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Phase I Study of CTL Anti-DP Infusion Post-hematopoietic Stem Cell Transplantation (CTL-DP 01)

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ClinicalTrials.gov Identifier: NCT04180059
Recruitment Status : Not yet recruiting
First Posted : November 27, 2019
Last Update Posted : December 2, 2019
Sponsor:
Collaborator:
INSERM U01232 CRCINA
Information provided by (Responsible Party):
Nantes University Hospital

Brief Summary:

For several decades, allogeneic hematopoietic stem cell trans-plantation (allo-HSCT) has remained an important strategy in the management of patients with high-risk hematological malignancies. The acceptance of umbilical cord blood (UCBT) and haploidentical grafts (Haplo) as viable alternative donors for allo-HSCT has increased the options for patients with no matched donors and now ensures that a donor can be identified for virtually all patients. Relapsed disease is a principal threat to these patients and affects 30-50% of them. The therapeutic options for these relapsing patients are diverse but remain largely ineffective in altering their long-term outcomes. Therefore, pre-emptive treatment post allo-HSCT is considered.

MHC (major histocompatibility complex) class II molecules are a family of molecules normally found only on hematopoietic cells. cell-surface proteins are responsible for the regulation of the immune system in humans and are important in disease defense.

They are the major cause of organ transplant rejections. Different HLA-DPB1 alleles exist in the general population. HLA-DPB1*04:01 is the most frequent (70.5%) while HLA-DPB1*02:01 represents 32% and HLA-DPB1*03:01 20%. In allo-HSCT, the donor and the recipient may express different HLA-DPB1 molecules. HLA-DPB1 matching status has an impact on GVL (graft versus leukemia) and GVHD. In recipients of HSCT, a match for DPB1 is associated with a significantly increased risk of disease relapse, irrespective of the matching status of other HLA molecules.. Therefore, one could anticipate that a mismatched of HLA class II could induce a selective GVL reactivity without GVHD.

HLA-DP-expressing B cell and myeloid malignancies can be recognized and lysed by HLA-DP-specific T cells. The majority of leukemic cells (Acute Myeloid Leukemia, Acute Lymphoid Leukemia, Chronic Lymphoid Leukemia) express HLA-DP. A T cell clone recognizing specifically HLA-DPB1*0401 has been developed as a permanent cell line This clone has been demonstrated to be able to kill HLA-DPB1*0401 positive leukemic cells. In addition, this clone harbors a special suicide gene allowing the destruction of the clone in presence of a specific anti-viral drug named ganciclovir.

We hypothesize that infusion of a third party suicide gene-transduced T cell clone directed against HLA-DPB1*401 might protect against possible relapse of hematological malignancies.

We propose to inject iv escalating dose of a third party clone recognizing HLA-DPB1*04:01, 4 to 5 months following transplantation (when immunosuppressive drugs have been discontinued) in patients HLA-DPB1*04:01 positive with a donor HLA-DPB1*04:01 negative to evaluate the feasibility, toxicity, benefits of this immune intervention.


Condition or disease Intervention/treatment Phase
Haematologic Disease Combination Product: CTL 19 Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Intervention Model Description:

Biological, T cell clone

A standard 3 + 3 phase 1 dose-escalation study will be used:

Level 1: 1 x 104 cells/kg of recipient, Level 2: 5 x 104 cells/kg, Level 3: 25 x 104 cells/kg, Level 4: 50 x 104 cells/kg, Level 5: 100 x 104 cells/kg.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Dose-escalation Study Testing the Feasibility and the Tolerance of Infusion of a Specific Third Party Suicide Gene-transduced Anti-HLA-DPB1*0401 CD4+ T Cell Clone in HLA-DPB1*04:01 Positive Tumor Recipients Receiving an Allotransplant From a HLA-DPB1*04:01 Negative Donor.
Estimated Study Start Date : March 2020
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : March 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: CTL 19 : T cell therapy
Level 1: 1 x 104 cells/kg of recipient, Level 2: 5 x 104 cells/kg, Level 3: 25 x 104 cells/kg, Level 4: 50 x 104 cells/kg, Level 5: 100 x 104 cells/kg.
Combination Product: CTL 19
Patients candidate for allogeneic transplantation who are both HLA-DPB1*04:01 and with a HLA-DPB1*04:01-expressing hematological malignancy (almost 100% of cases) with a donor HLA-DPB1*04:01 negative, will be proposed to receive one single infusion of the T cell clone at 4-5 months post-transplantation, once the immunosuppression by cyclosporine and/or mycophenolate mofetil has been discontinued.
Other Name: T cell therapy




Primary Outcome Measures :
  1. determine maximal tolerated dose f infusion of a third party suicide gene-transduced anti-HLA-DPB1*04:01 CD4+ T cell clone in HLA-DPB1*04:01 tumor positive recipients receiving an allo-HSCT from a HLA-DPB1*04:01 negative alternative donor. [ Time Frame: 4 weeks after CTL injection ]

    the most likely side effects of the injection of the clone is the induction of an acute GVHD (severity measured by organ staging and overall clinical grading).

    acute GVHD will be evaluated for each patient. Maximal tolerated dose is defined as : none acute GVHD for 3 patients on 3 or for at least 5 patients on 6.

    A standard 3 + 3 phase 1 dose-escalation study will be used:

    Level 1: 1 x 104 cells/kg of recipient, Level 2: 5 x 104 cells/kg, Level 3: 25 x 104 cells/kg, Level 4: 50 x 104 cells/kg, Level 5: 100 x 104 cells/kg.



Secondary Outcome Measures :
  1. survival and persistence of the clone injected [ Time Frame: 60 first days post injection, 6 months post injection, 12 months post injection ]
    The survival of the clone will be tracked by PCR (polymerase chain reaction) during the 60 first days post injection as well as 6 and 12 months post injection in the blood and in the marrow

  2. immune reconstitution [ Time Frame: day of clone injection, 30 days after clone injection, 60 days after clone injection, 9 months after clone injection, 12 months after clone injection ]
    T cell reconstitution will be evaluated by measuring the levels of CD4+, CD8+, Natural Killer cells

  3. incidence of relapse [ Time Frame: 12 months post allograft ]
    Cumulative incidence of relapse

  4. survival [ Time Frame: 12 months post allograft ]
    event free survival, overall survival

  5. GVHD incidence [ Time Frame: 12 months post allograft ]
    cumulative incidence of acute and chronic GVHD

  6. mortality [ Time Frame: 12 months post allograft ]
    death not related to relapse

  7. complete remission [ Time Frame: 12 months post allograft ]
    for lymphoma patients in partial response before allograft

  8. side effects of Clone [ Time Frame: 12 months post allograft ]
    events related to clone (except GVHD)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients HLA-DPB1*04:01 positive, with confirmed diagnosis of hematologic malignancies (AML, Myelodysplasic syndrome, ALL, non-Hodgkin's lymphoma, Hodgkin's disease, CLL), undergoing an allo-HSCT using a HLA-DPB1*04:01 negative donor.
  • The graft can be PBSC (peripheric blood stem cells) or bone marrow.
  • Patients aged between 18-75 years.
  • Patients in complete remission or >50% of response (for lymphoma) at time of transplant.
  • have a donor with no contra-indications for mobilization of peripheral blood stem cells using G-CSF (colony-stimulating factors)
  • Affiliation number to the National Health Care System
  • Lack of reactivity of the clone against the donor's cells (PHA-blasts prepared for from PBMCs).
  • For cord blood transplants: cord blood must be HLA-DPB1*04:01 negative and the HLA compatibility (A, B, DR) between the cord blood and the recipient must be 4/6, 5/6 or 6/6.
  • ECOG <=2 or Karnofsky >60%
  • neutrophils ≥ 1 000 cells /μl and/or platelets ≥ 50 000 cells/μl (growth factor allowed)

Exclusion Criteria:

  • pregnant or breastfeeding woman
  • patient refusing contraception measure
  • minor
  • Adult patients under guardianship, curatorship or justice protection
  • Patients with post-transplant relapse within the clone injection time (before D100)
  • Karnofsky performance score below 60%or ECOG >2
  • Acute and chronic heart failure (NYHA Class III or IV) or symptomatic ischemic heart disease.
  • Severe liver failure (bilirubin >30 µmoles/L, SGPT (Serum Glutamo-Oxalacetic Transaminase)> 4 X upper limit of normal).
  • Impaired renal function (creatinine clearance < 30 ml/min)
  • Acute GVHD > grade 1
  • Active uncontrolled infection.
  • Denied to provide informed consent
  • Severe neurological or psychiatric disorders as determined by the study physician.
  • Treatment with other investigational drugs following allogeneic transplantation.

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): NCT04180059


Contacts
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Contact: thierry GUILLAUME, MD thierry.guillaume@chu-nantes.fr
Contact: Henri Vie henri.vie@univ-nantes.fr

Locations
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France
Chu de Nantes Not yet recruiting
Nantes, France
Contact: Thierry GUILLAUME, MD       thierry.guillaume@chu-nantes.fr   
Sponsors and Collaborators
Nantes University Hospital
INSERM U01232 CRCINA

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Responsible Party: Nantes University Hospital
ClinicalTrials.gov Identifier: NCT04180059     History of Changes
Other Study ID Numbers: RC16_0157
First Posted: November 27, 2019    Key Record Dates
Last Update Posted: December 2, 2019
Last Verified: November 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Nantes University Hospital:
hematopoietic stem cell transplantation
lymphocyte infusion
cytotoxic T lymphocyte
HLA-DP
T cell therapy
Additional relevant MeSH terms:
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Hematologic Diseases