Clinical trial NCT00967343: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Myeloid Leukemia
Lymphoblastic Leukemia
Lymphoma
Multiple Myeloma
Myelodysplastic Syndrome
Myeloproliferative Disorders
Keywords: Haploidentical stem cell transplantation
Graft-versus-host disease
Immune reconstitution
Alloreactive T-cells
Photodepletion
TH9402
Transplant related mortality
Hematologic malignancy
Lead sponsor: Kiadis Pharma
Sponsor class: INDUSTRY
First posted: 2009-08-27
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: 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 .

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Transplant Related Mortality
timeFrame: 6, 12 and 24 months after the transplantation
Secondary outcomes:
measure: Incidence and Severity Graft-versus-host Disease (GVHD)
timeFrame: Up to 24 months after the transplantation
measure: Progression Free Survival
timeFrame: Up to 24 months after the transplantation
measure: Incidence and Severity of Bacterial, Viral or Fungal Infection
timeFrame: Up to 24 months after the transplantation
measure: Immune Reconstitution
timeFrame: Up to 24 months after the transplantation
measure: Health Status (Including Quality of Life)
timeFrame: Up to 24 months after the transplantation
measure: Overall Survival
timeFrame: 6, 12, and 24 months after the transplantation
Other outcomes:
Locations:
city: Columbus
country: United States
facility: Ohio State University, Comprehesive Cancer Center
state: Ohio
city: Brugge
country: Belgium
facility: Algemeen Ziekenhuis Sint-Jan
city: Brussels
country: Belgium
facility: Université Libre de Bruxelles - Institute Jules Bordet
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Gasthuisberg
city: Liege
country: Belgium
facility: University of Liege - CHU Sart Tilman
city: Hamilton
country: Canada
facility: HHSC, Henderson Hospital Site
state: Ontario
city: Toronto
country: Canada
facility: Ontario Cancer Institute / Princess Margaret Hospital
state: Ontario
city: Montreal
country: Canada
facility: Maisonneuve-Rosemont Hospital
state: Quebec
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg, Medizinische UNI-Klinik
city: Kiel
country: Germany
facility: Universitätsklinikums Schleswig-Holstein Campus Kiel
city: Mainz
country: Germany
facility: Universitätsklinikum Mainz
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
city: Perugia
country: Italy
facility: Perugia University
city: Maastricht
country: Netherlands
facility: Academisch Ziekenhuis Maastricht
city: London
country: United Kingdom
facility: Hammersmith Hospital
Study officials:
affiliation: Julius Maximilian University of Würzburg, Germany
name: Stephan Mielke, MD
role: STUDY_CHAIR
affiliation: Maisonneuve-Rosemont Hospital, Montreal, Canada
name: Denis-Claude Roy, MD
role: STUDY_CHAIR
affiliation: University Of Perugia
name: Andrea Velardi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hammersmith Hospital, London, United Kingdom
name: Katy Rezvani, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.