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Allogeneic Hematopoietic Cell Transplantation HLA-matched Donor After Flu-Mel vs Flu-Mel-ATG Conditioning (HLA)

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ClinicalTrials.gov Identifier: NCT03852407
Recruitment Status : Suspended (Severe different but expected complications)
First Posted : February 25, 2019
Last Update Posted : October 2, 2019
Sponsor:
Collaborator:
Belgian Hematological Society Transplant Committee
Information provided by (Responsible Party):
Frédéric Baron, University of Liege

Brief Summary:
The present project aims at comparing two conditioning regimens (Fludarabine-Melphalan (FM) vs Fludarabine-Melphalan-ATG (FM-ATG)). The hypothesis is that the FM-ATG regimen will be associated to better cGRFS.

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 Phase 3

Detailed Description:
This study is a multicenter, randomized, open-label, phase III study, comparing 2 conditioning regimens. A total of 284 eligible patients with HLA (Human Leukocyte Antigen)-matched donors will be randomized 1/1 between the FM arm and the FM-ATG arm, with stratification for donor type (related or unrelated). The recruitment period is 5 years with a 5-year follow-up plus a 10-year additional long-term follow-up (for Graft-versus-host disease (GVHD) status, disease status, second malignancy and QOL). The whole study will be completed within 20 years. The hypothesis is that the FM-ATG regimen will be associated to better cGRFS (current GVHD-free, relapse-free survival).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 284 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 Fludarabine-Melphalan Versus Fludarabine-Melphalan-ATG Reduced-intensity Conditioning: a Phase III 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
It consists in IV fludarabine 30 mg/m2 on days -5, -4, -3, -2 and -1 (total dose 150 mg/m2; 80% of the dose if creatinine clearance between 30% and 70% and 60% of the dose if clearance < 30%.) and melphalan given at the dose of 140 mg/m2 on day -2 (Adjusted body weight should be use in case of patient body weight > 120% ideal body weight).
Drug: Melphalan
140mg/m² on day -2
Other Name: alkeran

Drug: Fludarabine
30mg/m² on days -5,-4,-3,-2,-1.

Experimental: Fludarabine-Melphalan-thymoglobulin
It consists in IV fludarabine 30 mg/m2 on days -5, -4, -3, -2 and -1 (total dose 150 mg/m2; 80% of the dose if creatinine clearance between 30% and 70% and 60% of the dose if clearance < 30%.) and melphalan given at the dose of 140 mg/m2 on day -2 (Adjusted body weight should be use in case of patient body weight > 120% ideal body weight) 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
140mg/m² on day -2
Other Name: alkeran

Drug: Fludarabine
30mg/m² on days -5,-4,-3,-2,-1.




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 compare 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 compare cGRFS for patients conditioned with FM or FM-ATG separately in those transplanted with a related or an unrelated donor

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

  3. Rate aGVHD [ Time Frame: 6 months ]
    To compare 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 compare 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 compare rate of Nonrelapse Mortality in patients conditioned with FM or FM-ATG.

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

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

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


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

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

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

  4. Incidences of bacterial infections [ Time Frame: 1 year ]
    To compare 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 compare 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 compare 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

  • Diseases: Hematological malignancies confirmed histologically:

    • Acute Myeloid Leukemia (AML) in morphological Complete Remission (CR) or not in morphological CR but not rapidly progressing (i.e. no need to give medications such as hydroxyurea to maintain White Blood Cell (WBC) count < 10 000 x109/mL);
    • Myelodysplastic syndromes (MDS);
    • Chronic myeloid leukemia (CML) in Chronic or Accelerated Phase;
    • Myeloproliferative Syndrome (MPS) not in blast crisis,
    • MDS/MPS overlap,
    • Acute Lymphoid Leukemia (ALL) in CR;
    • Multiple myeloma;
    • Chronic Lymphoid Leukemia (CLL);
    • Non-Hodgkin's lymphoma (NHL aggressive should have chemosensitive disease);
    • Hodgkin's disease with chemosensitive disease.
  • 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


Locations
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Belgium
ZNA Stuivenberg
Antwerp, Belgium, 2060
AZ Sint Jan Brugge
Brugge, Belgium, 8000
IJ Bordet
Brussels, Belgium, 1000
UZ Brussel
Brussels, Belgium, 1090
UCL St Luc
Brussels, Belgium, 1200
UZ Gent
Gent, Belgium, 9000
UZ Leuven
Leuven, Belgium, 3000
CHU de Liège
Liège, Belgium, 4000
AZ Delta Roeselare
Roeselare, Belgium, 8800
CHU UCL Namur Godinne
Yvoir, Belgium, 5530
Sponsors and Collaborators
University of Liege
Belgian Hematological Society Transplant Committee
Investigators
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Principal Investigator: Frédéric Baron, MD,Ph CHU Liège

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Responsible Party: Frédéric Baron, Professor, University of Liege
ClinicalTrials.gov Identifier: NCT03852407     History of Changes
Other Study ID Numbers: BHS-TC14
2017-000824-91 ( EudraCT Number )
First Posted: February 25, 2019    Key Record Dates
Last Update Posted: October 2, 2019
Last Verified: September 2019

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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
Vidarabine