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

Hematological Malignancies Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01428973
• Other study ID #: TJB1016P1
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: September 2011
• Est. completion date: December 2024

Study information

• Verified date: September 2022
• Source: University of Liege
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 200
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Graft vs Host Disease
• Graft-Versus-Host Disease
• Hematologic Neoplasms
• Hematological Malignancies

Intervention

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.
• 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.

Locations

Country	Name	City	State
Belgium	Ziekenhuis Netwerk Antwerpen (ZNA)	Antwerpen,	Antwerpen
Belgium	AZ Sint-Jan AV	Brugge	West Flanders
Belgium	AZ VUB Jette	Brussels	Brussels Region Capital
Belgium	Jules Bordet Institute	Brussels	Brabant
Belgium	Queen Fabiola Children's University Hospital	Brussels	Brussels, Region Capital
Belgium	Cliniques universitaires Saint-Luc- Université Catholique de Louvain	Brussels,	Brussels Region Capital
Belgium	University Hospital, Antwerp	Edegem	Antwerp
Belgium	UZ Gent	Gent	Flanders Ost
Belgium	Jolimont Hospital Haine Saint Paul	Haine St-Paul	Hainaut
Belgium	University Hospital, Gasthuisberg	Leuven	Flamish Brabant
Belgium	CHU Sart Tilman	Liège
Belgium	H.-Hart Hospital Roeselare-Menen	Roeselare	Western Flanders
Belgium	Cliniques Universitaires de Mont-Godinne	Yvoir	Namur

Sponsors (12)

Lead Sponsor	Collaborator
University of Liege	AZ Delta, AZ Sint-Jan AV, AZ-VUB, Cliniques Universitaires de Mont-Godinne, Cliniques universitaires Saint-Luc- Université Catholique de Louvain, Hospital de Jolimont, Jules Bordet Institute, University Hospital, Antwerp, University Hospital, Gasthuisberg, University Hospital, Ghent, Ziekenhuis Netwerk Antwerpen (ZNA)

Country where clinical trial is conducted

Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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