-73