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

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Recruiting

CT.gov ID

NCT03236129

Collaborator

(none)

Enrollment

Location

Arms

47.3

Anticipated Duration (Months)

1.1

Patients Per Site Per Month

Study Details

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

Condition or Disease	Intervention/Treatment	Phase
Hematological Malignancies Regulatory T Cell Depletion Relapse	Procedure: T-reg depleted DLI Procedure: Standard DLI	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

52 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Feb 22, 2018

Anticipated Primary Completion Date :

Feb 1, 2021

Anticipated Study Completion Date :

Feb 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treg depleted DLI Patients will receive a lymphodepleting treatment combining cyclophosphamide and fludarabine followed by Treg depleted (Donor Lymphocytes Infusion (DLI)	Procedure: T-reg depleted DLI The patients in the experimental arm benefit of a DLI depleted from regulatory T lymphocytes
Active Comparator: Unmanipulated DLI Patients will receive a lymphodepleting treatment combining cyclophosphamide and fludarabine followed by a standard DLI (unmanipulated)	Procedure: Standard DLI The patients in this arm benefit of a standard DLI.

Arm

Intervention/Treatment

Experimental: Treg depleted DLI

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

Procedure: T-reg depleted DLI

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

Active Comparator: Unmanipulated DLI

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

Procedure: Standard DLI

The patients in this arm benefit of a standard DLI.

Outcome Measures

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 [1 year after injection]

Secondary Outcome Measures

Cumulative incidence of relapse, taking into account the competitive risk of death unrelated to relapse [1 year after injection]
Relapse-free survival [1 year after injection]
Overall survival [1 year after injection]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts 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