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A Pilot Study to Evaluate the Co-Infusion of Ex Vivo Expanded Cord Blood Cells With an Unmanipulated Cord Blood Unit in Patients Undergoing Cord Blood Transplant for Hematologic Malignancies

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Damon Runyon Cancer Research Foundation
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT00343798
First received: June 22, 2006
Last updated: June 27, 2014
Last verified: June 2014
  Purpose

This phase I multicenter feasibility trial is studying the safety and potential efficacy of infusing ex vivo expanded cord blood progenitors with one unmanipulated umbilical cord blood unit for transplantation following conditioning with fludarabine, cyclophosphamide and total body irradiation (TBI), and immunosuppression with cyclosporine and mycophenolate mofetil (MMF) for patients with hematologic malignancies. Chemotherapy, such as fludarabine and cyclophosphamide, and TBI 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 are more likely to recover more quickly if increased numbers of 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 unexpanded cord blood unit 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 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
Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome
Adult Acute Lymphoblastic Leukemia in Remission
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)
Adult Nasal Type Extranodal NK/T-cell Lymphoma
Anaplastic Large Cell Lymphoma
Childhood Acute Lymphoblastic Leukemia in Remission
Childhood Acute Myeloid Leukemia in Remission
Childhood Burkitt Lymphoma
Childhood Chronic Myelogenous Leukemia
Childhood Diffuse Large Cell Lymphoma
Childhood Immunoblastic Large Cell Lymphoma
Childhood Myelodysplastic Syndromes
Childhood Nasal Type Extranodal NK/T-cell Lymphoma
Chronic Phase Chronic Myelogenous Leukemia
Contiguous Stage II Adult Burkitt Lymphoma
Contiguous Stage II Adult Diffuse Large Cell Lymphoma
Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma
Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma
Contiguous Stage II Adult Lymphoblastic Lymphoma
Contiguous Stage II Grade 3 Follicular Lymphoma
Contiguous Stage II Mantle Cell Lymphoma
de Novo Myelodysplastic Syndromes
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
Nodal Marginal Zone B-cell Lymphoma
Noncontiguous Stage II Adult Burkitt Lymphoma
Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma
Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma
Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma
Noncontiguous Stage II Adult Lymphoblastic Lymphoma
Noncontiguous Stage II Grade 3 Follicular Lymphoma
Noncontiguous Stage II Mantle Cell Lymphoma
Previously Treated Myelodysplastic Syndromes
Prolymphocytic Leukemia
Recurrent Adult Burkitt Lymphoma
Recurrent Adult Diffuse Large Cell Lymphoma
Recurrent Adult Diffuse Mixed Cell Lymphoma
Recurrent Adult Grade III Lymphomatoid Granulomatosis
Recurrent Adult Immunoblastic Large Cell Lymphoma
Recurrent Adult Lymphoblastic Lymphoma
Recurrent Childhood Anaplastic Large Cell Lymphoma
Recurrent Childhood Grade III Lymphomatoid Granulomatosis
Recurrent Childhood Large Cell Lymphoma
Recurrent Childhood Lymphoblastic Lymphoma
Recurrent Grade 1 Follicular Lymphoma
Recurrent Grade 2 Follicular Lymphoma
Recurrent Grade 3 Follicular Lymphoma
Recurrent Mantle Cell Lymphoma
Recurrent Marginal Zone Lymphoma
Recurrent Small Lymphocytic Lymphoma
Refractory Anemia
Refractory Anemia With Excess Blasts
Refractory Anemia With Excess Blasts in Transformation
Refractory Chronic Lymphocytic Leukemia
Refractory Multiple Myeloma
Secondary Acute Myeloid Leukemia
Secondary Myelodysplastic Syndromes
Splenic Marginal Zone Lymphoma
Stage I Adult Burkitt Lymphoma
Stage I Adult Diffuse Large Cell Lymphoma
Stage I Adult Diffuse Mixed Cell Lymphoma
Stage I Adult Immunoblastic Large Cell Lymphoma
Stage I Adult Lymphoblastic Lymphoma
Stage I Childhood Lymphoblastic Lymphoma
Stage I Grade 3 Follicular Lymphoma
Stage I Mantle Cell Lymphoma
Stage II Childhood Lymphoblastic Lymphoma
Stage III Adult Burkitt Lymphoma
Stage III Adult Diffuse Large Cell Lymphoma
Stage III Adult Diffuse Mixed Cell Lymphoma
Stage III Adult Immunoblastic Large Cell Lymphoma
Stage III Adult Lymphoblastic Lymphoma
Stage III Childhood Lymphoblastic Lymphoma
Stage III Grade 3 Follicular Lymphoma
Stage III Mantle Cell Lymphoma
Stage IV Adult Burkitt Lymphoma
Stage IV Adult Diffuse Large Cell Lymphoma
Stage IV Adult Diffuse Mixed Cell Lymphoma
Stage IV Adult Immunoblastic Large Cell Lymphoma
Stage IV Adult Lymphoblastic Lymphoma
Stage IV Childhood Lymphoblastic Lymphoma
Stage IV Grade 3 Follicular Lymphoma
Stage IV Mantle Cell Lymphoma
Drug: cyclophosphamide
Drug: fludarabine phosphate
Drug: cyclosporine
Drug: mycophenolate mofetil
Other: ex-vivo umbilical cord blood expansion
Procedure: double-unit umbilical cord blood transplantation
Procedure: biopsy
Other: immunologic technique
Other: diagnostic laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Study to Evaluate the Co-infusion of Ex Vivo Expanded Umbilical Cord Blood Progenitors With an Unmanipulated Cord Blood Graft in Patients Undergoing Umbilical Cord Blood Transplantation for Hematologic Malignancies

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Severe (grades 3 and 4) acute GVHD [ Time Frame: Up to day 100 ] [ Designated as safety issue: Yes ]
  • Grade greater than or equal to 3 infusional toxicity [ Time Frame: Day 0 ] [ Designated as safety issue: Yes ]
  • Graft failure as defined by failure to achieve ANC greater than or equal to 500/mm^3 of donor origin [ Time Frame: By day +42 ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 25
Study Start Date: April 2006
Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (umbilical cord blood transplant)

MYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 1 hour on days -8 to -6 and cyclophosphamide IV on days -7 and -6. Patients undergo TBI BID on days -4 to -1.

TRANSPLANTATION : Patients undergo double-unit umbilical cord blood transplantation comprising unmanipulated umbilical cord blood unit IV over 20-30 minutes, and 4-6 hours later patients receive ex vivo-expanded umbilical cord blood cells IV over 30 minutes on day 0.

GRAFT-VERSUS-HOST-DISEASE PROPHYLAXIS: Patients receive cyclosporine IV every 8 or 12 hours on days -3 to 100, followed by a taper to at least day 180. Patients also receive MMF IV every 8 hours on days -3 to 5 and then PO, if tolerated, on days 6-30.

Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: cyclosporine
Given IV
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Drug: mycophenolate mofetil
Given IV or PO
Other Names:
  • Cellcept
  • MMF
Other: ex-vivo umbilical cord blood expansion
Undergo double-unit umbilical cord blood transplantation
Procedure: double-unit umbilical cord blood transplantation
Undergo double-unit umbilical cord blood transplantation
Procedure: biopsy
Optional correlative studies
Other Name: biopsies
Other: immunologic technique
Correlative studies
Other Names:
  • immunological laboratory methods
  • laboratory methods, immunological
Other: diagnostic laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. Examine the safety and toxicity when ex vivo expanded cord blood cells are co-infused with a second non-human leukocyte antigen (HLA)-identical cord blood graft following myeloablative therapy in patients with hematologic malignancies.

II. Examine the in vivo persistence of the ex vivo expanded cord blood cells. The kinetics and durability of hematopoietic reconstitution (time to engraftment defined as the first of 2 consecutive days in which the absolute neutrophil count [ANC] > 500) will be determined and the relative contribution to engraftment of the expanded cord blood cells and the unmanipulated cord blood cells in early and long-term engraftment will be determined by donor chimerisms.

SECONDARY OBJECTIVES:

I. Estimate the incidence and severity of acute and chronic graft-versus-host disease (GVHD) in patients receiving Notch-expanded 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 phenotype and function of immune cells recovering in patients receiving expanded and unmanipulated cord blood grafts.

V. Obtain feasibility data on overnight shipment of ex vivo expanded progenitor cells for infusion in patients are distant sites.

OUTLINE:

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

TRANSPLANTATION : On Day 0, patients undergo double-unit umbilical cord blood transplantation which includes the infusion of one unmanipulated (not expanded) cord blood unit followed 4 hours later by infusion of one ex vivo-expanded cord blood unit.

GRAFT-VERSUS-HOST-DISEASE PROPHYLAXIS: Patients initially receive cyclosporine IV beginning on day -3. Cyclosporine may be given orally when the patient can tolerate oral medications and has a normal gastrointestinal transit time. Cyclosporine is given until day 100, and may taper on day 101 if there is no graft versus host disease. Patients also receive MMF IV on days -3 to 5 and then may receive oral MMF beginning day 6 to 30. MMF is stopped at Day 30 or 7 days after engraftment, whichever day is later, if no acute GVHD.

After completion of study treatment, patients are followed up periodically for 2 years.

  Eligibility

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

Inclusion Criteria:

  • Patient has no existing 0-1 HLA-A, B, C, DRB1 and DQB1 matched related donor
  • Acute Myeloid Leukemia:

    • High risk first complete remission (CR1) as evidenced by preceding myelodysplastic syndromes (MDS), high risk cytogenetics (for example, monosomy 5 or 7, or HR as defined by referring institution treatment protocol), >= 2 cycles to obtain complete remission (CR), erythroblastic or megakaryocytic leukemia; >= second complete remission (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 cannot be obtained to determine remission status by morphologic assessment, but have fulfilled criteria of remission by flow cytometry (< 5% blasts) and, recovery of peripheral blood counts with no circulating blasts, may still be eligible; reasonable attempts must be made to obtain an adequate specimen for morphologic assessment, including possible repeat procedures
  • 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);
    • > 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 (< 5% blasts) and, recovery of peripheral blood counts with no circulating blasts, may still be eligible; reasonable attempts must be made to obtain an adequate specimen for morphologic assessment, including possible repeat procedures
  • Chronic Myelogenous Leukemia:

    • Patients in blast crisis (BC) must receive therapy and must achieve accelerated phase (AP)/chronic phase (CP) in order to be eligible (patients who remain in BC are not eligible);
    • If in first chronic phase, patient must have failed or be intolerant to imatinib mesylate
  • Myelodysplasia (MDS):

    • International Prognostic Scoring System (IPSS) Int-2 or high risk (Refractory anemia with excess blasts [RAEB], refractory anemia with excess blasts in transformation [RAEBt]) or refractory anemia with severe pancytopenia or high risk cytogenetics;
    • Blasts must be < 10% morphologically in representative bone marrow aspirate (obtained < 2 weeks from enrollment)
  • Lymphoblastic lymphoma, Burkitt's lymphoma, and other high-grade non-Hodgkin lymphoma (NHL) after initial therapy if stage III/IV in first partial remission (PR1) or after progression if stage I/II < 1 year; Stage III/IV patients are eligible after progression in complete response (CR)/partial response (PR)
  • Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma or follicular lymphoma that have progressed after at least two different prior therapies; patients with bulky disease (nodal mass greater than 5 cm) should be considered for debulking chemotherapy before transplant (these patients must be presented at Patient Care Conference [PCC] prior to enrollment given potential competing eligibility on autotransplant protocols)
  • Mantle-cell lymphoma, prolymphocytic leukemia: Eligible after initial therapy in >= CR1 or >= PR1
  • Large cell NHL > CR2/ > PR2:

    • Patients in CR2/PR2 with initial short remission (< 6 months) are eligible;
    • These patients must be presented at PCC prior to enrollment given potential competing eligibility on autotransplant protocols
  • Multiple myeloma beyond PR2: Patients with chromosome 13 abnormalities, first response lasting less than 6 months, or beta-2 microglobulin > 3 mg/L, may be considered for this protocol after initial therapy
  • Serum creatinine =< 2.0 mg/dL (adults) and creatinine clearance > 60 ml/min (pediatrics)
  • Patients with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function, histology, and the degree of portal hypertension; patients with fulminant liver failure, cirrhosis with evidence of portal hypertension or bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, or correctable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL and symptomatic biliary disease will be excluded
  • Diffusing capacity of the lung for carbon monoxide corrected (DLCOcorr) > 50% normal
  • Left ventricular ejection fraction >= 45% or shortening fraction > 26%
  • Karnofsky score >= 70% (adults) or Lansky score >= 50% (pediatrics)

Exclusion Criteria:

  • Acute leukemia in relapse (>= 5% marrow blasts by morphology)
  • Active central nervous system (CNS) leukemia involvement at the time of study enrollment (cerebrospinal fluid with > 5 white blood cells (WBC)/mm^3 AND malignant cells on cytospin)
  • Chemotherapy refractory large cell lymphoma and high grade NHL (progressive disease after > 2 salvage regimens)
  • Female patients who are pregnant or breastfeeding
  • Karnofsky performance status < 70% (adults) or Lanksy score < 50% (pediatrics)
  • Prior autologous or allogeneic stem cell transplant with myeloablative preparative regimen (If =< 18 years old, prior myeloablative transplant within the last 6 months)
  • Uncontrolled viral, or bacterial infection at the time of study enrollment
  • Active or recent (prior 6 months) invasive fungal infection without ID consult and approval
  • Seropositive for human immunodeficiency virus (HIV)
  • Consenting 5 of 6 or 6 of 6 HLA-matched related donor available
  • Unable to provide informed consent
  • Use of any other experimental drug within 28 days of baseline
  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: NCT00343798

Locations
United States, California
City of Hope Medical Center
Duarte, California, United States, 91010
United States, Colorado
University of Colorado Cancer Center - Anschutz Cancer Pavilion
Aurora, Colorado, United States, 80045
University of Colorado
Denver, Colorado, United States, 80217-3364
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
Damon Runyon Cancer Research Foundation
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: NCT00343798     History of Changes
Other Study ID Numbers: 2044.00, NCI-2010-00236, R43HL106868, R24HL074445, RC2HL101844
Study First Received: June 22, 2006
Last Updated: June 27, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Anemia
Anemia, Refractory
Anemia, Refractory, with Excess of Blasts
Burkitt Lymphoma
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid
Leukemia, Myeloid, Accelerated Phase
Leukemia, Myeloid, Acute
Leukemia, Myeloid, Chronic-Phase
Leukemia, Prolymphocytic
Lymphoma
Lymphoma, B-Cell
Lymphoma, B-Cell, Marginal Zone
Lymphoma, Extranodal NK-T-Cell
Lymphoma, Follicular
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Large-Cell, Anaplastic
Lymphoma, Large-Cell, Immunoblastic
Lymphoma, Mantle-Cell
Lymphoma, Non-Hodgkin
Lymphoma, T-Cell
Lymphomatoid Granulomatosis
Multiple Myeloma
Myelodysplastic Syndromes
Neoplasm Metastasis
Neoplasms, Plasma Cell
Precursor Cell Lymphoblastic Leukemia-Lymphoma

ClinicalTrials.gov processed this record on November 27, 2014