Infusion of Off-the-Shelf Expanded Cord Blood Cells to Augment Cord Blood Transplant in Patients With Hematologic Malignancies

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT01175785
First received: August 3, 2010
Last updated: January 17, 2014
Last verified: January 2014
  Purpose

This phase II trial is studying the safety and potential efficacy of infusing non-human leukocyte antigen matched ex vivo expanded cord blood progenitors with one or two unmanipulated umbilical cord blood units for transplantation following conditioning with fludarabine, cyclophosphamide and total body irradiation, and immunosuppression with cyclosporine and mycophenolate mofetil for patients with hematologic malignancies. Chemotherapy, such as fludarabine and cyclophosphamide, and total-body irradiation given before an umbilical cord blood transplant stops the growth of leukemia cells and works to prevent the patient's immune system from rejecting the donor's stem cells. The healthy stem cells from the donor's umbilical cord blood help the patient's bone marrow make new red blood cells, white blood cells, and platelets. It may take several weeks for these new blood cells to grow. During that period of time, patients are at increased risk for bleeding and infection. Faster recovery of white blood cells may decrease the number and severity of infections. Studies have shown that counts recover more quickly when more cord blood cells are given with the transplant. We have developed a way of growing or "expanding" the number of cord blood cells in the lab so that there are more cells available for transplant. We are doing this study to find out whether or not giving these expanded cells along with one or two unexpanded cord blood units is safe and if use of expanded cells can decrease the time it takes for white blood cells to recover after transplant. We will study the time it takes for blood counts to recover, which of the two or three cord blood units makes up the patient's new blood system, and how quickly immune system cells return


Condition Intervention Phase
Accelerated Phase Chronic Myelogenous Leukemia
Adult Acute Myeloid Leukemia in Remission
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Childhood Acute Lymphoblastic Leukemia in Remission
Childhood Acute Myeloid Leukemia in Remission
Childhood Chronic Myelogenous Leukemia
Childhood Myelodysplastic Syndromes
Chronic Eosinophilic Leukemia
Chronic Neutrophilic Leukemia
Chronic Phase Chronic Myelogenous Leukemia
de Novo Myelodysplastic Syndromes
Previously Treated Myelodysplastic Syndromes
Refractory Anemia
Refractory Anemia With Excess Blasts
Refractory Anemia With Excess Blasts in Transformation
Relapsing Chronic Myelogenous Leukemia
Secondary Myelodysplastic Syndromes
Procedure: umbilical cord blood transplantation
Drug: fludarabine phosphate
Drug: cyclophosphamide
Procedure: ex vivo-expanded cord blood progenitor cell infusion
Radiation: total-body irradiation
Drug: cyclosporine
Drug: mycophenolate mofetil
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Infusion of Off-the-Shelf Ex Vivo Expanded Cryopreserved Cord Blood Progenitor Cells to Augment Single or Double Myeloablative Cord Blood Transplantation in Patients With Hematologic Malignancies

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Time to neutrophil and platelet engraftment [ Time Frame: By day 30 ] [ Designated as safety issue: No ]
    Defined as the first of 2 consecutive days in which the absolute neutrophil count (ANC) >= 500.

  • Overall survival at day 100, day 180, 1 and 2 years [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
  • Event-free survival at day 100, day 180, 1 and 2 years [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
  • Severe (Grades 3-4) acute GVHD [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
  • Grade greater than or equal to 3 infusional toxicity [ Time Frame: By day 100 ] [ Designated as safety issue: Yes ]
    Toxicities will be graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0.


Secondary Outcome Measures:
  • Primary and secondary graft failure [ Time Frame: By day 42 ] [ Designated as safety issue: No ]
    Defined as failure to achieve ANC >= 500/mm^3 of donor origin.


Estimated Enrollment: 15
Study Start Date: August 2010
Estimated Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (chemo, radiation, transplant, GVHD prophylaxis)
Patients receive fludarabine IV over 1 hour on days -8 to -6 and cyclophosphamide IV on days -7 and -6. Patients undergo TBI twice daily on days -4 to -1. Patients undergo unmanipulated single- or double-unit umbilical cord blood transplantation on day 0 and receive ex vivo-expanded cord blood progenitor cells IV over 4 hours following the last unmanipulated cord blood infusion. Patients initially receive CSP IV over 1 hour beginning on day -3. CSP may be given PO when the patient can tolerate oral medications and has a normal gastrointestinal transit time. CSP is given until day 100, and may taper on day 101 if there is no graft versus host disease. Patients also receive MMF IV every 8 hours on days 0 to 7 and then may receive MMF PO beginning day 8 to 30. MMF is continued for a minimum of 30 days or until 7 days after blood counts recover whichever is later. If there is no evidence of acute GVHD and donor CD3 engraftment is at least 50% from one donor MMF may be tapered.
Procedure: umbilical cord blood transplantation
Undergo unmanipulated umbilical cord blood units
Other Names:
  • cord blood transplantation
  • transplantation, umbilical cord blood
  • UCB transplantation
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Procedure: ex vivo-expanded cord blood progenitor cell infusion
Undergo ex-vivo expanded cryopreserved cord blood progenitor cells
Radiation: total-body irradiation
Undergo TBI
Other Name: TBI
Drug: cyclosporine
Given IV
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Drug: mycophenolate mofetil
Given IV and PO
Other Names:
  • Cellcept
  • MMF
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. Examine the safety and toxicity when ex vivo expanded cord blood cells are infused as an off-the-shelf non-HLA matched product with the goal of providing rapid but transient myelopoiesis in the setting of a single or double umbilical cord blood transplant.

II. Examine the in vivo persistence of the ex vivo expanded cord blood product. The kinetics and durability of hematopoietic reconstitution will be determined and the relative contribution to engraftment of the expanded cord blood product and the unmanipulated cord blood unit(s) in early and long-term engraftment will be determined by frequent determination of donor chimerisms in the peripheral blood.

SECONDARY OBJECTIVES I. Estimate the incidence and severity of acute and chronic graft-versus-host-disease (GVHD) in patients receiving off-the-shelf ex vivo expanded and cryopreserved cord blood cells.

II. Estimate the incidence of transplant related mortality at day 100. III. Estimate the incidence of malignant relapse and probabilities of overall and event-free survival at 1 and 2 years post transplant.

IV. Obtain preliminary data on the incidence of infections/viral reactivation from the start of conditioning to 100 days post transplant and then at 6 months, 1 year and 2 years post transplant as possible.

V. Obtain preliminary data on the phenotype and function of immune cells recovering in patients receiving expanded and unmanipulated cord blood grafts.

VI. Examination of possible immunologic factors leading to emergence of a dominant unit.

OUTLINE:

MYELOABLATIVE CONDITIONING: Patients receive fludarabine intravenously (IV) over 1 hour on days -8 to -6 and cyclophosphamide IV on days -7 and -6. Patients undergo total-body irradiation (TBI) twice daily on days -4 to -1.

TRANSPLANTATION: Patients undergo unmanipulated single- or double-unit umbilical cord blood transplantation on day 0 and receive ex vivo-expanded cord blood progenitor cells IV over 4 hours following the last unmanipulated cord blood infusion.

GVHD PROPHYLAXIS: Patients initially receive cyclosporine (CSP) IV over 1 hour beginning on day -3. CSP may be given orally (PO) when the patient can tolerate oral medications and has a normal gastrointestinal transit time. CSP is given until day 100, and may taper on day 101 if there is no graft versus host disease. Patients also receive mycophenolate mofetil (MMF) IV every 8 hours on days 0 to 7 and then may receive MMF PO beginning day 8 to 30. MMF is continued for a minimum of 30 days or until 7 days after blood counts recover whichever is later. If there is no evidence of acute GVHD and donor CD3 engraftment is at least 50% from one donor MMF may be tapered.

  Eligibility

Ages Eligible for Study:   6 Months to 45 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Acute myeloid leukemia:

    • High risk complete response (CR)1 as evidenced by preceding myelodysplastic syndromes (MDS), high risk cytogenetics (for example, monosomy 5 or 7, or as defined by referring institution treatment protocol), >= 2 cycles to obtain CR, erythroblastic or megakaryocytic leukemia; >= CR2
    • All patients must be in CR as defined by hematologic recovery and < 5% blasts by morphology within the bone marrow and a cellularity of >= 15%
    • Patients in which adequate marrow/biopsy specimens can not be obtained to determine remission status by morphologic assessment, but have fulfilled criteria of remission by flow cytometry, recovery of peripheral blood counts with no circulating blasts, and/or normal cytogenetics (if applicable) may still be eligible; reasonable attempts must be made to obtain an adequate specimen for morphologic assessment, including possible repeat procedures; these patients must be discussed with the Principal Investigator, Colleen Delaney prior to enrollment
  • Acute lymphoblastic leukemia:

    • High risk CR1 [for example, but not limited to: t(9;22), t(1;19), t(4;11) or other mixed lineage leukemia (MLL) rearrangements, hypodiploid]
    • Greater than 1 cycle to obtain CR
    • >= CR2
    • All patients must be in CR as defined by hematologic recovery and < 5% blasts by morphology within the bone marrow and a cellularity of >= 15%
    • Patients in which adequate marrow/biopsy specimens can not be obtained to determine remission status by morphologic assessment, but have fulfilled criteria of remission by flow cytometry, recovery of peripheral blood counts with no circulating blasts, and/or normal cytogenetics (if applicable) may still be eligible; reasonable attempts must be made to obtain an adequate specimen for morphologic assessment, including possible repeat procedures; these patients must be discussed with the Principal Investigator, Colleen Delaney prior to enrollment
  • Chronic myelogenous leukemia excluding refractory blast crisis; to be eligible in first chronic phase (CP1) patient must have failed or be intolerant to imatinib mesylate
  • Myelodysplasia International Prognostic Scoring System (IPSS) intermediate 2 (Int-2) or High risk (i.e., refractory anemia with excess myeloblasts [RAEB], refractory anemia with excess blasts in transformation [RAEB-T]) or refractory anemia with severe pancytopenia or high risk cytogenetics; blasts must be < 10% by a representative bone marrow aspirate morphology
  • Karnofsky (>= 16 years old) >= 70%
  • Lansky (< 16 years old) >= 50%
  • Calculated creatinine clearance must be > 60 mL and serum creatinine =< 2 mg/dL (adults)
  • Calculated creatinine clearance must be > 60 mL/min (children < 18 years old)
  • Total serum bilirubin must be < 3mg/dl and transaminases must be < 3 x the upper limit of normal
  • Diffusion capacity of carbon monoxide (DLCO) corrected > 50% normal; for pediatric patients unable to perform pulmonary function tests, O2 saturation > 92% on room air
  • Left ventricular ejection fraction > 45% OR shortening fraction > 26%
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Uncontrolled viral or bacterial infection at the time of study enrollment
  • Active or recent (prior 6 month) invasive fungal infection without infectious disease (ID) consult and approval
  • History of human immunodeficiency virus (HIV) infection
  • Pregnant or breastfeeding
  • If =< 18 years old, prior myeloablative transplant within the last 6 months
  • If > 18 years old prior myeloablative allotransplant or autologous transplant
  • Extensive prior therapy including > 12 months alkylator therapy or > 6 months alkylator therapy with extensive radiation
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01175785

Locations
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: Colleen Delaney Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT01175785     History of Changes
Other Study ID Numbers: 2378.00, NCI-2010-01426, RC2HL101844
Study First Received: August 3, 2010
Last Updated: January 17, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Congenital Abnormalities
Anemia
Anemia, Refractory
Anemia, Refractory, with Excess of Blasts
Leukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myeloid, Accelerated Phase
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid, Chronic-Phase
Leukemia, Neutrophilic, Chronic
Myelodysplastic Syndromes
Preleukemia
Hypereosinophilic Syndrome
Hematologic Neoplasms
Hematologic Diseases
Bone Marrow Diseases
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Myeloproliferative Disorders
Precancerous Conditions
Eosinophilia
Leukocyte Disorders
Neoplasms by Site

ClinicalTrials.gov processed this record on August 21, 2014