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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) (HTLP-ONCO)

Primary Purpose

Hematologic Malignancy

Status
Recruiting
Phase
Phase 1
Locations
France
Study Type
Interventional
Intervention
Human T Lymphoid Progenitor (HTLP) injection
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hematologic Malignancy focused on measuring acute myeloid leukemia, minimal residual disease, hematologic malignancies, human T Lymphoid Progenitor, umbilical cord blood transplantation

Eligibility Criteria

18 Years - 66 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Service d'Hématologie et thérapie cellulaire / CHU of BordeauxRecruiting
  • IUCT Oncopole ToulouseRecruiting
  • Institut Gustave Roussy
  • Hematology department / Necker Children's HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Human T Lymphoid Progenitor (HTLP) injection

Arm Description

HTLP cellular product obtained after 7 days of culture of immune-selected CB

Outcomes

Primary Outcome Measures

Cumulative incidence of grade III-IV graft-versus-host disease (GvHD)
according to Glucksberg grading system, to define toxicity
CD4 + T cells analysis
Efficacy defined by the presence of >50/μl CD4+ CD3+ TCRαβ+ T cells at 2 consecutive measures < within 4 months post HSCT.

Secondary Outcome Measures

Time course of T cell immune reconstitution
time needed to exceed a count of 100 naive CD4+ and >100 total CD8+ cells per μL
Time to hematologic engraftment
Time to ANC > 0.5G/L with platelets > 20G/L
Numbers of neutrophils, platelets and red blood cell transfusions
time course of reconstitution of the different T-cell subpopulations
by immunophenotyping (flow cytometry analysis)
Presence of Recent thymic emigrants (RTEs)
by immunophenotyping (flow cytometry analysis)
Tregs numbers
by immunophenotyping (flow cytometry analysis)
B-cell reconstitution
number and phenotype for naïve IgD+CD27-, marginal zone IgD+CD27+, switched memory IgD-CD27+, and IgD-CD27- cells
Immunoglobulin levels
focus on time needed for cessation of intravenously IgG replacement therapy
Reconstitution of the NK cell
compartment (CD3-CD56dimCD16bright)
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.
the graft failure/rejection rate
detected by hematological monitoring of each UCB unit
Cumulative incidence of infections
Cumulative incidence of acute and chronic episodes of GVHD and their grade
according to Glucksgberg GvHD staging
relapse rate
overall survival
Disease-free survival
Progression-free survival

Full Information

First Posted
November 30, 2020
Last Updated
October 31, 2022
Sponsor
Assistance Publique - Hôpitaux de Paris
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1. Study Identification

Unique Protocol Identification Number
NCT04707300
Brief Title
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)
Acronym
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

2. Study Status

Record Verification Date
September 2022
Overall Recruitment Status
Recruiting
Study Start Date
February 16, 2022 (Actual)
Primary Completion Date
May 2024 (Anticipated)
Study Completion Date
February 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hematologic Malignancy
Keywords
acute myeloid leukemia, minimal residual disease, hematologic malignancies, human T Lymphoid Progenitor, umbilical cord blood transplantation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Human T Lymphoid Progenitor (HTLP) injection
Arm Type
Experimental
Arm Description
HTLP cellular product obtained after 7 days of culture of immune-selected CB
Intervention Type
Drug
Intervention Name(s)
Human T Lymphoid Progenitor (HTLP) injection
Intervention Description
The HTLP cell suspension will be injected intravenously at the time of UCB HSCT on D0
Primary Outcome Measure Information:
Title
Cumulative incidence of grade III-IV graft-versus-host disease (GvHD)
Description
according to Glucksberg grading system, to define toxicity
Time Frame
100 Days following HSCT
Title
CD4 + T cells analysis
Description
Efficacy defined by the presence of >50/μl CD4+ CD3+ TCRαβ+ T cells at 2 consecutive measures < within 4 months post HSCT.
Time Frame
100 days following HSCT
Secondary Outcome Measure Information:
Title
Time course of T cell immune reconstitution
Description
time needed to exceed a count of 100 naive CD4+ and >100 total CD8+ cells per μL
Time Frame
Month 1, 2, 3, 4, 5, 6 and 12 post-transplantation
Title
Time to hematologic engraftment
Description
Time to ANC > 0.5G/L with platelets > 20G/L
Time Frame
Up to 24 months post-transplantation
Title
Numbers of neutrophils, platelets and red blood cell transfusions
Time Frame
Month 1,2, 3, 6 and 12 post -transplantation
Title
time course of reconstitution of the different T-cell subpopulations
Description
by immunophenotyping (flow cytometry analysis)
Time Frame
Month 1,2, 3, 6 and 12 post -transplantation
Title
Presence of Recent thymic emigrants (RTEs)
Description
by immunophenotyping (flow cytometry analysis)
Time Frame
Month 1,2, 3, 6 and 12 post -transplantation
Title
Tregs numbers
Description
by immunophenotyping (flow cytometry analysis)
Time Frame
Month 1,2, 3, 6 and 12 post -transplantation
Title
B-cell reconstitution
Description
number and phenotype for naïve IgD+CD27-, marginal zone IgD+CD27+, switched memory IgD-CD27+, and IgD-CD27- cells
Time Frame
Month 6 and 12 post -transplantation
Title
Immunoglobulin levels
Description
focus on time needed for cessation of intravenously IgG replacement therapy
Time Frame
Month 6 and 12 post -transplantation
Title
Reconstitution of the NK cell
Description
compartment (CD3-CD56dimCD16bright)
Time Frame
Month 6 and 12 post -transplantation
Title
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
Description
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.
Time Frame
at 1, 2, 3, 6 and 12 months following HSCT.
Title
the graft failure/rejection rate
Description
detected by hematological monitoring of each UCB unit
Time Frame
3 months following HSCT
Title
Cumulative incidence of infections
Time Frame
3, 6 and 12 months post- transplantation
Title
Cumulative incidence of acute and chronic episodes of GVHD and their grade
Description
according to Glucksgberg GvHD staging
Time Frame
3, 6, 12 and 24 months post-transplantation
Title
relapse rate
Time Frame
2 years post -transplantation
Title
overall survival
Time Frame
2 years post -transplantation
Title
Disease-free survival
Time Frame
2 years post -transplantation
Title
Progression-free survival
Time Frame
2 years post -transplantation

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
66 Years
Accepts Healthy Volunteers
No
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 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Olivier HERMINE, PhD & MD
Phone
+33 144495282
Email
olivier.hermine@aphp.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Jinmi BAEK, Master
Phone
+33 1 42 19 28 49
Email
jinmi.baek@aphp.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Olivier HERMINE, PhD & MD
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Elisa MAGRIN, MD
Organizational Affiliation
Département de Biothérapie : Hôpital Necker Enfants malades
Official's Role
Study Director
Facility Information:
Facility Name
Service d'Hématologie et thérapie cellulaire / CHU of Bordeaux
City
Pessac
ZIP/Postal Code
33604
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Edouard FORCADE, PhD & MD
Email
edouard.forcade@chu-bordeaux.fr
Facility Name
IUCT Oncopole Toulouse
City
Toulouse
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Anne HUYNH, PhD, MD
Phone
05 31 15 71 91
Email
huynh.anne@iuct-oncopole.fr
Facility Name
Institut Gustave Roussy
City
Villejuif
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jean-Henri BOURHIS, PhD MD
Phone
01 42 11 53 82
Email
jean-henri.bourhuis@gustaveroussy.fr
Facility Name
Hematology department / Necker Children's Hospital
City
Paris
State/Province
Île-de-France
ZIP/Postal Code
75015
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Olivier HERMINE, PhD & MD
Phone
+33 144495282
Email
olivier.hermine@aphp.fr
First Name & Middle Initial & Last Name & Degree
Felipe SUAREZ, PhD & MD
Email
felipe.suarez@aphp.fr

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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)

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