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Allogeneic Hematopoietic Cell Transplantation From HLA-matched Donor After Flu-Mel-PTCy Versus Flu-Mel-ATG Reduced-intensity Conditioning (HLA)

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ClinicalTrials.gov Identifier: NCT03852407
Recruitment Status : Recruiting
First Posted : February 25, 2019
Last Update Posted : October 12, 2022
Sponsor:
Collaborator:
Belgian Hematological Society
Information provided by (Responsible Party):
Frédéric Baron, University of Liege

Brief Summary:
The present project aims at comparing two conditioning regimens (FM-PTCy vs FM-ATG). The hypothesis is that one or the two regimens will lead to a 2-year cGRFS rate improvement from 30% (the cGRFS rate with FM without ATG/PTCy) to 45% (Pick-a-winner phase 2 randomized study).

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia in Remission Myelodysplastic Syndromes Chronic Myeloid Leukemia in Remission Myeloproliferative Syndrome Myeloproliferative Disorder Acute Lymphoid Leukemia in Remission Multiple Myeloma Chronic Lymphoid Leukemia Non Hodgkin Lymphoma Hodgkin Lymphoma Drug: Thymoglobulin Drug: Melphalan Drug: Fludarabine Drug: Cyclophosphamid Phase 2

Detailed Description:
This study is a multicenter, randomized, open-label, phase II study pick-a-winner study, comparing 2 conditioning regimens. A total of 114 eligible patients with HLA-matched donors will be randomized 1:1 between the FM-PTCy arm and the FM-ATG arm, with stratification for donor type (related or unrelated). The recruitment period is 3 years with a 5-year follow-up plus a 10-year additional long-term follow-up (for GVHD status, disease status, second malignancy and QOL). The whole study will be completed within 18 years.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 114 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Allogeneic Hematopoietic Cell Transplantation From HLA-matched Donor After Flu-Mel-PTCy Versus Flu-Mel-ATG Reduced-intensity Conditioning: a Phase II Randomized Study From the Belgian Hematology Society (BHS)
Actual Study Start Date : February 4, 2019
Estimated Primary Completion Date : November 1, 2033
Estimated Study Completion Date : November 1, 2038


Arm Intervention/treatment
Experimental: Fludarabine-Melphalan-Cyclophosphamide
FM-PTCy conditioning will consist in IV fludarabine 30 mg/m2 on days -6, -5, -4, -3, and -2 (total dose 150 mg/m2), melphalan given at the dose of 100 mg/m2 on day -2, and cyclophosphamide 50 mg/kg on days +3 and +4.
Drug: Melphalan
100mg/m² on day -2
Other Name: alkeran

Drug: Fludarabine
30mg/m² on days -6, -5, -4, -3, and -2

Drug: Cyclophosphamid
50 mg/kg on days +3 and +4.
Other Name: PTCy

Experimental: Fludarabine-Melphalan-thymoglobulin
FM-ATG conditioning will consist in IV fludarabine 30 mg/m2 on days -6, -5, -4, -3, and -2 (total dose 150 mg/m2), melphalan given at the dose of 100 mg/m2 on day -2, and ATG (Thymoglobulin®, Genzyme), at a dose of 2.5 mg/kg/d on days -2 and -1.
Drug: Thymoglobulin
ATG: 2.5 mg /kg/day on day -2 and -1 (day 0 is allogenic transplantation)
Other Name: ATG

Drug: Melphalan
100mg/m² on day -2
Other Name: alkeran

Drug: Fludarabine
30mg/m² on days -6, -5, -4, -3, and -2




Primary Outcome Measures :
  1. Current GVHD-free, relapse-free survival (cGRFS) [ Time Frame: 15 years (the primary endpoint will be first assessed after 191 events have been reached) ]
    To assess the current GVHD-free, relapse-free survival (cGRFS) for patients in the 2 arms


Secondary Outcome Measures :
  1. cGRFS according donor [ Time Frame: 15 years ]
    To assess cGRFS for patients conditioned with FM-PTCy or FM-ATG separately in those transplanted with a related or an unrelated donor

  2. Relapse/progression rate [ Time Frame: 15 years ]
    To assess the relapse/progression rate for patients conditioned with FM-PTCy or FM-ATG

  3. Rate aGVHD [ Time Frame: 6 months ]
    To assess rate of grade II-IV and III-IV acute GVHD (Graft-versus-host disease) in patients conditioned with FM or FM-ATG.

  4. Rate cGVHD [ Time Frame: 24 months ]
    To assess rate of grade of moderate-severe chronic GVHD in patients conditioned with FM or FM-ATG.

  5. Rate of Nonrelapse Mortality (NRM) [ Time Frame: 15 years ]
    To assess rate of Nonrelapse Mortality in patients conditioned with FM-PTCy or FM-ATG.

  6. Rate of Leukemia Free Survival (LFS) [ Time Frame: 15 years ]
    To assess rate of Leukemia Free Survival in patients conditioned with FM-PTCy or FM-ATG.

  7. Rate of Overall Survival (OS) [ Time Frame: 15 years ]
    To assess rate of Overall Survival in patients conditioned with FM-PTCy or FM-ATG.

  8. Proportion of patients alive [ Time Frame: 15 years ]
    To assess the proportion of patients alive without active disease and without systemic immunosuppression


Other Outcome Measures:
  1. Hematopoietic engraftment [ Time Frame: 2 years ]
    To assess hematopoietic (whole blood and T cell chimerism) engraftment in the 2 arms.

  2. Quality of immunologic reconstitution [ Time Frame: 5 years ]
    To assess the quality of immunologic reconstitution in the 2 arms

  3. Timing of immunologic reconstitution [ Time Frame: 5 years ]
    To assess the timing (days) of immunologic reconstitution in the 2 arms

  4. Incidences of bacterial infections [ Time Frame: 1 year ]
    To assess the incidences of bacterial infections (number of episode, site, grade) in the 2 arms, in the whole group of patients

  5. Incidences of fungal infections [ Time Frame: 1 year ]
    To assess the incidences of fungal infections (number of episode, site, grade) in the 2 arms, in the whole group of patients

  6. Incidences of viral infections [ Time Frame: 1 year ]
    To assess the incidences of viral infections (number of episode, site, grade) in the 2 arms, in the whole group of patients

  7. Assess Thymoglobulin (ATG) Pharmacokinetic [ Time Frame: 10 days ]
    To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm

  8. Assess ATG Pharmacokinetic in association with cGRFS [ Time Frame: 15 years ]
    To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with cGRFS

  9. Assess ATG Pharmacokinetic in association with NRM [ Time Frame: 15 years ]
    To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with NRM

  10. Assess ATG Pharmacokinetic in association with OS [ Time Frame: 15 years ]
    To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with OS

  11. Assess ATG Pharmacokinetic in association with Relapse/progression [ Time Frame: 15 years ]
    To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with Relapse/progression

  12. Assess ATG Pharmacokinetic in association with Infections [ Time Frame: 1 years ]
    To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with Infections

  13. Assess ATG Pharmacokinetic in association with immunologic reconstitution [ Time Frame: 5 years ]
    To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with immunologic reconstitution (CD4 and NAIVE T cells counts)



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 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Patients V.1.1. Diseases

Hematological malignancies confirmed histologically:

  • AML in morphological CR or not in morphological CR but not rapidly progressing (i.e. no need to give treatments such as hydroxyurea to maintain WBC count < 10 000 x109/mL);
  • MDS;
  • CML in CP or AP;
  • MPD not in blast crisis,
  • MDS/MPD overlap,
  • ALL in CR;
  • Multiple myeloma;
  • CLL;
  • Non-Hodgkin's lymphoma (aggressive NHL should have chemosensitive disease);
  • Hodgkin's disease with chemosensitive disease or responding to checkpoint inhibitors.

    * Clinical situations

    • Theoretical indication for a standard allo-transplant, but not feasible because:

  • Age > 50 yrs;
  • Unacceptable end organ performance;
  • The physician's decision;
  • The patient's decision

    • Underlying 'lower risk' disease, for which Reduced Intensity Conditioning is preferred (eg CLL, MCL)

      * Other inclusion criteria

    • Male or female; fertile patients must use a reliable contraception method;
    • Age 18-75 yrs (children of any age are not allowed in the protocol);
    • Informed consent given by patient or his/her guardian if indicated.

Donors

  • Male or female;
  • Any age;
  • Human Leukocyte Antigen (HLA)-identical sibling donor or 10 of 10 (HLA-A, -B, -C, -DRB1, and -DQB1) HLA allele matched unrelated donor;
  • Weight > 15 Kg (because of leukapheresis);
  • Fulfills criteria for allogeneic Peripheral Blood Stem Cell (PBSC) donation according to standard procedures;
  • Informed consent given by donor or his/her guardian if indicated, as per donor center standard procedures.

Exclusion Criteria:

Patients

  • Any condition not fulfilling inclusion criteria;
  • Human Immunodeficiency Virus positive;
  • Non-hematological malignancy(ies) (except non-melanoma skin cancer) active < 3 years before Hematopoietic Cell Transplantation (HCT).
  • Life expectancy severely limited by disease other than malignancy;
  • Central Nervous System involvement with disease refractory to intrathecal chemotherapy.
  • Terminal organ failure, except for renal failure (dialysis acceptable)

    1. Cardiac: Symptomatic coronary artery disease; ejection fraction <40%; uncontrolled arrhythmia, uncontrolled hypertension;
    2. Pulmonary: Diffusing Capacity of the Lung for Carbon Monoxide (DLCO)< 40% and/or receiving supplementary continuous oxygen, Forced Expiratory Volume in 1 Second (FEV1)< 40%;
    3. Hepatic: Fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin >3 mg/dL, and symptomatic biliary disease;
  • Uncontrolled infection;
  • Karnofsky Performance Score <70%;
  • Patient is a fertile man or woman who is unwilling to use contraceptive techniques during and for 12 months following treatment;
  • Patient is a female who is pregnant or breastfeeding;
  • Any condition precluding the use of melphalan or Thymoglobulin;

Donors

  • Any condition not fulfilling inclusion criteria;
  • Unable to undergo leukapheresis because of poor vein access or other reasons.

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): NCT03852407


Contacts
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Contact: Frédéric Baron, MD,Ph +32 4 366 72 01 ext 0032497121806 F.Baron@uliege.be

Locations
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Belgium
ZNA Stuivenberg Recruiting
Antwerp, Belgium, 2060
Contact: Dimitri Breems, MD PhD       dimitri.Breems@zna.be   
AZ Sint Jan Brugge Recruiting
Brugge, Belgium, 8000
Contact: Dominik Selleslag, MD, PhD       dominik.selleslag@AZsintjan.be   
IJ Bordet Recruiting
Brussels, Belgium, 1000
Contact: Philippe Lewalle, MD PhD       philippe.lewalle@bordet.be   
UZ Brussel Recruiting
Brussels, Belgium, 1090
Contact: Ann De Becker, MD PhD       ann.debecker@uzbrussel.be   
Sub-Investigator: Rik Schots, MD PhD         
UCL St Luc Recruiting
Brussels, Belgium, 1200
Contact: Xavier Poiré, MD       xavier.poire@uclouvain.be   
UZ Gent Recruiting
Gent, Belgium, 9000
Contact: Tessa Kerre, MD PhD       t.Kerre@UGent.be   
UZ Leuven Recruiting
Leuven, Belgium, 3000
Contact: Johan Maertens, MD PhD       johan.maertens@uzleuven.be   
Sub-Investigator: Hélène Schoemans, MD PhD         
CHU de Liège Recruiting
Liège, Belgium, 4000
Contact: Frédéric Baron, MD, PhD    +3243667201 ext +3243667201    F.Baron@uliege.be   
Contact: Yves Beguin, MD, PhD    +3243667201 ext +3243667201    yves.beguin@chuliege.be   
Sub-Investigator: Evelyne Willems, MD         
Sub-Investigator: Sophie Servais, MD         
AZ Delta Roeselare Recruiting
Roeselare, Belgium, 8800
Contact: Dries Deeren, MD       dries.deeren@AZdelta.be   
CHU UCL Namur Godinne Recruiting
Yvoir, Belgium, 5530
Contact: Carlos Graux, MD PhD       carlos.graux@uclouvain.be   
Sponsors and Collaborators
University of Liege
Belgian Hematological Society
Investigators
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Principal Investigator: Frédéric Baron, MD,Ph Centre Hospitalier Universitaire de Liege
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Responsible Party: Frédéric Baron, Professor, University of Liege
ClinicalTrials.gov Identifier: NCT03852407    
Other Study ID Numbers: BHS-TC14
2017-000824-91 ( EudraCT Number )
First Posted: February 25, 2019    Key Record Dates
Last Update Posted: October 12, 2022
Last Verified: October 2022

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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 Frédéric Baron, University of Liege:
hematological malignancies
Graft versus host disease
GVHD
Progression free survival
Allogeneic hematopoeitic cell transplantation
HLA-matched donor
reduced intensity conditioning
Overall survival
ATG PK
Immunosuppressive regimen
Prophylaxis
Additional relevant MeSH terms:
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Lymphoma
Leukemia
Leukemia, Myeloid
Multiple Myeloma
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphocytic, Chronic, B-Cell
Myelodysplastic Syndromes
Myeloproliferative Disorders
Syndrome
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease
Pathologic Processes
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Bone Marrow Diseases
Leukemia, B-Cell
Cyclophosphamide