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

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ClinicalTrials.gov Identifier: NCT02849886
Recruitment Status : Recruiting
First Posted : July 29, 2016
Last Update Posted : April 16, 2019
Sponsor:
Collaborators:
Etablissement Français du Sang
Bellicum Pharmaceuticals
Information provided by (Responsible Party):
Centre Hospitalier Universitaire de Besancon

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

Condition or disease Intervention/treatment Phase
Graft Versus Host Disease Hematological Malignancies Drug: T lymphocytes iCASP9 ΔCD19 Drug: Dimerizer drug AP1903 Phase 1 Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
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.
Actual Study Start Date : April 10, 2019
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: LT icasp9 ΔCD19 (cohort1)
Injection T lymphocytes iCASP9 ΔCD19 (2.10e6, 5.10e6 and 10.10e6 Gene Modified Cells (GMC)/kg).
Drug: T lymphocytes iCASP9 ΔCD19
Intravenous injection of the T lymphocytes armed with the iCASP9 suicide gene
Other Name: T lymphocytes Gene Modified Cells (GMC)

Experimental: LT iCASP9 ΔCD19 & GvHD (cohort2)
Injection 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)
Drug: T lymphocytes iCASP9 ΔCD19
Intravenous injection of the T lymphocytes armed with the iCASP9 suicide gene
Other Name: T lymphocytes Gene Modified Cells (GMC)

Drug: Dimerizer drug AP1903

AP1903 drug will be administrated at a dose of 0.4 mg/kg by intravenous route in the two following cases:

  • Acute Grade ≥II or symptomatic Grade I GvHD justifying systemic immunosuppression therapy;
  • Grade ≥3 toxicity attributable to GMC.
Other Name: Dimerizer drug




Primary Outcome Measures :
  1. GvHD response to Dimerizer AP1903 [ Time Frame: 72 hours after administration of Dimerizer AP1903 ]
    Disappearance of clinical signs of GvHD


Secondary Outcome Measures :
  1. Haematopoietic reconstitution (Blood) [ Time Frame: 1 month, 3 months, 6 months, and 1 year ]

    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.


  2. Haematopoietic engraftment (bone marrow) [ Time Frame: 1 month, 3 months, 6 months, and 1 year ]

    Bone marrow smear analysis.

    Haematopoietic engraftment will be assessed when proportion of marrow cells reach normal account values.


  3. Haematopoietic engraftment (chimerism) [ Time Frame: 1 month, 3 months, 6 months, and 1 year ]

    Chimerism Analysis by quantitative mesurement (mesure of % of Donor & recipient cells)

    Full chimerism will be assessed when chimerim will reach 100% of donor profile.


  4. Infections post Transplantation [ Time Frame: 1 month, 3 months, 6 months, and 1 year ]

    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)


  5. GvL effect [ Time Frame: 1 month, 3 months, 6 months, and 1 year ]

    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.




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Ages Eligible for Study:   40 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02849886


Contacts
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Contact: Eric DECONINCK, MD, PhD, HDR +33381668404 edeconinck@chu-besancon.fr
Contact: Fabrice LAROSA, MD +33381668411 flarosa@chu-besancon.fr

Locations
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France
CHU Jean Minjoz Recruiting
Besançon, France, 25000
Sponsors and Collaborators
Centre Hospitalier Universitaire de Besancon
Etablissement Français du Sang
Bellicum Pharmaceuticals
Investigators
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Principal Investigator: DECONINCK Eric, MD, PhD, HDR CHRU de Besançon
Study Chair: Christophe FERRAND, PhD, HDR EFSBFC-INSERM UMR1098
Study Chair: Marina DESCHAMPS, PhD EFSBFC-INSERM UMR1098

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Responsible Party: Centre Hospitalier Universitaire de Besancon
ClinicalTrials.gov Identifier: NCT02849886     History of Changes
Other Study ID Numbers: N/2000/39-B
First Posted: July 29, 2016    Key Record Dates
Last Update Posted: April 16, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Centre Hospitalier Universitaire de Besancon:
GvHD
Suicide gene
Dimerizer drug AP1903
Hematological stem cell transplantation
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases