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)

Hematologic Malignancy Clinical Trial

— 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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04707300
• Other study ID #: APHP191116
• Secondary ID: 2019-004883-23
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: February 16, 2022
• Est. completion date: February 2026

Study information

• Verified date: September 2022
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Olivier HERMINE, PhD & MD
• Phone: +33 144495282
• Email: olivier.hermine[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 10
• Est. completion date: February 2026
• Est. primary completion date: May 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 66 Years

Eligibility

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

• SORROR score compatible with the pre specified conditioning and to discuss with the Principal Investigator

• 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

• No treatment with another investigational drug within one month before inclusion

• Patient affiliated to social security

• Written, informed consent of the patient

• Absence of Donor Specific Antibodies (DSA) with a MFI > 5000

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

Related Conditions & MeSH terms

• Hematologic Malignancy
• Hematologic Neoplasms
• Neoplasms

Intervention

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

Locations

Country	Name	City	State
France	Hematology department / Necker Children's Hospital	Paris	Île-de-France
France	Service d'Hématologie et thérapie cellulaire / CHU of Bordeaux	Pessac
France	IUCT Oncopole Toulouse	Toulouse
France	Institut Gustave Roussy	Villejuif

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cumulative incidence of grade III-IV graft-versus-host disease (GvHD)	according to Glucksberg grading system, to define toxicity	100 Days following HSCT
Primary	CD4 + T cells analysis	Efficacy defined by the presence of >50/µl CD4+ CD3+ TCRaß+ T cells at 2 consecutive measures < within 4 months post HSCT.	100 days following HSCT
Secondary	Time course of T cell immune reconstitution	time needed to exceed a count of 100 naive CD4+ and >100 total CD8+ cells per µL	Month 1, 2, 3, 4, 5, 6 and 12 post-transplantation
Secondary	Time to hematologic engraftment	Time to ANC > 0.5G/L with platelets > 20G/L	Up to 24 months post-transplantation
Secondary	Numbers of neutrophils, platelets and red blood cell transfusions		Month 1,2, 3, 6 and 12 post -transplantation
Secondary	time course of reconstitution of the different T-cell subpopulations	by immunophenotyping (flow cytometry analysis)	Month 1,2, 3, 6 and 12 post -transplantation
Secondary	Presence of Recent thymic emigrants (RTEs)	by immunophenotyping (flow cytometry analysis)	Month 1,2, 3, 6 and 12 post -transplantation
Secondary	Tregs numbers	by immunophenotyping (flow cytometry analysis)	Month 1,2, 3, 6 and 12 post -transplantation
Secondary	B-cell reconstitution	number and phenotype for naïve IgD+CD27-, marginal zone IgD+CD27+, switched memory IgD-CD27+, and IgD-CD27- cells	Month 6 and 12 post -transplantation
Secondary	Immunoglobulin levels	focus on time needed for cessation of intravenously IgG replacement therapy	Month 6 and 12 post -transplantation
Secondary	Reconstitution of the NK cell	compartment (CD3-CD56dimCD16bright)	Month 6 and 12 post -transplantation
Secondary	Assessment of engraftment of each UCB unit over time by hematological monitoring and chimerism analysis on neutrophils, T, B, NK, pDC and macrophages at 1, 2, 3, 6 and 12 months following HSCT	To assess engraftment of each UCB unit over time by hematological monitoring and chimerism analysis on neutrophils, T, B, NK, pDC and macrophages at 1, 2, 3, 6 and 12 months following HSCT.	at 1, 2, 3, 6 and 12 months following HSCT.
Secondary	the graft failure/rejection rate	detected by hematological monitoring of each UCB unit	3 months following HSCT
Secondary	Cumulative incidence of infections		3, 6 and 12 months post- transplantation
Secondary	Cumulative incidence of acute and chronic episodes of GVHD and their grade	according to Glucksgberg GvHD staging	3, 6, 12 and 24 months post-transplantation
Secondary	relapse rate		2 years post -transplantation
Secondary	overall survival		2 years post -transplantation
Secondary	Disease-free survival		2 years post -transplantation
Secondary	Progression-free survival		2 years post -transplantation