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

Allogeneic Hematopoietic Cell Transplantation From HLA-matched Donors After Reduced-intensity Conditioning: a Phase II Randomized Study Comparing 2 GVHD Prophylaxis Regimens

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 a reduced-intensity conditioning with Fludarabine/total body irradiation (TBI) or Fludarabine/Busulfan/anti-thymoglobuline. Following the interim analysis of October 2014, the protocol has been amended to allow inclusion only after Flu-TBI conditioning. 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.

Study Overview

• Status: Active, not recruiting
• Conditions: Hematological Malignancies; Graft-Versus-Host Disease
• Intervention / Treatment: Drug: Mycophenolate mofetil; Drug: Sirolimus

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Liège, Belgium, 4000
    • CHU Sart Tilman
  • Antwerp
    • Edegem, Antwerp, Belgium, 2650
      • University Hospital, Antwerp
  • Antwerpen
    • Antwerpen,, Antwerpen, Belgium, 2060
      • Ziekenhuis Netwerk Antwerpen (ZNA)
  • Brabant
    • Brussels, Brabant, Belgium, 1000
      • Jules Bordet Institute
  • Brussels Region Capital
    • Brussels, Brussels Region Capital, Belgium, 1090
      • AZ VUB Jette
    • Brussels,, Brussels Region Capital, Belgium, 1200
      • Cliniques universitaires Saint-Luc- Université Catholique de Louvain
  • Brussels, Region Capital
    • Brussels, Brussels, Region Capital, Belgium, 1020
      • Queen Fabiola Children's University Hospital
  • Flamish Brabant
    • Leuven, Flamish Brabant, Belgium, 3000
      • University Hospital, Gasthuisberg
  • Flanders Ost
    • Gent, Flanders Ost, Belgium, 9000
      • UZ Gent
  • Hainaut
    • Haine St-Paul, Hainaut, Belgium, 7100
      • Jolimont Hospital Haine Saint Paul
  • Namur
    • Yvoir, Namur, Belgium, 5530
      • Cliniques Universitaires de Mont-Godinne
  • West Flanders
    • Brugge, West Flanders, Belgium, 8000
      • AZ Sint-Jan AV
  • Western Flanders
    • Roeselare, Western Flanders, Belgium, 8800
      • H.-Hart Hospital Roeselare-Menen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: 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 Names: Rapamune

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	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.	1 year after transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse rate; nonrelapse mortality and overall survival	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.	1, 2 and 5 years after transplantation
Progression free survival	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.	2 and 5 years after transplantation
Engraftment	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.	1 year after transplantation
Acute GVDH	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.	6 months after transplantation
Chronic GVDH	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.	1 year after transplantation
Immunological reconstitution	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.	3 mo, 6 mo, 1 yr, 2 yrs and 5 yrs after transplantation
Infection	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.	1 year after transplantation

Collaborators and Investigators

• Sponsor: University of Liege
• Collaborators: University Hospital, Gasthuisberg; University Hospital, Ghent; University Hospital, Antwerp; AZ Sint-Jan AV; AZ Delta; Cliniques universitaires Saint-Luc- Université Catholique de Louvain; Ziekenhuis Netwerk Antwerpen (ZNA); Jules Bordet Institute; AZ-VUB; Cliniques Universitaires de Mont-Godinne; Hospital de Jolimont
• Investigators: Principal Investigator: Frédéric Baron, MD; PhD, University of Liège

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2011
• Primary Completion (Anticipated): December 1, 2024
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: September 1, 2011
• First Submitted That Met QC Criteria: September 2, 2011
• First Posted (Estimate): September 5, 2011

Study Record Updates

• Last Update Posted (Actual): September 21, 2022
• Last Update Submitted That Met QC Criteria: September 19, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Prophylaxis; Graft-Versus-Host Disease; Overall survival; Progression free survival; Reduced-intensity conditioning; Allogeneic hematopoeitic cell transplantation; HLA-matched donor; Immunosuppressive regimen
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms; Neoplasms by Site; Hematologic Diseases; Hematologic Neoplasms; Graft vs Host Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Mycophenolic Acid; Sirolimus
• Other Study ID Numbers: TJB1016P1