Minitransplants With HLA-matched Donors : Comparison Between 2 GVHD Prophylaxis Regimens

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2013 by University Hospital of Liege
Sponsor:
Collaborators:
AZ Sint-Jan AV
Ziekenhuis Netwerk Antwerpen (ZNA)
Jules Bordet Institute
University Hospital, Gasthuisberg
AZ-VUB
Cliniques universitaires Saint-Luc- Université Catholique de Louvain
University Hospital, Antwerp
Cliniques Universitaires de Mont-Godinne
Jolimont Hospital Haine Saint Paul
Queen Fabiola Children's University Hospital
University Hospital, Ghent
H.-Hart Hospital Roeselare-Menen
Information provided by (Responsible Party):
Yves Beguin, University Hospital of Liege
ClinicalTrials.gov Identifier:
NCT01428973
First received: September 1, 2011
Last updated: January 17, 2013
Last verified: January 2013
  Purpose

The present project is a multicenter phase II trail aiming at comparing which of the two postgrafting immunosuppressive regimens proposed in this study will be best suited to prevent graft-versus-host disease (GVDH).

The immunosuppressive regimens will consist of: Tacrolimus plus Mycophenolate Mofetil or Tacrolimus plus Sirolimus. Before grafting patients will undergo two reduced-intensity conditioning: Fludarabine/total body irradiation (TBI) or Fludarabine+Busulfan+anti-thymocyte globulin. The hypothesis is that the Tacrolimus plus Sirolimus regimen will be associated with better progression-free survival due to a lower incidence of relapse/progression.


Condition Intervention Phase
Graft-Versus-Host Disease
Hematological Malignancies
Drug: Mycophenolate mofetil
Drug: Sirolimus
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Allogeneic Hematopoietic Cell Transplantation From HLA-matched Donors After Reduced-intensity Conditioning: a Phase II Randomized Study Comparing 2 GVHD Prophylaxis Regimens

Resource links provided by NLM:


Further study details as provided by University Hospital of Liege:

Primary Outcome Measures:
  • Progression-free survival [ Time Frame: 1 year after transplantation ] [ Designated as safety issue: No ]
    To compare the 1-year progression-free survival between the 2 prophylactic arms (Tracolimus/Mycophenolate Mofetil and Tracolimus/Sirolimus) in the whole group of patients and separately in those conditioned with Fluradabine/TBI or Fluradabine plus Busulfan and anti-thymocyte globulin.


Secondary Outcome Measures:
  • Relapse rate; nonrelapse mortality and overall survival [ Time Frame: 1, 2 and 5 years after transplantation ] [ Designated as safety issue: No ]
    To compare relapse rate, nonrelapse mortality, and overall survival in the 2 prophyltic arms (Tracolimus/Mycophenolate Mofetil and Tracolimus/Sirolimus) 1, 2 and 5 years after hematopietic stem cell transplantation (HSCT) in the whole group of patients and separately in those conditioned with Fluradabine/TBI or Fluradabine plus Busulfan and anti-thymocyte globulin.

  • Progression free survival [ Time Frame: 2 and 5 years after transplantation ] [ Designated as safety issue: No ]
    To compare progression-free survival in the 2 phrophylactic arms (Tracolimus/Mycophenolate Mofetil and Tracolimus/Sirolimus) 2 and 5 years after HSCT, in the whole group of patients and separately in those conditioned with Fluradabine/TBI or Fluradabine plus Busulfan and anti-thymocyte globulin.

  • Engraftment [ Time Frame: 1 year after transplantation ] [ Designated as safety issue: No ]
    To compare hematopoietic (whole blood and T cell chimerism) engraftment and to evaluate the 1-year incidence of graft rejection in the 2 prophylctic arms (Tracolimus/Mycophenolate Mofetil and Tracolimus/Sirolimus), in the whole group of patients and separately in those conditioned with Fluradabine/TBI or Fluradabine plus Busulfan and anti-thymocyte globulin.

  • Acute GVDH [ Time Frame: 6 months after transplantation ] [ Designated as safety issue: No ]
    To compare the 6-mo incidence of grades II-IV and III-IV acute GVHD in the 2 prophylactic arms (Tracolimus/Mycophenolate Mofetil and Tracolimus/Sirolimus), in the whole group of patients and separately in those conditioned with Fluradabine/TBI or Fluradabine plus Busulfan and anti-thymocyte globulin.

  • Chronic GVDH [ Time Frame: 1 year after transplantation ] [ Designated as safety issue: No ]
    To compare the 1-yr incidence of chronic GVHD in the phrophylactic 2 prophylactic arms (Tracolimus/Mycophenolate Mofetil and Tracolimus/Sirolimus), in the whole group of patients and separately in those conditioned with Fluradabine/TBI or Fluradabine plus Busulfan and anti-thymocyte globulin.

  • Immunological reconstitution [ Time Frame: 3 mo, 6 mo, 1 yr, 2 yrs and 5 yrs after transplantation ] [ Designated as safety issue: No ]
    To compare the quality and timing of immunologic reconstitution in the 2 prophylactic arms (Tracolimus/Mycophenolate Mofetil and Tracolimus/Sirolimus),in the whole group of patients and separately in those conditioned with Fluradabine/TBI or Fluradabine plus Busulfan and anti-thymocyte globulin.

  • Infection [ Time Frame: 1 year after transplantation ] [ Designated as safety issue: No ]
    To compare the 1-yr incidences of bacterial, fungal and viral infections in the 2 prophylactic arms (Tracolimus/Mycophenolate Mofetil and Tracolimus/Sirolimus), in the whole group of patients and separately in those conditioned with Fluradabine/TBI or Fluradabine plus Busulfan and anti-thymocyte globulin.


Estimated Enrollment: 200
Study Start Date: September 2011
Estimated Study Completion Date: September 2017
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm 1
GVHD prophylaxis: Mycophenolate mofetil (MMF) orally from the evening of day 0 through day 28 (sibling recipients) or day 42 (alternative donor recipients) at the dose of 15 mg/kg t.i.d. Tacrolimus (Tac)given orally at the dose of 0.06 mg/kg bid starting on day -3. The dose adapted according to through whole blood values following standard procedures (between 10 and 15 ng/ml the first 28 days and between 5-10 ng/ml thereafter). Full doses given until day 100 (sibling recipients) or 180 (alternative donor recipients). Doses tapered to be definitely discontinued by day 180 (sibling donors) or 365 (alternative donor recipients) in the absence of GVHD.
Drug: Mycophenolate mofetil
Tablets. For HLA-identical sibling donors:15 mg/kg t.i.d from day 0 to day 28. For alternative donor: 15 mg/kg, from day 0 to day 42.
Other Name: CellCept
Experimental: Arm 2
GVHD prophylaxis: Tacrolimus, orally (0.06 mg/kg) bid starting on day -3. The dose adapted between 5-10 ng/ml. Full doses until day 60 (sibling recipients) or day 100 (alternative donor recipients). Doses tapered to be definitely discontinued by day 100 (sibling donors) or 180 (alternative donor recipients) in the absence of GVHD. Sirolimus 6 mg loading dose on day −3, followed by (1)-2 mg daily to a target trough level of 5 to 10 ng/mL. Full doses until day 100 (sibling recipients) or 180 (alternative donor recipients). Doses will then be progressively tapered to be definitely discontinued by day 180 (sibling donors) or 365 (alternative donor recipients) in the absence of GVHD
Drug: Sirolimus
Tablets. 6 mg loading dose on day −3, followed by (1)-2 mg daily to a target trough level of 5 to 10 ng/mL. Full doses will be given until day 100 (sibling recipients) or 180 (alternative donor recipients). Doses will then be progressively tapered to be definitely discontinued by day 180 (sibling donors) or 365 (alternative donor recipients) in the absence of GVHD.
Other Name: Rapamune

  Eligibility

Ages Eligible for Study:   16 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Hematological malignancies confirmed histologically and not rapidly progressing:

    • Acute myeloid leukemia (AML) in complete remission (CR) (defined as ≤ 5% marrow blasts and absence of blasts in the peripheral blood);
    • Myelodysplastic syndromes (MDS) with ≤ 5% marrow blasts and absence of blasts in the peripheral blood;
    • Chronic myeloid leukemia (CML) in chronic phase (CP);
    • Myeloproliferative neoplasms not in blast crisis and not with extensive marrow fibrosis;
    • Acute lymphoid leukemia (ALL)in CR;
    • Multiple myeloma not rapidly progressing;
    • chronic lymphocytic leukemia (CLL);
    • Non-Hodgkin's lymphoma (aggressive NHL should have chemosensitive disease);
    • Hodgkin's disease with chemosensitive disease;
  2. 10/10 HLA-A, -B, -C, DRB1 and DQBI allele-matched donor fit to/willing to donate PBSC.
  3. Clinical situations:

    1. Theoretical indication for a standard allotransplant, but not feasible because:

      • Age > 50 yrs;
      • Unacceptable end organ performance;
      • At the physician's decision;
      • Patient's refusal.
    2. Indication for a standard auto-transplant: perform mini-allotransplantation 2-6 months after standard autotransplant.
  4. Other inclusion criteria:

    • Male or female; fertile patients must use a reliable contraception method;
    • Age ≤ 75 yrs (children of any age are allowed in the protocol);
    • Informed consent given by patient or his/her guardian if of minor age.

Exclusion Criteria:

  • Any condition not fulfilling inclusion criteria;
  • HIV positive;
  • Non-hematological malignancy(ies) (except non-melanoma skin cancer) < 3 years before nonmyeloablative hematopoietic cell transplantation (HCT);
  • Life expectancy severely limited by disease other than malignancy;
  • Administration of cytotoxic agent(s) for "cytoreduction" within three weeks prior to initiating the nonmyeloablative transplant conditioning (Exceptions are hydroxyurea and imatinib mesylate);
  • CNS involvement with disease refractory to intrathecal chemotherapy;
  • Terminal organ failure, except for renal failure (dialysis acceptable)

    1. Cardiac: Symptomatic coronary artery disease or other cardiac failure requiring therapy; ejection fraction <35%; uncontrolled arrhythmia, uncontrolled hypertension;
    2. Pulmonary: DLCO < 35% and/or receiving supplementary continuous oxygen;
    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 sirolimus or MMF;
  • One HLA mismatch with peripheral blood stem cells (PBSC) fit to/willing to donate.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01428973

Contacts
Contact: Frédéric Baron, MD; PhD 32-4-3667201 F.Baron@ulg.ac.be
Contact: Yves Beguin, MD; PhD 32-4-3667201 yves.beguin@chu.ulg.ac.be

Locations
Belgium
Ziekenhuis Netwerk Antwerpen (ZNA) Recruiting
Antwerpen,, Antwerpen, Belgium, 2060
Contact: Pierre Zachee, MD; PhD    32-3-2177111    pierre.zachee@zna.be   
University Hospital, Antwerp Recruiting
Edegem, Antwerp, Belgium, 2650
Contact: Wilfried Schroyens, MD; PhD    32-03-2204111    wilfried.schroyens@uza.be   
Jules Bordet Institute Recruiting
Brussels, Brabant, Belgium, 1000
Contact: Philippe Lewalle, MD; PhD    32-02-5417208    plewalle@ulb.ac.be   
AZ VUB Jette Recruiting
Brussels, Brussels Region Capital, Belgium, 1090
Contact: Rik Schots, MD; PhD    32-02-4763105    Rik.Schots@uzbrussel.be   
Cliniques universitaires Saint-Luc- Université Catholique de Louvain Recruiting
Brussels,, Brussels Region Capital, Belgium, 1200
Contact: Xavier Poiré, MD; PhD    32-02-7641880    xavier.poire@uclouvain.be   
Queen Fabiola Children's University Hospital Recruiting
Brussels, Brussels, Region Capital, Belgium, 1020
Contact: Alice Fester, MD    32-02-4772678    afester@ulb.ac.be   
University Hospital, Gasthuisberg Recruiting
Leuven, Flamish Brabant, Belgium, 3000
Contact: Johan Maertens, MD    32-16-33 22 11    johan.maertens@uz.kuleuven.ac.be   
UZ Gent Recruiting
Gent, Flanders Ost, Belgium, 9000
Contact: Lucien Noens, MD; PhD    32-09-332 21 31    Lucien.Noens@Ugent.be   
Contact: Tessa Kerre, MD; PhD    32-09-3323464    Tessa.Kerre@Ugent.be   
Jolimont Hospital Haine Saint Paul Recruiting
Haine St-Paul, Hainaut, Belgium, 7100
Contact: Nicole Straetmans, MD    32-64-233989    nicole.straetmans@scarlet.be   
Cliniques Universitaires de Mont-Godinne Recruiting
Yvoir, Namur, Belgium, 5530
Contact: Carlos Graux, MD; PhD    32-081-423831    carlos.graux@uclouvain.be   
AZ Sint-Jan AV Recruiting
Brugge, West Flanders, Belgium, 8000
Contact: Dominik Selleslag, MD    32-50-453060    dominik.selleslag@azbrugge.be   
H.-Hart Hospital Roeselare-Menen Recruiting
Roeselare, Western Flanders, Belgium, 8800
Contact: Dries Deeren, MD    32-51-237437    ddeeren@hhr.be   
CHU Sart Tilman Recruiting
Liège, Belgium, 4000
Principal Investigator: Frédéric Baron, MD; PhD         
Sub-Investigator: Yves Beguin, MD; PhD         
Sub-Investigator: Evelyne Willems, MD; PhD         
Sponsors and Collaborators
University Hospital of Liege
AZ Sint-Jan AV
Ziekenhuis Netwerk Antwerpen (ZNA)
Jules Bordet Institute
University Hospital, Gasthuisberg
AZ-VUB
Cliniques universitaires Saint-Luc- Université Catholique de Louvain
University Hospital, Antwerp
Cliniques Universitaires de Mont-Godinne
Jolimont Hospital Haine Saint Paul
Queen Fabiola Children's University Hospital
University Hospital, Ghent
H.-Hart Hospital Roeselare-Menen
Investigators
Principal Investigator: Frédéric Baron, MD; PhD University of Liège
  More Information

No publications provided

Responsible Party: Yves Beguin, Prof, University Hospital of Liege
ClinicalTrials.gov Identifier: NCT01428973     History of Changes
Other Study ID Numbers: TJB1016P1
Study First Received: September 1, 2011
Last Updated: January 17, 2013
Health Authority: Belgium: Federal Agency for Medicinal Products and Health Products

Keywords provided by University Hospital of Liege:
Allogeneic hematopoeitic cell transplantation
Graft-Versus-Host Disease
Prophylaxis
Reduced-intensity conditioning
Immunosuppressive regimen
HLA-matched donor
Progression free survival
Overall survival

Additional relevant MeSH terms:
Neoplasms
Graft vs Host Disease
Hematologic Neoplasms
Immune System Diseases
Neoplasms by Site
Hematologic Diseases
Mycophenolate mofetil
Mycophenolic Acid
Sirolimus
Everolimus
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Anti-Bacterial Agents
Anti-Infective Agents
Antifungal Agents

ClinicalTrials.gov processed this record on August 28, 2014