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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)

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ClinicalTrials.gov Identifier: NCT04707300
Recruitment Status : Recruiting
First Posted : January 13, 2021
Last Update Posted : October 29, 2021
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia (AML) or Minimal Residual Disease (MRD Plus) Drug: Human T Lymphoid Progenitor (HTLP) injection Phase 1 Phase 2

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. 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : October 2021
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : May 2025


Arm Intervention/treatment
Experimental: Human T Lymphoid Progenitor (HTLP) injection
HTLP cellular product obtained after 7 days of culture of immune-selected CB
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 :
  1. Cumulative incidence of grade III-IV graft-versus-host disease (GvHD) [ Time Frame: 100 Days following HSCT ]
    according to Glucksberg grading system, to define toxicity

  2. CD4 + T cells analysis [ Time Frame: 100 days following HSCT ]
    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 :
  1. Time course of T cell immune reconstitution [ Time Frame: Month 1, 2, 3, 4, 5, 6 and 12 post-transplantation ]
    time needed to exceed a count of 100 naive CD4+ and >100 total CD8+ cells per μL

  2. Time to hematologic engraftment [ Time Frame: Up to 24 months post-transplantation ]
    Time to ANC > 0.5G/L with platelets > 20G/L

  3. Numbers of neutrophils, platelets and red blood cell transfusions [ Time Frame: Month 1,2, 3, 6 and 12 post -transplantation ]
  4. time course of reconstitution of the different T-cell subpopulations [ Time Frame: Month 1,2, 3, 6 and 12 post -transplantation ]
    by immunophenotyping (flow cytometry analysis)

  5. Presence of Recent thymic emigrants (RTEs) [ Time Frame: Month 1,2, 3, 6 and 12 post -transplantation ]
    by immunophenotyping (flow cytometry analysis)

  6. Tregs numbers [ Time Frame: Month 1,2, 3, 6 and 12 post -transplantation ]
    by immunophenotyping (flow cytometry analysis)

  7. B-cell reconstitution [ Time Frame: Month 6 and 12 post -transplantation ]
    number and phenotype for naïve IgD+CD27-, marginal zone IgD+CD27+, switched memory IgD-CD27+, and IgD-CD27- cells

  8. Immunoglobulin levels [ Time Frame: Month 6 and 12 post -transplantation ]
    focus on time needed for cessation of intravenously IgG replacement therapy

  9. Reconstitution of the NK cell [ Time Frame: Month 6 and 12 post -transplantation ]
    compartment (CD3-CD56dimCD16bright)

  10. 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 [ Time Frame: 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.

  11. the graft failure/rejection rate [ Time Frame: 3 months following HSCT ]
    detected by hematological monitoring of each UCB unit

  12. Cumulative incidence of infections [ Time Frame: 3, 6 and 12 months post- transplantation ]
  13. Cumulative incidence of acute and chronic episodes of GVHD and their grade [ Time Frame: 3, 6, 12 and 24 months post-transplantation ]
    according to Glucksgberg GvHD staging

  14. relapse rate [ Time Frame: 2 years post -transplantation ]
  15. overall survival [ Time Frame: 2 years post -transplantation ]
  16. Disease-free survival [ Time Frame: 2 years post -transplantation ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 66 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • High risk AML in CR1 (with t(6;9), t(v; 11q23), t(9;22), Inv(3), t(3;3), abnormalities of 3q, monosomy 5, 7, 17, complex caryotype, monosomal caryotype, FLT3-ITD (Ratio ≥O.5) without NPM1 mutations) OR
  • AML with any adverse genetic abnormality, secondary or therapy related AML excluding good risk genetic abnormalities, or any poor risk feature in CR1 OR
  • High-risk myelodysplastic syndrome (MDS) according to Revised International Prognostic Scoring System (IPSS-R).

OR

  • MRD+ patients after first line chemotherapy OR
  • Relapsed AML in CR2 OR
  • >=CR2
  • 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 6/8, 7/8 or 8/8 for HLA- A, -B, -C and DRB1 loci
  • Presence of at least one UCB unit with the following criteria*: ≥ 3 x 107 TNC/kg or ≥ 1.5 105 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 prior therapy with allogeneic stem cell transplantation
  • 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:

  • Previous allogeneic stem cell transplantation
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04707300


Contacts
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Contact: Olivier HERMINE, PhD & MD +33 144495282 olivier.hermine@aphp.fr
Contact: Valérie JOLAINE, Master +33 1 42 19 28 79 valerie.jolaine@aphp.fr

Locations
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France
Service d'Hématologie et thérapie cellulaire / CHU of Bordeaux Not yet recruiting
Pessac, France, 33604
Contact: Edouard FORCADE, PhD & MD       edouard.forcade@chu-bordeaux.fr   
Hematology department / Necker Children's Hospital Recruiting
Paris, Île-de-France, France, 75015
Contact: Olivier HERMINE, PhD & MD    +33 144495282    olivier.hermine@aphp.fr   
Contact: Felipe SUAREZ, PhD & MD       felipe.suarez@aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Principal Investigator: Olivier HERMINE, PhD & MD Assistance Publique - Hôpitaux de Paris
Study Director: Elisa MAGRIN, MD Département de Biothérapie : Hôpital Necker Enfants malades
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT04707300    
Other Study ID Numbers: APHP191116
2019-004883-23 ( EudraCT Number )
First Posted: January 13, 2021    Key Record Dates
Last Update Posted: October 29, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
acute myeloid leukemia
minimal residual disease
hematologic malignancies
human T Lymphoid Progenitor
umbilical cord blood transplantation
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms
Hematologic Neoplasms
Neoplasm, Residual
Leukemia
Neoplasms by Histologic Type
Neoplasms by Site
Hematologic Diseases
Neoplastic Processes
Pathologic Processes