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MSC and HSC Coinfusion in Mismatched Minitransplants

Primary Purpose

Leukemia, Myeloid, Acute, Leukemia, Lymphoblastic, Acute, Leukemia, Myelocytic, Chronic

Status

Terminated

Phase

Phase 2

Locations

Belgium

Study Type

Interventional

Intervention

Mesenchymal stem cells

Isotonic solution

About this trial

This is an interventional treatment trial for Leukemia, Myeloid, Acute focused on measuring HSC transplantation, HLA-mismatched, Mesenchymal stem cells, GVHD, co-infusion

Eligibility Criteria

undefined - 75 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Mensenchymal Stem Cells

Placebo

Arm Description

Efficacy of MSC infusion on one-year overall survival of patients transplanted with HLA-mismatched PBSC. Patients will receive a conditioning regimen consisting in fludarabine (total dose 90 mg/square meter) and 2 Gy total body irradiation. MSC cells (1,5-3,0 x 10E6 MSC/Kg BW) will be injected, followed, at least one hour later, by the infusion of HLA-mismatched PBSC from related or unrelated donor.

Patients will receive a conditioning regimen consisting in fludarabine (total dose 90 mg/square meter) and 2Gy total body irradiation. Isotonic solution will be injected will be injected, followed, at least one hour later, by the infusion of HLA-mismatched PBSC from related or unrelated donor.

Outcomes

Primary Outcome Measures

One-year overall survival in the 2 arms.

Secondary Outcome Measures

Incidence of grade II-IV and grade III-IV acute GVDH

Number of absolute donor T cells after HCT in each arm

Cumulative incidence of non-relapse mortality

Incidence of extensive chronic GVHD in each arm

Incidence of graft rejection in each arm.

Quality and timing of immunologic reconstitution in each arm.

Detection of MSC from donor origin in recipient marrow after HCT in patients given MSC

Proportion of patients with measurable disease at HCT who achieve a complete response in each arm.

Cumulative incidence of relapse

Incidence of progression-free survival

Incidence of infections

Full Information

NCT ID

NCT01045382

First Posted

January 8, 2010

Last Updated

August 31, 2021

Sponsor

University of Liege

Collaborators

AZ Sint-Jan AV, Ziekenhuis Netwerk Antwerpen (ZNA), Jules Bordet Institute, Universiteit Antwerpen, AZ-VUB, Cliniques universitaires Saint-Luc- Université Catholique de Louvain, University Hospital, Ghent

1. Study Identification

Unique Protocol Identification Number

NCT01045382

Brief Title

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

2. Study Status

Record Verification Date

August 2021

Overall Recruitment Status

Terminated

Why Stopped

recruitment too slow

Study Start Date

July 2010 (Actual)

Primary Completion Date

August 2021 (Actual)

Study Completion Date

August 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Liege

Collaborators

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare Provider

Allocation

Randomized

Enrollment

39 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Mensenchymal Stem Cells

Arm Type

Experimental

Arm Description

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Biological

Intervention Name(s)

Mesenchymal stem cells

Intervention Description

Mesenchymal stem cell injection

Intervention Type

Other

Intervention Name(s)

Isotonic solution

Intervention Description

Isotonic solution injection

Primary Outcome Measure Information:

Title

One-year overall survival in the 2 arms.

Time Frame

One year

Secondary Outcome Measure Information:

Title

Incidence of grade II-IV and grade III-IV acute GVDH

Time Frame

100 days

Title

Number of absolute donor T cells after HCT in each arm

Time Frame

Title

Cumulative incidence of non-relapse mortality

Time Frame

100, 365 and 730 days

Title

Incidence of extensive chronic GVHD in each arm

Time Frame

365 days

Title

Incidence of graft rejection in each arm.

Time Frame

365 days

Title

Quality and timing of immunologic reconstitution in each arm.

Time Frame

100, 365 and 730 days

Title

Detection of MSC from donor origin in recipient marrow after HCT in patients given MSC

Time Frame

40 days

Title

Proportion of patients with measurable disease at HCT who achieve a complete response in each arm.

Time Frame

100, 365 and 730 days

Title

Cumulative incidence of relapse

Time Frame

365 and 730 days

Title

Incidence of progression-free survival

Time Frame

365 and 730 days

Title

Incidence of infections

Time Frame

100 days

10. Eligibility

Sex

All

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

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.

Overall Study Officials: