- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02849886
T Lymphocytes (LT) Expressing iCASP9 and ΔCD19 in Allogeneic Haematopoietic Transplantation. (Side_by_Cide)
Use of Genetically Modified T-lymphocytes Expressing the Inducible Human Caspase 9 Gene (iCASP9) and the Selection Gene ΔCD19 in Allogeneic Haematopoietic Transplantation.
Study Overview
Status
Intervention / Treatment
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.
Study Type
Enrollment (Anticipated)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Contact
- Name: Eric DECONINCK, MD, PhD, HDR
- Phone Number: +33381668404
- Email: edeconinck@chu-besancon.fr
Study Contact Backup
- Name: Fabrice LAROSA, MD
- Phone Number: +33381668411
- Email: flarosa@chu-besancon.fr
Study Locations
-
-
-
Besançon, France, 25000
- Recruiting
- CHU Jean Minjoz
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Non-Randomized
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / 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).
|
Intravenous injection of the T lymphocytes armed with the iCASP9 suicide gene
Other Names:
|
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)
|
Intravenous injection of the T lymphocytes armed with the iCASP9 suicide gene
Other Names:
AP1903 drug will be administrated at a dose of 0.4 mg/kg by intravenous route in the two following cases:
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
GvHD response to Dimerizer AP1903
Time Frame: 72 hours after administration of Dimerizer AP1903
|
Disappearance of clinical signs of GvHD
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72 hours after administration of Dimerizer AP1903
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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. |
1 month, 3 months, 6 months, and 1 year
|
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. |
1 month, 3 months, 6 months, and 1 year
|
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. |
1 month, 3 months, 6 months, and 1 year
|
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) |
1 month, 3 months, 6 months, and 1 year
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GvL effect
Time Frame: 1 month, 3 months, 6 months, and 1 year
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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. |
1 month, 3 months, 6 months, and 1 year
|
Collaborators and Investigators
Investigators
- 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
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- N/2000/39-B
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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