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Allogeneic Immunotherapy for Hematological Malignancies by Selective Depletion of Regulatory T Cells (DLI-Boost)

Primary Purpose

Hematological Malignancies, Regulatory T Cell Depletion, Relapse

Status

Unknown status

Phase

Phase 3

Locations

France

Study Type

Interventional

Intervention

T-reg depleted DLI

Standard DLI

About this trial

This is an interventional treatment trial for Hematological Malignancies focused on measuring DLI, Regulatory T cells depletion, Hematological malignancies, Relapse

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Children and adults regardless of age or weight allograft for primary or secondary acute leukemia, MDS, lympho-proliferative syndrome (CLL, Myeloma, Lymphoma) or myelo-proliferative syndrome.
Prior allogeneic HSCT (myeloablative or non-myeloablative conditioning) from a family donor geno-identical HLA or a volunteer donor HLA 10/10 or 9/10.
Molecular, cytogenetic, cytological relapse regardless of the date after the transplant.
Previous standard DLI should have brought a total dose of at least 5.106 CD3 + / kg (donor HLA-geno idendique) or 2.106 CD3 + / kg (voluntary donor).
Patient corresponding to the failure criteria of a previous standard DLI, defined for each type of hematological malignancies in the test model "DLI-Treg-1" after a delay of at least 30 days in the case of a progressive disease after DLI and at least 60 days in the case of stable disease (due to possible delayed responses after DLI).
Patient consented to the study (the consent of both parents will be collected for minors)
Patients insured by a social security system.
Negative pregnancy test (β-HCG hormone) within the 7 days prior to enrollment

Exclusion Criteria:

Presence of acute GVHD grade> II or extensive chronic GVHD since the first DLI
Patient receiving immunosuppressive therapy for the treatment of GVHD or other reason
Impairment of liver function (transaminases> 5 N or bilirubin> 50 µM except Gilbert's disease) or renal function (creatinine clearance <30 ml / min)
OMS performance status > 2
Non controlled severe infection
Patient under tutorship, curatorship or legal protection

Donor Inclusion Criteria

Being the initial HSC donor (HLA geno-identical family or non-family HLA 10/10 or 9/10)
Weight ≥20 kg authorizing the lymphapheresis
Having no contra-indications for donating blood
Absence of severe heart failure, unstable heart disease, uncontrolled hypertension, type 1 diabetes
Negative serology for HIV1-2, HBV, HCV, HTLV 1 and VDRL/TPHA in the 30 days prior to apheresis. Negative viral genomics diagnosis is required for HIV, HBV and HCV
Being informed of the study, and have given an oral non opposition

Sites / Locations

Henri Mondor HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Treg depleted DLI

Unmanipulated DLI

Arm Description

Patients will receive a lymphodepleting treatment combining cyclophosphamide and fludarabine followed by Treg depleted (Donor Lymphocytes Infusion (DLI)

Patients will receive a lymphodepleting treatment combining cyclophosphamide and fludarabine followed by a standard DLI (unmanipulated)

Outcomes

Primary Outcome Measures

Cumulative incidence of clinical manifestations of GVHD, in the form of acute GVHD with grade ≥ 2 and/or extensive chronic. This parameter will take into account the competitive risk of death unrelated to the GVHD

Secondary Outcome Measures

Cumulative incidence of relapse, taking into account the competitive risk of death unrelated to relapse

Relapse-free survival

Overall survival

Full Information

NCT ID

NCT03236129

First Posted

July 5, 2017

Last Updated

November 19, 2020

Sponsor

Assistance Publique - Hôpitaux de Paris

1. Study Identification

Unique Protocol Identification Number

NCT03236129

Brief Title

Allogeneic Immunotherapy for Hematological Malignancies by Selective Depletion of Regulatory T Cells

Acronym

DLI-Boost

Official Title

Allogeneic Immunotherapy for Hematological Malignancies by Selective Depletion of Regulatory T Cells: A Confirmatory, Randomized, Double Blinded Trial

Study Type

Interventional

2. Study Status

Record Verification Date

November 2020

Overall Recruitment Status

Unknown status

Study Start Date

February 22, 2018 (Actual)

Primary Completion Date

February 2021 (Anticipated)

Study Completion Date

February 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Assistance Publique - Hôpitaux de Paris

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

The investigators have previously shown the absence of toxicity of Treg-depleted-DLI and the possibility to triggering alloreactivity (GVHD/GVT) in relapsing patients dealing with hematological malignancies who had never shown any signs of GVHD after transplant or after one or more DLI. The Investigators, we plan to demonstrate the benefit of Treg-depleted DLI as compared to the reference treatment of relapse in hematological malignancies after allogeneic HSCT which is currently based on standard DLI

Detailed Description

This clinical trial is designed to demonstrate the benefit of Treg-depleted DLI as compared to the reference treatment of relapse in hematological malignancies after allogeneic HSCT which is currently based on standard DLI. Patients who have never shown any signs of GVHD and for which one (or more) unmanipulated DLI have been ineffective. Those patients will receive a subsequent DLI, which will be either unmanipulated (control arm) or Treg depleted (experimental arm) after a randomization. In both cases, the second DLI will be immediately preceded by a lymphodepleting treatment based on cyclophosphamide and fludarabine association.

6. Conditions and Keywords

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

Hematological Malignancies, Regulatory T Cell Depletion, Relapse

Keywords

DLI, Regulatory T cells depletion, Hematological malignancies, Relapse

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

52 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Treg depleted DLI

Arm Type

Experimental

Arm Description

Patients will receive a lymphodepleting treatment combining cyclophosphamide and fludarabine followed by Treg depleted (Donor Lymphocytes Infusion (DLI)

Arm Title

Unmanipulated DLI

Arm Type

Active Comparator

Arm Description

Patients will receive a lymphodepleting treatment combining cyclophosphamide and fludarabine followed by a standard DLI (unmanipulated)

Intervention Type

Procedure

Intervention Name(s)

T-reg depleted DLI

Intervention Description

The patients in the experimental arm benefit of a DLI depleted from regulatory T lymphocytes

Intervention Type

Procedure

Intervention Name(s)

Standard DLI

Intervention Description

The patients in this arm benefit of a standard DLI.

Primary Outcome Measure Information:

Title

Time Frame

1 year after injection

Secondary Outcome Measure Information:

Title

Cumulative incidence of relapse, taking into account the competitive risk of death unrelated to relapse

Time Frame

1 year after injection

Title

Relapse-free survival

Time Frame

1 year after injection

Title

Overall survival

Time Frame

1 year after injection

10. Eligibility

Sex

All

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Children and adults regardless of age or weight allograft for primary or secondary acute leukemia, MDS, lympho-proliferative syndrome (CLL, Myeloma, Lymphoma) or myelo-proliferative syndrome. Prior allogeneic HSCT (myeloablative or non-myeloablative conditioning) from a family donor geno-identical HLA or a volunteer donor HLA 10/10 or 9/10. Molecular, cytogenetic, cytological relapse regardless of the date after the transplant. Previous standard DLI should have brought a total dose of at least 5.106 CD3 + / kg (donor HLA-geno idendique) or 2.106 CD3 + / kg (voluntary donor). Patient corresponding to the failure criteria of a previous standard DLI, defined for each type of hematological malignancies in the test model "DLI-Treg-1" after a delay of at least 30 days in the case of a progressive disease after DLI and at least 60 days in the case of stable disease (due to possible delayed responses after DLI). Patient consented to the study (the consent of both parents will be collected for minors) Patients insured by a social security system. Negative pregnancy test (β-HCG hormone) within the 7 days prior to enrollment Exclusion Criteria: Presence of acute GVHD grade> II or extensive chronic GVHD since the first DLI Patient receiving immunosuppressive therapy for the treatment of GVHD or other reason Impairment of liver function (transaminases> 5 N or bilirubin> 50 µM except Gilbert's disease) or renal function (creatinine clearance <30 ml / min) OMS performance status > 2 Non controlled severe infection Patient under tutorship, curatorship or legal protection Donor Inclusion Criteria Being the initial HSC donor (HLA geno-identical family or non-family HLA 10/10 or 9/10) Weight ≥20 kg authorizing the lymphapheresis Having no contra-indications for donating blood Absence of severe heart failure, unstable heart disease, uncontrolled hypertension, type 1 diabetes Negative serology for HIV1-2, HBV, HCV, HTLV 1 and VDRL/TPHA in the 30 days prior to apheresis. Negative viral genomics diagnosis is required for HIV, HBV and HCV Being informed of the study, and have given an oral non opposition

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Florence BECKERICH, MD

Phone

(0)1 49 81 20 57

Ext

+33

florence.beckerich@aphp.fr

First Name & Middle Initial & Last Name or Official Title & Degree

Sébastien MAURY, MD/ PhD

Phone

(0)1 49 81 20 57

Ext

+33

sebastien.maury@aphp.fr

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Florence BEKCERICH, MD

Organizational Affiliation

Assistance Publique - Hôpitaux de Paris

Official's Role

Principal Investigator

Facility Information:

Facility Name

Henri Mondor Hospital

City

Creteil

ZIP/Postal Code

94010

Country

France

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Damien VANHOYE, PhD

Phone

(0)1 44 84 17 93

Ext

+33

damien.vanhoye@drc.aphp.fr

First Name & Middle Initial & Last Name & Degree

Laetitia GREGOIRE, M. Sc

Phone

(0)1 49 81 41 64

Ext

+33

Laetitia.gregoire@aphp.fr

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

20650872

Citation

Maury S, Lemoine FM, Hicheri Y, Rosenzwajg M, Badoual C, Cherai M, Beaumont JL, Azar N, Dhedin N, Sirvent A, Buzyn A, Rubio MT, Vigouroux S, Montagne O, Bories D, Roudot-Thoraval F, Vernant JP, Cordonnier C, Klatzmann D, Cohen JL. CD4+CD25+ regulatory T cell depletion improves the graft-versus-tumor effect of donor lymphocytes after allogeneic hematopoietic stem cell transplantation. Sci Transl Med. 2010 Jul 21;2(41):41ra52. doi: 10.1126/scitranslmed.3001302.

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Allogeneic Immunotherapy for Hematological Malignancies by Selective Depletion of Regulatory T Cells

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