Clinical Trials /

T Lymphocytes (LT) Expressing iCASP9 and ΔCD19 in Allogeneic Haematopoietic Transplantation.

NCT02849886

Description:

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

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Lymphocytic Leukemia
  • Chronic Myeloid Leukemia
  • Hodgkin Lymphoma
  • Myelodysplastic Syndromes
  • Myeloma
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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.

Clinical Trial IDs

  • ORG STUDY ID: N/2000/39-B
  • NCT ID: NCT02849886

Conditions

  • Graft Versus Host Disease
  • Hematological Malignancies

Interventions

DrugSynonymsArms
T lymphocytes iCASP9 ΔCD19T lymphocytes Gene Modified Cells (GMC)LT icasp9 ΔCD19 (cohort1)
Dimerizer drug AP1903Dimerizer drugLT iCASP9 ΔCD19 & GvHD (cohort2)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
LT icasp9 ΔCD19 (cohort1)ExperimentalInjection T lymphocytes iCASP9 ΔCD19 (2.10e6, 5.10e6 and 10.10e6 Gene Modified Cells (GMC)/kg).
  • T lymphocytes iCASP9 ΔCD19
LT iCASP9 ΔCD19 & GvHD (cohort2)ExperimentalInjection T lymphocytes iCASP9 ΔCD19 (2.10e6, 5.10e6 and 10.10e6 GMC/kg). Patients who develop GVHD after administration of Gene Modified Cells (GMC) will be treated with dimerizer drug (AP1903)
  • T lymphocytes iCASP9 ΔCD19
  • Dimerizer drug AP1903

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.
      
Maximum Eligible Age:55 Years
Minimum Eligible Age:40 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:GvHD response to Dimerizer AP1903
Time Frame:72 hours after administration of Dimerizer AP1903
Safety Issue:
Description:Disappearance of clinical signs of GvHD

Secondary Outcome Measures

Measure:Haematopoietic reconstitution (Blood)
Time Frame:1 month, 3 months, 6 months, and 1 year
Safety Issue:
Description:Full Blood count and Blood Cell phenotyping (T & B Lymphocytes, Natural Killers cells (NK), polynuclear cells...) Hematopoietic reconstitution will be assessed when % of Blood cells reach normal account values.
Measure:Haematopoietic engraftment (bone marrow)
Time Frame:1 month, 3 months, 6 months, and 1 year
Safety Issue:
Description:Bone marrow smear analysis. Haematopoietic engraftment will be assessed when proportion of marrow cells reach normal account values.
Measure:Haematopoietic engraftment (chimerism)
Time Frame:1 month, 3 months, 6 months, and 1 year
Safety Issue:
Description:Chimerism Analysis by quantitative mesurement (mesure of % of Donor & recipient cells) Full chimerism will be assessed when chimerim will reach 100% of donor profile.
Measure:Infections post Transplantation
Time Frame:1 month, 3 months, 6 months, and 1 year
Safety Issue:
Description:Monitoring of Infections post-transplantation will be studied by analysis of frequency of infection's events. (number of infection's events by patients and/or frequency)
Measure:GvL effect
Time Frame:1 month, 3 months, 6 months, and 1 year
Safety Issue:
Description:Molecular residual disease (MRD) analysis of biological markers of the initial hematological disease either by molecular biology and/or flow cytometry. GvL effect will be assessed by evaluation of decrease of initial tumoral load.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Centre Hospitalier Universitaire de Besancon

Trial Keywords

  • GvHD
  • Suicide gene
  • Dimerizer drug AP1903
  • Hematological stem cell transplantation

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