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

Primary Purpose

Graft Versus Host Disease, Hematological Malignancies

Status

Unknown status

Phase

Phase 1

Locations

France

Study Type

Interventional

Intervention

T lymphocytes iCASP9 ΔCD19

Dimerizer drug AP1903

About this trial

This is an interventional prevention trial for Graft Versus Host Disease focused on measuring GvHD, Suicide gene, Dimerizer drug AP1903, Hematological stem cell transplantation

Eligibility Criteria

40 Years - 55 Years (Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

CHU Jean MinjozRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

LT icasp9 ΔCD19 (cohort1)

LT iCASP9 ΔCD19 & GvHD (cohort2)

Arm Description

Injection T lymphocytes iCASP9 ΔCD19 (2.10e6, 5.10e6 and 10.10e6 Gene Modified Cells (GMC)/kg).

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)

Outcomes

Primary Outcome Measures

GvHD response to Dimerizer AP1903

Disappearance of clinical signs of GvHD

Secondary Outcome Measures

Haematopoietic reconstitution (Blood)

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.

Haematopoietic engraftment (bone marrow)

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

Haematopoietic engraftment (chimerism)

Chimerism Analysis by quantitative mesurement (mesure of % of Donor & recipient cells) Full chimerism will be assessed when chimerim will reach 100% of donor profile.

Infections post Transplantation

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)

GvL effect

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.

Full Information

NCT ID

NCT02849886

First Posted

May 19, 2016

Last Updated

January 29, 2021

Sponsor

Centre Hospitalier Universitaire de Besancon

Collaborators

Etablissement Français du Sang, Bellicum Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT02849886

Brief Title

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

Acronym

Side_by_Cide

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

2. Study Status

Record Verification Date

July 2020

Overall Recruitment Status

Unknown status

Study Start Date

April 10, 2019 (Actual)

Primary Completion Date

December 2021 (Anticipated)

Study Completion Date

December 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Centre Hospitalier Universitaire de Besancon

Collaborators

Etablissement Français du Sang, Bellicum Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Graft Versus Host Disease, Hematological Malignancies

Keywords

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

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

12 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

LT icasp9 ΔCD19 (cohort1)

Arm Type

Experimental

Arm Description

Injection T lymphocytes iCASP9 ΔCD19 (2.10e6, 5.10e6 and 10.10e6 Gene Modified Cells (GMC)/kg).

Arm Title

LT iCASP9 ΔCD19 & GvHD (cohort2)

Arm Type

Experimental

Arm Description

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)

Intervention Type

Drug

Intervention Name(s)

T lymphocytes iCASP9 ΔCD19

Other Intervention Name(s)

T lymphocytes Gene Modified Cells (GMC)

Intervention Description

Intravenous injection of the T lymphocytes armed with the iCASP9 suicide gene

Intervention Type

Drug

Intervention Name(s)

Dimerizer drug AP1903

Other Intervention Name(s)

Dimerizer drug

Intervention Description

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.

Primary Outcome Measure Information:

Title

GvHD response to Dimerizer AP1903

Description

Disappearance of clinical signs of GvHD

Time Frame

72 hours after administration of Dimerizer AP1903

Secondary Outcome Measure Information:

Title

Haematopoietic reconstitution (Blood)

Description

Time Frame