Study Evaluating the Safety and the Efficacy of Human T Lymphoid Progenitor (HTLP) Injection to Accelerate Immune Reconstitution After Umbilical Cord Blood (UCB) Transplantation in Adult Patients With Hematologic Malignancies (HTLP-ONCO)

Official title

A Phase I/II Study Evaluating the Safety and the Efficacy of Human T Lymphoid Progenitor (HTLP) Injection to Accelerate Immune Reconstitution After Umbilical Cord Blood (UCB) Transplantation in Adult Patients With Hematologic Malignancies

Overview

This is an open-labelled and non-controlled Phase I/II clinical trial, evaluating the safety and the efficacy of Human T Lymphoid Progenitor (HTLP) injection to accelerate immune reconstitution after umbilical cord blood (UCB) transplantation in adult patients with hematologic malignancies. The dose limiting toxicity of HTLP injection will be evaluated using a model-based design.

Detailed description

Allogeneic bone marrow transplantation (AlloSCT) is the treatment of choice for high- risk acute myeloid leukemias in complete first remission after induction therapy and other high-risk hematological malignancies. Umbilical cord blood grafts are frequently used for patients lacking an HLA- matched family donor (Matched-sibling donor, MSD) as well as in the absence of an appropriate unrelated donor (10/10 MUD). As any HSCT, UCB transplantations are associated with the risk of acute and chronic GVHD, post- transplant immunodeficiency with increased risk of infections as well as relapse. Especially the risk of infection and therefore non- relapse mortality (NRM) or transplant- related mortality (TRM) is significantly higher in UCB transplantations as compared to MSD or 10/10 MUD transplantations. All of these risks have been linked to a significant delay in immune reconstitution including various immune cell populations like CD4 and CD8 T cells, Treg, NK, iNKT, pDC and others.

The investigators therefore make the hypothesis that if T-cell-mediated immunity was rapidly generated after a partially HLA-compatible UCB transplantation will reduce the risk of infection and to prevent relapse without increasing the risk of GVHD.

Interventions

• Drug Human T Lymphoid Progenitor (HTLP) injection
  The HTLP cell suspension will be injected intravenously at the time of UCB HSCT on D0

Primary outcome measures

• Cumulative incidence of grade III-IV graft-versus-host disease (GvHD) [Time frame: Within 100 Days following HSCT]
• CD4 + T cells analysis [Time frame: Within 100 days following HSCT]

Secondary outcome measures (12)

• Time to hematologic engraftment [Time frame: Up to 24 months post-transplantation]
• Last transfusion of platelets and red blood cell [Time frame: During the follow-up]
• Absolute numbers of neutrophils [Time frame: Month 1, 2, 3, 6 and 12 post -transplantation]
• Time course of T cell immune reconstitution [Time frame: Month 1, 2, 3, 6 and 12 post -transplantation]
• Immune phenotype (flow-cytometry analysis) of the different TCRαβ+ cell subpopulations [Time frame: Month 1, 2, 3, 6 and 12 post -transplantation]
• B-cell reconstitution [Time frame: Month 1, 2, 3, 6 and 12 post -transplantation]
• Reconstitution of the NK cell [Time frame: Month 1, 2, 3, 6 and 12 post -transplantation]
• Assessment of engraftment of each UCB unit over time by hematological monitoring and chimerism analysis [Time frame: at 1, 2, 3, 6 and 12 months following HSCT.]
• Graft failure/rejection rate [Time frame: at 3 months following HSCT]
• Cumulative incidence of infections [Time frame: at 3, 6 and 12 months post- transplantation]
• Cumulative incidence of acute and chronic episodes of GVHD and their grade according to Glucksberg GvHD staging. [Time frame: at 3, 6, 12 and 24 months post-transplantation]
• Relapse rate [Time frame: 2 years]

Eligibility criteria

Inclusion criteria

• Adult patients (≥ 18 years old and <66 years old) at the time of inclusion and eligible for an allogeneic stem cells transplantation and fit to receive the specified conditioning regimen
• Patients with hematologic malignancies
• Absence of a matched - related sibling donor (MSD) or a matched unrelated donor (MUD) 10/10
• Presence of two UCB units with the following criteria\*: HLA- matched 4/8, 5/8, 6/8, 7/8 or 8/8 for HLA- A, -B, -C and DRB1 loci

AND

• Presence of at least one UCB unit with the following criteria\*: ≥ 3 x 10e7 TNC/kg or ≥ 1.5 10e5 CD34+/kg pre- freezing

\* For the UCB taken into HTLP culture, the CD34+ content does not need to meet the above cellularity criteria, as expansion during HTLP culture has been proven to ensure the appropriate number of CD7+ needed for each dose.

The non- cultured UCB will be chosen to have a higher CD34+ cell content in order to enable long- term hematopoietic engraftment

• Absence of Donor Specific Antibodies (DSA) with a MFI > 5000
• Patient affiliated to social security
• Written, informed consent of the patient

Exclusion criteria

• Any of the standard contraindications to allogeneic transplant
• Left ventricular ejection fraction <50%
• Abnormal biochemistry results (ALT/AST>10xULN, total bilirubin>2.5xULN, creatinin clearance <60ml/min)
• Inability to understand and provide informed consent
• Concomitant infectious disease: HTLV-I, HIV-I or HIV-II
• Pregnancy or breastfeeding for women of childbearing potential
• Patients with progressive hematologic malignancies
• Previous participation within one month before inclusion in another protocol in which drugs may influence immune reconstitution of bone marrow transplantation

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

France · 5 centers

• Hôpital Saint Louis — Paris
• Service d'Hématologie et thérapie cellulaire / CHU of Bordeaux — Pessac
• IUCT Oncopole Toulouse — Toulouse
• Institut Gustave Roussy — Villejuif
• Hematology department / Necker Children's Hospital — Paris

Identifiers

NCT: NCT04707300 · APHP191116 · 2019-004883-23

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗