Clinical Trials /

Umbilical Cord Blood Transplant, Cyclophosphamide, Fludarabine, and Total-Body Irradiation in Treating Patients With Hematologic Disease

NCT00719888

Description:

This phase II trial studies how well giving an umbilical cord blood transplant together with cyclophosphamide, fludarabine, and total-body irradiation (TBI) works in treating patients with hematologic disease. Giving chemotherapy, such as cyclophosphamide and fludarabine, and TBI before a donor umbilical cord blood transplant helps stop the growth of cancer and abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after transplant may stop this from happening.

Related Conditions:
  • Acute Biphenotypic Leukemia
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Anaplastic Large Cell Lymphoma
  • Burkitt Lymphoma
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
  • Chronic Myeloid Leukemia
  • Follicular Lymphoma
  • Lymphoblastic Lymphoma
  • Lymphoplasmacytic Lymphoma
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
  • Mixed Phenotype Acute Leukemia
  • Multiple Myeloma
  • Myelodysplastic Syndromes
  • Myelofibrosis
  • Non-Hodgkin Lymphoma
  • Prolymphocytic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Umbilical Cord Blood Transplant, Cyclophosphamide, Fludarabine Phosphate, and Total-Body Irradiation in Treating Patients With Hematologic Disease
  • Official Title: Transplantation of Umbilical Cord Blood for Patients With Hematological Diseases With Cyclophosphamide/Fludarabine/Total Body Irradiation Myeloablative Preparative Regimen

Clinical Trial IDs

  • ORG STUDY ID: 2010.00
  • SECONDARY ID: NCI-2010-00190
  • SECONDARY ID: FHCRC 2010.00
  • SECONDARY ID: Protocol 2010
  • SECONDARY ID: 2010
  • SECONDARY ID: 2010.00
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT00719888

Conditions

  • Acute Biphenotypic Leukemia
  • Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
  • Acute Myeloid Leukemia in Remission
  • Adult Acute Lymphoblastic Leukemia in Complete Remission
  • Aggressive Non-Hodgkin Lymphoma
  • Beta-2-Microglobulin Greater Than 3 g/mL
  • Blasts Under 5 Percent of Bone Marrow Nucleated Cells
  • Burkitt Lymphoma
  • Childhood Acute Lymphoblastic Leukemia in Complete Remission
  • Chromosome 13 Abnormality
  • Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Lymphoblastic Lymphoma
  • Mantle Cell Lymphoma
  • Myelodysplastic Syndrome With Excess Blasts
  • Myelofibrosis
  • Pancytopenia
  • Plasma Cell Myeloma
  • Prolymphocytic Leukemia
  • Recurrent Childhood Acute Myeloid Leukemia
  • Recurrent Chronic Lymphocytic Leukemia
  • Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Recurrent Follicular Lymphoma
  • Recurrent Lymphoplasmacytic Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Small Lymphocytic Lymphoma

Interventions

DrugSynonymsArms
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (myeloablative UCBT)
Cyclosporine27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Gengraf, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCyaTreatment (myeloablative UCBT)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Treatment (myeloablative UCBT)
Mycophenolate MofetilCellcept, MMFTreatment (myeloablative UCBT)

Purpose

This phase II trial studies how well giving an umbilical cord blood transplant together with cyclophosphamide, fludarabine phosphate, and total-body irradiation (TBI) works in treating patients with hematologic disease. Giving chemotherapy, such as cyclophosphamide and fludarabine phosphate, and TBI before a donor umbilical cord blood transplant helps stop the growth of cancer and abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after transplant may stop this from happening.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the one year survival of patients undergoing umbilical cord blood
      transplantation (UCBT) after a myeloablative preparative regimen consisting of
      cyclophosphamide (CY), fludarabine phosphate (fludarabine [FLU]), and fractionated total body
      irradiation (TBI).

      SECONDARY OBJECTIVES:

      I. Incidence of transplant-related mortality (TRM) at 6 months.

      II. Chimerism at multiple time points.

      III. Incidence of neutrophil engraftment at day 42.

      IV. Incidence of platelet engraftment 6 months.

      V. Incidence of acute graft-versus-host disease (GVHD) grade II-IV and grade III-IV at day
      100.

      VI. Incidence of chronic GVHD at day 100, 1 year and 2 years.

      VII. Incidence of clinically significant infections at 6 months, 1 year and 2 years.

      VIII. Incidence of disease free survival at 1 and 2 years.

      IX. Incidence of relapse at 1 and 2 years.

      OUTLINE:

      Patients receive myeloablative conditioning comprising fludarabine phosphate intravenously
      (IV) over 30 minutes on days -8 to -6, cyclophosphamide IV on days -7 and -6, and undergo TBI
      twice daily (BID) on days -4 to -1. Patients then undergo single- or double-unit UCBT on day
      0.

      Patients receive GVHD prophylaxis comprising cyclosporine IV over 1 hour every 8 or 12 hours,
      then cyclosporine orally (PO) (if tolerated), on days -3 to 100 with taper on day 101.
      Patients also receive mycophenolate mofetil IV every 8 hours on days 0 to 7 and then PO (if
      tolerated) three times daily (TID) on days 8-30. Mycophenolate mofetil is tapered to BID on
      day 30 or 7 days after engraftment if there is no acute GVHD, and then tapered over 2-3 weeks
      beginning on day 45 (or 15 days after engraftment if engraftment occurred > day 30) after
      engraftment if there continues to be no evidence of acute GVHD.

      After completion of study treatment, patients are followed up at 6 months, 1 year, and 2
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (myeloablative UCBT)ExperimentalPatients receive myeloablative conditioning comprising fludarabine phosphate IV over 30 minutes on days -8 to -6, cyclophosphamide IV on days -7 and -6, and undergo TBI BID on days -4 to -1. Patients then undergo single- or double-unit UCBT on day 0. Patients receive GVHD prophylaxis comprising cyclosporine IV over 1 hour every 8 or 12 hours, then cyclosporine PO (if tolerated), on days -3 to 100 with taper on day 101. Patients also receive mycophenolate mofetil IV every 8 hours on days 0 to 7 and then PO (if tolerated) TID on days 8-30. Mycophenolate mofetil is tapered to BID on day 30 or 7 days after engraftment if there is no acute GVHD, and then tapered over 2-3 weeks beginning on day 45 (or 15 days after engraftment if engraftment occurred > day 30) after engraftment if there continues to be no evidence of acute GVHD.
  • Cyclophosphamide
  • Cyclosporine
  • Fludarabine Phosphate
  • Mycophenolate Mofetil

Eligibility Criteria

        Inclusion Criteria:

          -  GRAFT CRITERIA:

               -  UCB units will be selected according to current umbilical cord blood graft
                  selection algorithm; one or 2 UCB units may be used to achieve the required cell
                  dose

               -  The UCB graft is matched at 4-6 human leukocyte antigen (HLA)-A, B, DRB1 antigens
                  with the recipient; this may include 0-2 antigen mismatches at the A or B or DRB1
                  loci; unit selection based on cryopreserved nucleated cell dose and HLA-A,B, DRB1
                  using intermediate resolution A, B antigen and DRB1 allele typing

               -  If 2 UCB units are required to reach the target cell dose, each unit must be a
                  4-6 antigen match to the recipient

          -  Acute myeloid leukemia, including biphenotypic acute leukemia or mixed-lineage
             leukemia:

               -  All patients must be in CR as defined by hematologic recovery and < 5% blasts by
                  morphology/flow cytometry in a representative bone marrow sample with cellularity
                  >= 15% for age; patients who do not have high-risk features (for example
                  preceding myelodysplastic syndrome [MDS], high-risk cytogenetics, >= 2 cycles to
                  obtain CR, erythroblastic or megakaryocytic leukemia or >= CR2) must be discussed
                  with the principal investigator (PI) prior to enrollment and at the Patient Care
                  Conference or equivalent group such as the pediatric leukemia board as an
                  alternative

               -  Patients in whom adequate marrow/biopsy specimens cannot 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 PI prior to enrollment; patients persistently aplastic for
                  greater than one month since completing last chemotherapy are also eligible with
                  PI approval

          -  Very high risk pediatric/young adult patients with acute myeloid leukemia (AML):
             Patients =< 25 years, however, are eligible with (M2 marrow) with =< 25% blasts in
             marrow after having failed one or more cycles of chemotherapy; this group of patients
             will be analyzed separately

          -  Acute lymphoblastic leukemia, including biphenotypic acute leukemia or mixed-lineage
             leukemia:

               -  All patients must be in CR as defined by < 5% blasts by morphology; flow
                  cytometry in a representative bone marrow sample with cellularity >= 15% for age;
                  patients who do not have high-risk disease (high risk CR1, greater than one cycle
                  to obtain CR or >= CR2) must be discussed with the PI prior to enrollment and at
                  the Patient Care Conference or equivalent group such as the pediatric leukemia
                  board as an alternative

               -  Patients in whom adequate marrow/biopsy specimens cannot 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 Ann Dahlberg prior to enrollment;
                  patients persistently aplastic for greater than one month since completing last
                  chemotherapy are also eligible with PI approval

          -  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

          -  Advanced myelofibrosis

          -  Myelodysplasia (MDS) International Prognostic Scoring System (IPSS) intermediate
             (Int)-2 or high risk (i.e., refractory anemia with excess blasts [RAEB], RAEB in
             transformation [RAEBt]) or refractory anemia with severe pancytopenia or high risk
             cytogenetics; blasts must be < 10% by a representative bone marrow aspirate morphology

          -  Lymphoblastic lymphoma, Burkitt's lymphoma, and other high-grade non-Hodgkin lymphoma
             (NHL) after initial therapy if stage III/IV in first partial response (PR1) or after
             progression if stage I/II < 1 year; stage III/IV patients are eligible after
             progression in CR/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 primary care center (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/> second partial response (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

          -  Performance status score: Karnofsky (for adults) >= 70% or Eastern Cooperative
             Oncology Group (ECOG) 0-1 or Lansky (for children) >= 50%

          -  Creatinine < 2.0 mg/dL (for adults) or creatinine clearance > 60 ml/min (for children)

          -  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

          -  Diffusion capacity for carbon monoxide corrected (DLCOcorr) > 50% normal or a
             pediatric patient who is unable to perform pulmonary function tests (PFTs) but has
             adequate pulmonary function

          -  Left ventricular ejection fraction > 45% or shortening fraction > 26%

        Exclusion Criteria:

          -  Uncontrolled viral or bacterial infection at the time of study enrollment

          -  Active or recent (prior 6 month) invasive fungal infection without interdisciplinary
             (ID) consult and approval

          -  History of human immunodeficiency virus (HIV) infection

          -  Pregnant or breastfeeding

          -  Chemotherapy refractory large cell and high grade NHL (i.e., progressive disease after
             > 2 salvage regimens)

          -  Prior myeloablative transplant containing full dose TBI (greater than 8 Gray [Gy])

          -  Any prior myeloablative transplant within the last 6 months

          -  Patients who have received Y-90 ibritumomab (Zevalin) or I-131 tositumomab (Bexxar),
             as part of their salvage therapy are not eligible for myeloablative umbilical cord
             blood transplant
      
Maximum Eligible Age:45 Years
Minimum Eligible Age:6 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival
Time Frame:1 year
Safety Issue:
Description:A non-statistical comparison with historical controls will be made. Monitoring will take place separately for the single and double umbilical cord blood transplantation (UCBT) cohorts.

Secondary Outcome Measures

Measure:Incidence of transplant-related mortality
Time Frame:At 6 months
Safety Issue:
Description:Monitoring will take place separately for the single and double UCBT cohorts.
Measure:Chimerism analysis
Time Frame:Assessed up to 2 years
Safety Issue:
Description:Monitoring will take place separately for the single and double UCBT cohorts. Chimerism studies from peripheral blood and bone marrow samples will be sorted for CD3, CD14, CD33, and CD56 cells.
Measure:Incidence of neutrophil engraftment
Time Frame:At day 42
Safety Issue:
Description:Monitoring will take place separately for the single and double UCBT cohorts.
Measure:Incidence of platelet recovery
Time Frame:At 6 months
Safety Issue:
Description:Monitoring will take place separately for the single and double UCBT cohorts.
Measure:Incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD)
Time Frame:At day 100
Safety Issue:
Description:Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level. Monitoring will take place separately for the single and double UCBT cohorts.
Measure:Incidence of chronic GVHD
Time Frame:Up to 2 years
Safety Issue:
Description:Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level.
Measure:Incidence of clinically significant infections
Time Frame:Up to 2 years
Safety Issue:
Description:Monitoring will take place separately for the single and double UCBT cohorts.
Measure:Incidence of relapse
Time Frame:Up to 2 years
Safety Issue:
Description:Cumulative incidence estimates will be used to summarize the time-to-event outcomes.
Measure:Progression-free survival
Time Frame:Up to 2 years
Safety Issue:
Description:A non-statistical comparison with historical controls will be made. Cumulative incidence estimates will be used to summarize the time-to-event outcomes. Monitoring will take place separately for the single and double UCBT cohorts.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

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