Clinical trial NCT00603330: Mesenchymal Stem Cell Infusion as Treatment for Steroid-Resistant Acute Graft Versus Host Disease (GVHD) or Poor Graft Function
Official title: Infusion of Mesenchymal Stem Cells as Treatment for Steroid-Resistant Grade II to IV Acute GVHD or Poor Graft Function: a Multicenter Phase II Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Graft-versus-host Disease
Poor Graft Function
Low Donor T-cell Chimerism
Keywords: Mesenchymal stem cells
Graft-versus-host disease
Poor graft function
Chimerism
Hematopoietic cell transplantation recipients
Low donor T-cell chimerism
Lead sponsor: University of Liege
Sponsor class: OTHER
Collaborators: name: KU Leuven
name: Maastricht University Medical Center
name: Ziekenhuis Netwerk Antwerpen (ZNA)
name: University Hospital, Antwerp
name: University Hospital, Ghent
name: AZ-VUB
name: AZ Sint-Jan AV
name: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
name: University Hospital of Mont-Godinne
name: Jolimont Hospital Haine Saint Paul
name: Queen Fabiola Children's University Hospital
First posted: 2008-01-29
Enrollment: 100
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The present project aims at investigating the role of MSC for the treatment of patients with

Part 1: Steroid-refractory grade II-IV acute GVHD.

Part 2: Poor graft function (PGF)

Part 3: Low or falling donor T-cell chimerism after allogeneic HCT.

This is a multicenter phase II study examining the feasibility and efficacy of this approach.

Detailed description: Part 1: complete recruitment Part 2: complete recruitment Part 3: recruiting

Eligibility criteria: Inclusion Criteria:

Patient eligibility criteria

1. Male or female of any age.
2. Previous allogeneic transplantation (related or unrelated donor, any degree of HLA matching) or autologous transplantation (for part 2 only) of HSC at any time before.
3. Any source of HSC (marrow, PBSC, cord blood) and any conditioning regimen.
4. Informed consent given by donor or his/her guardian if of minor age.
5. Additional criteria for each part of the protocol:

Part 1: MSC for steroid-refractory grade II-IV acute GVHD

1. Allogeneic transplantation.
2. Grade II-IV acute GVHD (see appendix A for acute GVHD grading) de novo or following DLI.
3. Acute GVHD refractory to mPDN 2 mg/kg/day or equivalent, defined as

   * progression of GVHD on day 3 after initiation of steroids
   * no improvement of GVHD on day 7 after initiation of steroids
   * absence of complete resolution of acute GVHD on day 14 after initiation of steroids
   * relapse of acute GVHD during or after steroid taper.
4. Ongoing therapy with Ciclosporine or Tacrolimus at therapeutic doses.
5. Patient may have received previously any other form of treatment for acute GVHD, but no new treatment started within 1 month of study entry.

Part 2: MSC for poor graft function (PGF)

1. Allogeneic or autologous transplantation.
2. Cytopenia in 2 or 3 lineages:

   * Hb \< 8.0 g/dL and reticulocytes \< 1%, with or without transfusion
   * Plt \< 20,000/µL without transfusion
   * Neutrophils \< 500/µL, without G-CSF administration

   OR severe cytopenia in 1 lineage:
   * RBC transfusion dependent (if autologous transplantation; despite EPO administration if allogeneic transplantation)
   * Plt transfusion dependent
   * Neutrophils \< 500/µL despite G-CSF administration
3. Cytopenia duration ≥ 2 weeks beyond day 28 after autologous HCT, or day 42 (day 60 for cord blood transplantation) after allogeneic HCT.
4. Cytopenia is not related to CMV or other infection, myelosuppressive/toxic drugs, renal failure, peripheral cell destruction or other identifiable cause.
5. In case of HLA-identical related donor and full donor chimerism, patient can only be included if a boost of donor CD34+ cells has been unsuccessful or is not feasible.

Part 3: MSC + DLI for poor donor T-cell chimerism

1. Nonmyeloablative allogeneic transplantation.
2. Donor T-cell chimerism \< 50% for at least 2 consecutive weeks beyond day 21 after HCT OR

   * 20% decrease in donor T-cell chimerism with the second value \< 50%.

MSC donor inclusion criteria

1. Related to the recipient (sibling, parent or child) or unrelated.
2. Male or female.
3. Age \> 16 yrs (no age limit if same as HSC donor).
4. No HLA matching required.
5. Fulfills generally accepted criteria for allogeneic HSC donation.
6. Informed consent given by donor or his/her guardian if of minor age.

Exclusion Criteria:

Patient exclusion criteria

1. HIV positive.
2. Active uncontrolled infection at time of scheduled MSC infusion.
3. Relapsing or progressing malignancy.

MSC donor exclusion criteria

1. HIV positive
2. Known allergy to Lidocaine
3. If donor other than HSC donor : any risk factor for transmissible infectious diseases.

Primary outcomes:
measure: Arm 1. Efficacy of MSC infusion as treatment for steroid-resistant grade II - IV acute GVHD.
timeFrame: 30 days
measure: Arm 2. Efficacy of MSC infusion as treatment for poor graft function
timeFrame: 180 days
measure: Arm 3. Efficacy of MSC infusion followed by donor lymphocyte infusion for preventing graft rejection in patients with low or failing donor T-cell chimerism after allogeneic HCT
timeFrame: 180 days
Secondary outcomes:
measure: Toxicity of MSC infusion
timeFrame: 180 days
Other outcomes:
Locations:
city: Edeghem
country: Belgium
facility: UZA
state: Antwerpen
city: Brussels
country: Belgium
facility: Hôpital des enfants Reine Fabiola
state: Brabant
city: Brussels
country: Belgium
facility: AZ VUB Jette
state: Brabant
city: Brussels
country: Belgium
facility: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
state: Brabant
city: Leuven
country: Belgium
facility: AZ Gasthuisberg Leuven
state: Flamish Brabant
city: Gent
country: Belgium
facility: UZ Gent
state: Flanders Ost
city: Haine St Paul
country: Belgium
facility: Hôpital de Jolimont
state: Hainaut
city: Yvoir
country: Belgium
facility: Cliniques Universitaires Mont-Godinne
state: Namur
city: Brugge
country: Belgium
facility: AZ St Jan
state: West Flanders
city: Antwerpen
country: Belgium
facility: Hôpital Stuyvenberg
city: Liege
country: Belgium
facility: CHU Sart Tilman
city: Maastricht
country: Netherlands
facility: University Hospital Maastricht
state: Limburg
Study officials:
affiliation: CHU-ULg
name: Yves Beguin, MD, PhD
role: STUDY_CHAIR
affiliation: CHU-ULg
name: Frédéric Baron, MD, PhD
role: STUDY_CHAIR
affiliation: KU Leuven
name: Johan Maertens, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Maastricht University Medical Center
name: Harry Schouten, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Stuyvenberg Hospital Antwerpen
name: Pierre Zachée, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UZA Antwerpen
name: Zwi Berneman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UZ-Gent
name: Lucien Noens, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: AZ VUB Jette
name: Rick Schots, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: AZ St. Jan Bugge
name: Dominik Selleslag, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UCL St. Luc Brussels
name: Augustin Ferrant, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Cliniques Universitaires Mont-Godinne at Yvoir
name: Chantal Doyen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital de Jolimont at Haine-St-Paul
name: Nicole Straetmans, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital des enfants Reine Fabiola at Brussels
name: Nicole Ferster, MD
role: PRINCIPAL_INVESTIGATOR
References: