Official Title: “Suicide Gene Therapy for Donor Lymphocytes Infusion After Allogeneic Hematopoietic Stem Cell Transplantation: a Phase I/II Clinical Study”

The main complications of allogeneic hematopoietic stem cell transplantation (HSCT) include graft-versus-host disease (GVHD) and poor immune reconstitution leading to severe infections and leukemia relapse. Mature donor T-cells present in the transplant facilitate T-cell reconstitution but also induce GVHD, which itself impairs immune reconstitution. We have developed a strategy of alloreactive T-cell depletion, using T-cells expressing the Herpes simplex thymidine kinase (TK) suicide gene combined with a ganciclovir (GCV) treatment. This system permits the selective elimination of dividing TK+ T-cells in vivo. To test this hypothesis in preclinical settings, we have previously developed several experimental models of GVHD using TK+ T-cells in mice. The demonstration that a preventive treatment with GCV administered close to the time of HSCT could control GVHD brought the proof of concept. We now propose a clinical trial to test whether donor lymphocytes infusion (DLI) using TK-transduced cells permits to induce a graft-versus-tumor (GVT) effect for treatment of relapse after HSCT, while GVHD can be controlled by GCV treatment.

Study Type: Interventional

Study Design: Allocation: Non-Randomized, Control: Uncontrolled, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Study Primary Completion Date: March 2012

DLI-TK is administered either after failure of 1 or several previous standard (std-) DLI of, defined after a minimal follow-up of 2 months after the last injection. To prepare DLI-TK, donor T-cells are transduced with a retroviral vector encoding TK. Transduced cells are selected using a CliniMACS device (MYLTENYI). In case of previous std-DLI received, the DLI-TK cell dose is adjusted to be below or equal to the maximal cell dose previously received in std-DLI. No comparison is planned in the analysis.

Intervention(s) in this Clinical Trial

• Biological: donor lymphocyte infusion
  • Donor T-cell transduction

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: donor lymphocyte infusion
  • Donor T-cell transduction

Primary Measures

• Incidence of "severe" GHVD (acute grade >II or chronic extensive) following DLI-TK and treatment with GCV
  • Time Frame: during the 12 months of follow-up
    Safety Issue?: Yes

Secondary Measures

• The incidence of GVHD of any grade after DLI-TK
  • Time Frame: during the 12 months of follow-up
    Safety Issue?: No
• The anti-tumoral efficiency of DLI-TK to treat the relapse of the hematological malignancy
  • Time Frame: during the 12 months of follow-up
    Safety Issue?: No
• The survival and the survival without disease after DLI-TK
  • Time Frame: during the 12 months of follow-up
    Safety Issue?: Yes

Inclusion Criteria:

• Hematological malignancy.
• Previous allogeneic hematopoietic stem cell transplantation.
• Relapse diagnosed at the molecular, cytogenetic, or cytological level.
• Failure of a previous stdILD or inclusion in first intention without previous stdDLI.
• Age > 18 years and < 70 years at the time of inclusion. For patients between 15 and 18 years of age, a case-per case inclusion will be studied.
• Performance status considered on the score ECOG < 2.
• Life expectation 1-month-old superior.
• Signed written informed consent.
• Negative HCG in the 7 days preceding the inclusion for women in age of procreation.
• Membership of the French national insurance.

Exclusion Criteria:

• Grade >II acute GVHD or chronic extensive GVHD at the time of inclusion.
• Patient receiving an immunosuppressive treatment for GVHD treatment at the time of inclusion.
• Dysfunction of liver (ALAT/ASAT > 5 N, or bilirubin > 50 µM), or of the renal function (creatinine clearance < 30 ml / min).

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 70 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Assistance Publique - Hôpitaux de Paris

Overall Clinical Trial Officials and Contacts

Sébastien Maury, MD, PhD Principal Investigator Assistance Publique - Hôpitaux de Paris  

Overall Contact: Sébastien Maury, MD, PhD (0) 1 49 81 20 57 sebastien.maury@hmn.aphp.fr

Information obtained from ClinicalTrials.gov on September 01, 2010

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01086735

Study ID Number: P010506

ClinicalTrials.gov Identifier: NCT01086735

Health Authority: France: Ministry of Health