Clinical trial NCT04707300: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Hematologic Malignancy
Keywords: acute myeloid leukemia
minimal residual disease
hematologic malignancies
human T Lymphoid Progenitor
umbilical cord blood transplantation
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2021-01-13
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 66
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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

Primary outcomes:
measure: Cumulative incidence of grade III-IV graft-versus-host disease (GvHD)
timeFrame: Within 100 Days following HSCT
measure: CD4 + T cells analysis
timeFrame: Within 100 days following HSCT
Secondary outcomes:
measure: Time to hematologic engraftment
timeFrame: Up to 24 months post-transplantation
measure: Last transfusion of platelets and red blood cell
timeFrame: During the follow-up
measure: Absolute numbers of neutrophils
timeFrame: Month 1, 2, 3, 6 and 12 post -transplantation
measure: Time course of T cell immune reconstitution
timeFrame: Month 1, 2, 3, 6 and 12 post -transplantation
measure: Immune phenotype (flow-cytometry analysis) of the different TCRαβ+ cell subpopulations
timeFrame: Month 1, 2, 3, 6 and 12 post -transplantation
measure: B-cell reconstitution
timeFrame: Month 1, 2, 3, 6 and 12 post -transplantation
measure: Reconstitution of the NK cell
timeFrame: Month 1, 2, 3, 6 and 12 post -transplantation
measure: Assessment of engraftment of each UCB unit over time by hematological monitoring and chimerism analysis
timeFrame: at 1, 2, 3, 6 and 12 months following HSCT.
measure: Graft failure/rejection rate
timeFrame: at 3 months following HSCT
measure: Cumulative incidence of infections
timeFrame: at 3, 6 and 12 months post- transplantation
measure: Cumulative incidence of acute and chronic episodes of GVHD and their grade according to Glucksberg GvHD staging.
timeFrame: at 3, 6, 12 and 24 months post-transplantation
measure: Relapse rate
timeFrame: 2 years
measure: Overall survival
timeFrame: 2 years
measure: Disease-free survival
timeFrame: 2 years
measure: Progression-free survival
timeFrame: 2 years
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Saint Louis
city: Pessac
country: France
facility: Service d'Hématologie et thérapie cellulaire / CHU of Bordeaux
city: Toulouse
country: France
facility: IUCT Oncopole Toulouse
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Paris
country: France
facility: Hematology department / Necker Children's Hospital
state: Île-de-France
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Olivier HERMINE, PhD & MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Département de Biothérapie : Hôpital Necker Enfants malades
name: Elisa MAGRIN, MD
role: STUDY_DIRECTOR
References: