Clinical trial NCT01045382: MSC and HSC Coinfusion in Mismatched Minitransplants
Official title: Co-transplantation of Mesenchymal Stem Cells and HLA-mismatched Allogeneic Hematopoietic Cells After Nonmyeloablative Conditioning: a Phase II Randomized Double-blind Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Leukemia, Myeloid, Acute
Leukemia, Lymphoblastic, Acute
Leukemia, Myelocytic, Chronic
Myeloproliferative Disorders
Myelodysplastic Syndromes
Multiple Myeloma
Leukemia, Lymphocytic, Chronic
Hodgkin's Disease
Lymphoma, Non-Hodgkin
Keywords: HSC transplantation
HLA-mismatched
Mesenchymal stem cells
GVHD
co-infusion
Lead sponsor: University of Liege
Sponsor class: OTHER
Collaborators: name: AZ Sint-Jan AV
name: Ziekenhuis Netwerk Antwerpen (ZNA)
name: Jules Bordet Institute
name: Universiteit Antwerpen
name: AZ-VUB
name: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
name: University Hospital, Ghent
First posted: 2010-01-11
Enrollment: 39
Sex: ALL
Maximum age (years): 75
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The present project aims at evaluating the capacity of MSC to improve one-year overall survival of patients transplanted with HLA-mismatched PBSC from related or unrelated donors after non-myeloablative conditioning.

Co-infusion of MSC has been shown to facilitate engraftment of hematopoietic stem cell (HSC) in an immunodeficient mouse model. In addition, it has been shown that infusion of third party MSC in HSC transplantation could be successfully used as treatment for grade II-IV steroid-refractory acute graft versus host disease.

One hundred and twenty patients with HLA-mismatched donors will be included over 6 years at multiple centers across Belgium through the transplant committee of the Belgian Hematological Society. The conditioning regimen will consist of fludarabine and 2 Gy TBI, followed by the infusion of donor HSC. Patients will be randomized 1/1 in double-blind fashion to receive or not MSC (1.5-.3.0 x106/kg) from third-party (either haploidentical family members or unrelated volunteer) donors on day 0. Postgrafting immunosuppression will combine tacrolimus and MMF. Except for the collection, expansion and infusion of MSC, the clinical management of the patient will not differ from that of routine NM-HCT.


Eligibility criteria: Inclusion Criteria:

* Theoretical indication for a standard allo-transplant, but not feasible because: Age \> 55 yrs. Unacceptable end organ performance. Patient's refusal.
* Indication for a standard auto-transplant: perform mini-allotransplantation 2-6 months after standard autotransplant.
* Male or female; fertile female patients must use a reliable contraception method
* Age ≤ 75 year old
* Informed consent given by patient or his/her guardian if of minor age.
* One or two HLA mismatches with PBSC:

  * One antigenic mismatch at HLA-A or -B or -C or -DRB1 or -DQB1
  * Two allelic mismatches at HLA-A or -B or -C or -DRB1 or -DQB1
  * One antigenic mismatch: 1 allelic mismatch at HLA-A or -B or -C or -DRB1 or -DQB1.
  * One antigenic mismatch at -DQB1 and one other antigenic mismatch at HLA-A or -B or -C or -DRB1
  * Patients with one single allelic mismatch at HLA-A or -B or -C or -DRB1 or -DQB1 can also be included in the protocol.
* Hematological malignancies confirmed histologically and not rapidly progressing:

  * AML in complete remission
  * ALL in complete remission
  * CML unresponsive/intolerant to Imatinib but not in blast crisis
  * Other myeloproliferative disorders not in blast crisis and not with extensive myelofibrosis
  * MDS with \<5% blasts
  * Multiple myeloma not rapidly progressing
  * CLL
  * Non-Hodgkin's lymphoma (aggressive NHL should be chemosensitive)
  * Hodgkin's disease

Exclusion Criteria:

* Any condition not fulfilling inclusion criteria
* HIV positive
* Terminal organ failure, except for renal failure (dialysis acceptable)

  * Cardiac: Symptomatic coronary artery disease or other cardiac failure requiring therapy; ejection fraction \<35%; uncontrolled arrhythmia; uncontrolled hypertension
  * Pulmonary: DLCO \< 35% and/or receiving supplementary continuous oxygen
  * 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, arrhythmia or hypertension
* Previous radiation therapy precluding the use of 2 Gy TBI
* 10/10 HLA-A, -B, -C, DRB1 and DQBI allele-matched donor fit to/willing to donate PBSC.

Primary outcomes:
measure: One-year overall survival in the 2 arms.
timeFrame: One year
Secondary outcomes:
measure: Incidence of grade II-IV and grade III-IV acute GVDH
timeFrame: 100 days
measure: Number of absolute donor T cells after HCT in each arm
timeFrame: 28
measure: Cumulative incidence of non-relapse mortality
timeFrame: 100, 365 and 730 days
measure: Incidence of extensive chronic GVHD in each arm
timeFrame: 365 days
measure: Incidence of graft rejection in each arm.
timeFrame: 365 days
measure: Quality and timing of immunologic reconstitution in each arm.
timeFrame: 100, 365 and 730 days
measure: Detection of MSC from donor origin in recipient marrow after HCT in patients given MSC
timeFrame: 40 days
measure: Proportion of patients with measurable disease at HCT who achieve a complete response in each arm.
timeFrame: 100, 365 and 730 days
measure: Cumulative incidence of relapse
timeFrame: 365 and 730 days
measure: Incidence of progression-free survival
timeFrame: 365 and 730 days
measure: Incidence of infections
timeFrame: 100 days
Other outcomes:
Locations:
city: Edeghem
country: Belgium
facility: UZA
state: Antwerpen
city: Brussels
country: Belgium
facility: St-Luc UCL
state: Brabant
city: Leuven
country: Belgium
facility: AZ Gasthuisberg Leuven
state: Flamish Brabant
city: Gent
country: Belgium
facility: UZ Gent
state: Flanders Ost
city: Brugge
country: Belgium
facility: AZ St-Jan
state: Flanders West
city: Yvoir
country: Belgium
facility: Cliniques Universitaires Mont-Godinne
state: Namur
city: Antwerpen
country: Belgium
facility: Hôpital Stuyvenberg
city: Brussels
country: Belgium
facility: Bordet Institute
city: Brussels
country: Belgium
facility: Vrije Universiteit Brussel
city: Liège
country: Belgium
facility: CHU-ULg
Study officials:
affiliation: CHU-ULg
name: Yves Beguin, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU-ULg
name: Frédéric Baron, MD, PhD
role: STUDY_CHAIR
affiliation: CHU-ULg
name: Evelyne Willems, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: AZ Brugge
name: Dominik Selleslag, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: ZNA Antwerpen
name: Pierre Zachée, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Bordet Institute, Brussels
name: Philippe Lewalle, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Bordet Institute, Brussels
name: Dominique Bron, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: UZA Antwerpen
name: Wilfried Schroyens, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU-ULg
name: Chantal Lechanteur, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU-ULg
name: Etienne Baudoux, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: KUL, Leuven
name: Johan Maertens, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: AZ VUB, Brussels
name: Rik Schots, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: UCL St. LUC, Brussels
name: Augustin Ferrant, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: UZG Gent
name: Lucien Noens, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Cliiques Universitaire Mont-Godinne, Yvoir
name: Chantal Doyen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: UZA, Antwerpen
name: Tessa Kerre, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Cliniques Universitaires, Mont-Godinne
name: Carlos Graux, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: