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Clinical Ex Vivo Expansion of Human Umbilical Cord Blood Stem and Progenitor Cells

Primary Purpose

Acute Leukemia, Chronic Leukemia, Myelodysplastic Syndrome

Status
Terminated
Phase
Phase 1
Locations
Singapore
Study Type
Interventional
Intervention
Ex vivo expanded cord blood cells
Sponsored by
Singapore General Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Leukemia focused on measuring Cord blood, unrelated donor, allogeneic, cell dose

Eligibility Criteria

12 Years - 60 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients will be from the Department of Haematology, Singapore General Hospital, who have the diagnoses listed below and who meet the inclusion criteria. They have to be deemed suitable for trial by the respective attending doctor as well as a panel of at least three hematologists. Suitability will be reassessed by the Principal Investigator again

    1. Patients aged 12 years to 60 years.
    2. Patient has no currently available HLA-A, B, C, DRB1 and DQB1 matched related or unrelated donor.
    3. Patient must have a hematologic malignancy requiring allogeneic haematopoietic stem cell transplantation as further defined below (from National Marrow Donor Program and American Society of Blood and Marrow Transplantation Guidelines) and as further agreed upon by a panel of at least three hematologists specializing in transplantation.

  • Acute myelogenous leukemia (AML): High-risk AML including:

    • Antecedent hematological disease (e.g., myelodysplasia (MDS))
    • Treatment-related leukemia
    • Induction failure
    • 1st complete remission (CR1) with poor-risk cytogenetics or molecular markers (e.g. Flt 3 mutation, 11q23 etc)
    • 2nd complete remission (CR2) and beyond

  • Acute lymphoblastic leukemia (ALL)

    • CR1 up to age 35
    • High-risk over age 35 including:
    • Poor-risk cytogenetics (e.g., Philadelphia chromosome t(9;22)or 11q23 rearrangements)
    • High white cell count (> 30,000/mm3) at diagnosis
    • CNS or testicular leukemia
    • No CR within 4 weeks of initial treatment
    • Induction failure
    • CR2 and beyond

  • Myelodysplastic syndromes (MDS)

    • Intermediate-1 (INT-1), intermediate-2 (INT-2) or high IPSS score which includes:
    • > 5% marrow blasts
    • Other than good risk cytogenetics (not 5q- or normal)
    • > 1 lineage cytopenia

  • Chronic myelogenous leukemia (CML)

    • Disease progression
    • Accelerated phase
    • Blast crisis (myeloid or lymphoid)

  • Follicular lymphoma

    • Poor response to initial treatment
    • After second or subsequent relapse
    • Transformation to diffuse large B-cell lymphoma

  • Aggressive T-cell or B-Cell lymphoma

    • After second or subsequent relapse
    • No CR with initial treatment
  • Mantle Cell: After second or subsequent relapse

  • Hodgkin's lymphoma

    • No initial CR
    • After second or subsequent relapse
  • Multiple myeloma: Patients failing autologous transplantation with chromosome 13 abnormalities, first response lasting less than 6 months, or β-2 microglobulin > 3 mg/L may be considered for this protocol after initial therapy.

Exclusion Criteria:

  1. Inadequate Organ Function as defined by:

    • Renal: Creatinine clearance > 60ml/min
    • Hepatic: Bilirubin, AST/ALT < 2x upper limit of normal
    • Pulmonary function: DLCOcorr > 50% normal
    • Cardiac: left ventricular ejection fraction > 45%
  2. Karnofsky score (adults) < 70% or Lansky score < 50% (pediatrics)

Sites / Locations

  • Singapore General Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Expanded

Arm Description

'Ex vivo expanded cord blood cells

Outcomes

Primary Outcome Measures

Safety
Number of subjects with infusional toxicities (including fever, renal dysfunction within 72 hours of infusion) and potential immunologic competition (absent chimerism of donor cells by 21 days post transplantation).

Secondary Outcome Measures

Engraftment
Neutrophil engraftment (ANC>500/ul) in subjects as demonstrated by number of subjects with engraftment <=21 days.

Full Information

First Posted
March 20, 2012
Last Updated
November 26, 2015
Sponsor
Singapore General Hospital
Collaborators
Whitehead Institute for Biomedical Research, Blood Services Group, Health Sciences Authority of Singapore
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1. Study Identification

Unique Protocol Identification Number
NCT01624701
Brief Title
Clinical Ex Vivo Expansion of Human Umbilical Cord Blood Stem and Progenitor Cells
Official Title
Clinical Ex Vivo Expansion of Human Umbilical Cord Blood Stem and Progenitor Cells: A Pilot Trial in Collaboration With the Massachusetts Institute of Technology
Study Type
Interventional

2. Study Status

Record Verification Date
November 2015
Overall Recruitment Status
Terminated
Why Stopped
Funding expired
Study Start Date
March 2012 (undefined)
Primary Completion Date
July 2015 (Actual)
Study Completion Date
July 2016 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Singapore General Hospital
Collaborators
Whitehead Institute for Biomedical Research, Blood Services Group, Health Sciences Authority of Singapore

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a pilot clinical trial to assess the feasibility and efficacy of expanding umbilical cord blood derived blood stem cells for transplantation using a combination of chemical factors and stromal co-culture. Bone marrow (BM) mesenchymal stromal cells (MSC) will be obtained from a separate bone marrow donor. One cord blood unit will be expanded by this method while another cord blood unit will be infused without manipulation. The expanded cord blood unit will help boost the initial recovery of blood counts after transplantation, though it is expected that the unexpanded cord blood unit will provide the cells which will lead to long term engraftment of blood stem cells. A third cord blood unit will be identified for standby should the cord blood unit expansion fail.
Detailed Description
Clinical transplantation of two cord blood units: one ex vivo expanded while another unmanipulated unit to function as a back-up. Ten patients will be selected from those for whom: Allogeneic haematopoietic stem cell transplant is indicated (see details) No matched sibling or matched unrelated donor is available quickly enough for the transplant (no fully matched donor found within 1 month of initiation of donor search or donor found but not available for donation within 3 months of donor search). At least three unrelated donor cord blood unit can be identified with less than 2 antigens mismatches with the patient but with insufficient cell dose to meet the patient's requirements. If clinical efficacy of this protocol is demonstrated, we will proceed to a multicentre clinical trial with more patients. The investigators will obtain haplo-identical MSC from the bone marrow of sibling/parent/offspring of the patient. Although there will be some MSC co-infused with the cord blood cells, this has been shown to be safe in trials of MSC given for patients with graft versus host disease (GVHD) and human leukocyte antigen (HLA) matching of MSC and recipient has been shown to be not important. bone marrow mesenchymal stroma cells (BM-MSCs) derived from related donor bone marrow with a minimum of 2/6 HLA match have been safe for use in patients.1 If the haplo-identical MSC donor is not available, matched unrelated donor MSC would also be used. Efficacy will be assessed by the following and compared to published literature as well as historical controls: Neutrophil and platelet engraftment Post transplant 100-day mortality Overall and progression-free survival If clinical efficacy of this protocol is demonstrated, the investigators will proceed to a multicentre clinical trial with more patients.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Leukemia, Chronic Leukemia, Myelodysplastic Syndrome, Lymphoma, Myeloma
Keywords
Cord blood, unrelated donor, allogeneic, cell dose

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
3 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Expanded
Arm Type
Experimental
Arm Description
'Ex vivo expanded cord blood cells
Intervention Type
Other
Intervention Name(s)
Ex vivo expanded cord blood cells
Intervention Description
Cord blood cells will be expanded ex vivo using a combination of stem cell factor (SCF), thrombopoietin (TPO), Flt3 ligand and IGFBP2 with mesenchymal stromal cell (MSC) co-culture.
Primary Outcome Measure Information:
Title
Safety
Description
Number of subjects with infusional toxicities (including fever, renal dysfunction within 72 hours of infusion) and potential immunologic competition (absent chimerism of donor cells by 21 days post transplantation).
Time Frame
1 month
Secondary Outcome Measure Information:
Title
Engraftment
Description
Neutrophil engraftment (ANC>500/ul) in subjects as demonstrated by number of subjects with engraftment <=21 days.
Time Frame
2 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients will be from the Department of Haematology, Singapore General Hospital, who have the diagnoses listed below and who meet the inclusion criteria. They have to be deemed suitable for trial by the respective attending doctor as well as a panel of at least three hematologists. Suitability will be reassessed by the Principal Investigator again Patients aged 12 years to 60 years. Patient has no currently available HLA-A, B, C, DRB1 and DQB1 matched related or unrelated donor. Patient must have a hematologic malignancy requiring allogeneic haematopoietic stem cell transplantation as further defined below (from National Marrow Donor Program and American Society of Blood and Marrow Transplantation Guidelines) and as further agreed upon by a panel of at least three hematologists specializing in transplantation. Acute myelogenous leukemia (AML): High-risk AML including: Antecedent hematological disease (e.g., myelodysplasia (MDS)) Treatment-related leukemia Induction failure 1st complete remission (CR1) with poor-risk cytogenetics or molecular markers (e.g. Flt 3 mutation, 11q23 etc) 2nd complete remission (CR2) and beyond Acute lymphoblastic leukemia (ALL) CR1 up to age 35 High-risk over age 35 including: Poor-risk cytogenetics (e.g., Philadelphia chromosome t(9;22)or 11q23 rearrangements) High white cell count (> 30,000/mm3) at diagnosis CNS or testicular leukemia No CR within 4 weeks of initial treatment Induction failure CR2 and beyond Myelodysplastic syndromes (MDS) Intermediate-1 (INT-1), intermediate-2 (INT-2) or high IPSS score which includes: > 5% marrow blasts Other than good risk cytogenetics (not 5q- or normal) > 1 lineage cytopenia Chronic myelogenous leukemia (CML) Disease progression Accelerated phase Blast crisis (myeloid or lymphoid) Follicular lymphoma Poor response to initial treatment After second or subsequent relapse Transformation to diffuse large B-cell lymphoma Aggressive T-cell or B-Cell lymphoma After second or subsequent relapse No CR with initial treatment Mantle Cell: After second or subsequent relapse Hodgkin's lymphoma No initial CR After second or subsequent relapse Multiple myeloma: Patients failing autologous transplantation with chromosome 13 abnormalities, first response lasting less than 6 months, or β-2 microglobulin > 3 mg/L may be considered for this protocol after initial therapy. Exclusion Criteria: Inadequate Organ Function as defined by: Renal: Creatinine clearance > 60ml/min Hepatic: Bilirubin, AST/ALT < 2x upper limit of normal Pulmonary function: DLCOcorr > 50% normal Cardiac: left ventricular ejection fraction > 45% Karnofsky score (adults) < 70% or Lansky score < 50% (pediatrics)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
William YK Hwang, MBBS, FRCP
Organizational Affiliation
Singapore General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Singapore General Hospital
City
Singapore
ZIP/Postal Code
169608
Country
Singapore

12. IPD Sharing Statement

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Clinical Ex Vivo Expansion of Human Umbilical Cord Blood Stem and Progenitor Cells

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