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

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

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

Study Overview

• Status: Recruiting
• Conditions: Hematological Malignancies; Relapse; Regulatory T Cell Depletion
• Intervention / Treatment: Procedure: T-reg depleted DLI; Procedure: 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.

• Study Type: Interventional
• Enrollment (Estimated): 52
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Florence BECKERICH, MD; Phone Number: +33 (0)1 49 81 20 57; Email: florence.beckerich@aphp.fr
• Study Contact Backup: Name: Sébastien MAURY, MD/ PhD; Phone Number: +33 (0)1 49 81 20 57; Email: sebastien.maury@aphp.fr

Study Locations

• France
  • Creteil, France, 94010
    • Recruiting
    • Henri Mondor Hospital
    • Contact: Damien VANHOYE, PhD; Phone Number: +33 (0)1 44 84 17 93; Email: damien.vanhoye@drc.aphp.fr
    • Contact: Laetitia GREGOIRE, M. Sc; Phone Number: +33 (0)1 49 81 41 64; Email: Laetitia.gregoire@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 5.10^6 CD3 + / kg (donor HLA-geno idendique) or 2.10^6 CD3 + / kg (voluntary donor) or 5.10^5 CD3+/kg (donor haplo-idendique).
• 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 haplo-identique 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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	3 month after injection

Secondary Outcome Measures

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Florence BEKCERICH, MD, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2018
• Primary Completion (Estimated): February 1, 2025
• Study Completion (Estimated): February 1, 2026

Study Registration Dates

• First Submitted: July 5, 2017
• First Submitted That Met QC Criteria: July 31, 2017
• First Posted (Actual): August 1, 2017

Study Record Updates

• Last Update Posted (Actual): December 18, 2023
• Last Update Submitted That Met QC Criteria: December 12, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Relapse; DLI; Hematological malignancies; Regulatory T cells depletion
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Disease Attributes; Hematologic Diseases; Neoplasms; Hematologic Neoplasms; Recurrence
• Other Study ID Numbers: P140303; 2016-A00645-46 (Other Identifier: IDRCB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No