Clinical trial NCT02849886: T Lymphocytes (LT) Expressing iCASP9 and ΔCD19 in Allogeneic Haematopoietic Transplantation.
Official title: Use of Genetically Modified T-lymphocytes Expressing the Inducible Human Caspase 9 Gene (iCASP9) and the Selection Gene ΔCD19 in Allogeneic Haematopoietic Transplantation.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Graft Versus Host Disease
Hematological Malignancies
Keywords: GvHD
Suicide gene
Dimerizer drug AP1903
Hematological stem cell transplantation
Lead sponsor: Centre Hospitalier Universitaire de Besancon
Sponsor class: OTHER
Collaborators: name: Etablissement Français du Sang
name: Bellicum Pharmaceuticals
First posted: 2016-07-29
Enrollment: 12
Sex: ALL
Minimum age (years): 40
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: This study evaluates the frequency of occurrence, severity, and response to treatment by a chemical agent, notably the dimerizer AP1903 (Bellicum Pharmaceuticals compagny), in the case of acute Graft versus Host Disease (aGvHD) occurring after the administration of T-lymphocytes expressing iCASP9 and concomitantly to a bone marrow graft depleted in B- and T-lymphocytes

Detailed description: Haematopoietic transplantation may result in serious complications, notably graft versus host disease (GvHD).

T-lymphocyte depletion of the bone marrow graft is able to prevent GvHD, while increasing the risk of rejection and reducing the antileukaemic effect of the graft (graft versus leukaemia, GvL). In a previous study, the investigators showed that the ex vivo transfer of the Herpes simplex thymidine kinase suicide gene (HSV-TK) into the graft's T lymphocytes prior to reinjection was not associated with immediate toxicity, while allowing for the prolonged recirculation of genetically modified cells (GMC) and control of induced GvHD by ganciclovir (GCV). In addition, this study revealed the existence of GMC resistant to GCV, an immunodeficiency of transduced cells, as well as an increased risk of Epstein-Barr virus (EBV)-induced lymphoproliferative disease. To overcome these difficulties, investigators improved the methodology of producing GMC by using a new vector (pMSCV-iCASP9-2A-ΔCD19) whose susceptibility gene was of human origin and associated with a human surface marker (non-functional) enabling the cell selection process. Moreover, the demonstration that the induced GvHD in this setting could be controlled by the administration of GCV alone led to significantly increase the number of genetically modified T-lymphocytes administered and omit cyclosporin prophylaxis of GvHD.

This phase I study will include 12 patients and will be conducted according the dose escalation method (2.10e6, 5.10e6 and 10.10e6 GMC / kg respectively for levels I, II \& III). GMC will be prepared in the Cell and Tissue Engineering Laboratory (advanced therapy medicinal products departement) of the french Blood center (EFS) in Besançon, France, and sent to the transplantation department.

Eligibility criteria: Inclusion Criteria:

* Adult patients aged ≤55 years (40\< age ≤55 years);
* Patients who are candidates for myeloablative allogeneic bone marrow transplants: de novo or secondary acute lymphoblastic leukaemia (ALL) and acute myeloblastic leukaemia (AML) in complete remission (CR) ≥1; chronic myeloid leukaemia (CML) in chronic phase or in escape from tyrosine kinase inhibitors; myelodysplastic syndrome (MDS) with int-2 or high International Prognostic Scoring System (IPSS score, with medullary blastosis \>10%); chemosensitive malignant non-Hodgkin's lymphoma (MNHL) in CR or partial remission (PR) \>2 ; chemosensitive Hodgkin's disease in CR or PR \>2 ; chemosensitive chronic lymphoid leukaemia (CLL) in CR or PR \>2; chemosensitive myeloma in CR or PR ≥2;
* At high risk for GvHD: the risk for GvHD is considered high and the patient thus eligible for the study, if the receiver is \>40 years, or if the donor is a woman and the receiver a man, regardless their age;
* Karnofsky index \>70% or World Health Organization (WHO) index ≥2;
* Stable clinical conditions and life expectancy \>3 months;
* Absence of organic disease contraindicating the transplantation
* Availability of a genotypically identical donor, aged \>18 years, having given consent, and presenting no contraindications to bone marrow donation under general anaesthesia and to the required apheresis procedures;
* Written informed consent of the donor and patient.

Exclusion Criteria:

* Age \<40 years or \> 55 years
* Organic disease contraindicating the utilisation of myeloablative conditioning
* History of allogeneic Hematological Stem Cell Transplantation (HSCT);
* History of autologous HSCT \<1 year prior to the date for the scheduled allogeneic HSCT;
* Neurological location of the haemopathy justifying the transplantation;
* Pregnant or breastfeeding woman;
* Positive HIV serology;
* Positive hepatitis B or hepatitis C serology (except for post-vaccinal hepatitis B status);
* Absence of informed consent from the receiver or donor;
* Inability to adhere to the protocol instructions.

Primary outcomes:
measure: GvHD response to Dimerizer AP1903
timeFrame: 72 hours after administration of Dimerizer AP1903
Secondary outcomes:
measure: Haematopoietic reconstitution (Blood)
timeFrame: 1 month, 3 months, 6 months, and 1 year
measure: Haematopoietic engraftment (bone marrow)
timeFrame: 1 month, 3 months, 6 months, and 1 year
measure: Haematopoietic engraftment (chimerism)
timeFrame: 1 month, 3 months, 6 months, and 1 year
measure: Infections post Transplantation
timeFrame: 1 month, 3 months, 6 months, and 1 year
measure: GvL effect
timeFrame: 1 month, 3 months, 6 months, and 1 year
Other outcomes:
Locations:
city: Besançon
country: France
facility: CHU Jean Minjoz
Study officials:
affiliation: CHRU de Besançon
name: DECONINCK Eric, MD, PhD, HDR
role: PRINCIPAL_INVESTIGATOR
affiliation: EFSBFC-INSERM UMR1098
name: Christophe FERRAND, PhD, HDR
role: STUDY_CHAIR
affiliation: EFSBFC-INSERM UMR1098
name: Marina DESCHAMPS, PhD
role: STUDY_CHAIR
References: