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 Erythroid Leukemia
  • Acute Lymphoblastic Leukemia
  • Acute Megakaryoblastic Leukemia
  • Acute Myeloid Leukemia
  • Acute Myeloid Leukemia Arising from Previous Myelodysplastic Syndrome
  • 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
  • Refractory Anemia
  • Refractory Anemia with Excess Blasts
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Umbilical Cord Blood Transplant, Cyclophosphamide, Fludarabine, 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 or Cyclophosphamide/Fludarabine/Thiotepa/Total Body Irradiation Myeloablative Preparative Regimen

Clinical Trial IDs

  • ORG STUDY ID: 2010.00
  • SECONDARY ID: NCI-2010-00190
  • SECONDARY ID: 2010
  • SECONDARY ID: P30CA015704
  • SECONDARY ID: RG2807002
  • NCT ID: NCT00719888

Conditions

  • Acute Biphenotypic Leukemia
  • Acute Myeloid Leukemia in Remission
  • Ann Arbor Stage I Burkitt Lymphoma
  • Ann Arbor Stage I Non-Hodgkin Lymphoma
  • Ann Arbor Stage II Burkitt Lymphoma
  • Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Lymphoblastic Lymphoma
  • Mantle Cell Lymphoma
  • Myelodysplastic Syndrome
  • Myelofibrosis
  • Plasma Cell Myeloma
  • Prolymphocytic 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
  • Ann Arbor Stage II Non-Hodgkin Lymphoma
  • Ann Arbor Stage III Burkitt Lymphoma
  • Ann Arbor Stage III Non-Hodgkin Lymphoma
  • Ann Arbor Stage IV Burkitt Lymphoma
  • Ann Arbor Stage IV Non-Hodgkin Lymphoma
  • High Risk Acute Myeloid Leukemia
  • Refractory Anemia
  • Hematopoietic and Lymphoid Cell Neoplasm

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- 138719Arm II (myeloablative UCBT)
Cyclosporine27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Gengraf, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCyaArm II (myeloablative UCBT)
Fludarabine118218, FluorovidarabineArm II (myeloablative UCBT)
Mycophenolate MofetilCellcept, MMFArm II (myeloablative UCBT)
Thiotepa1,1',1"-phosphinothioylidynetrisaziridine, 1,1',1''-Phosphinothioyldynetrisaziridine, 52-24-4, 6396, Girostan, TriethylenethiophosphoramideArm II (myeloablative UCBT)

Purpose

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.

Detailed Description

      OUTLINE: Patients are assigned to 1 of 2 arms.

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

      ARM II: Patients receive myeloablative conditioning comprising fludarabine IV over 30-60
      minutes on days -6 to -2, cyclophosphamide IV on day -6, thiotepa IV over 2-4 hours on days
      -5 and -4, and middle-intensity TBI once daily (QD) on days -2 and -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 IV over 30 minutes on days -8 to -6, cyclophosphamide IV on days -7 and -6, and undergo high-dose 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
  • Mycophenolate Mofetil
Arm II (myeloablative UCBT)ExperimentalPatients receive myeloablative conditioning comprising fludarabine IV over 30-60 minutes on days -6 to -2, cyclophosphamide IV on day -6, thiotepa IV over 2-4 hours on days -5 and -4, and middle-intensity TBI QD on days -2 and -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
  • Mycophenolate Mofetil
  • Thiotepa

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

          -  Age and Disease Criteria:

               -  High-dose TBI regimen: 6 months to =< 45 years

               -  Middle-intensity TBI regimen: 6 months to =< 65 years

               -  Conditioning regimen selection should be based on the underlying disease,
                  presence of minimum residual disease (MRD), age, co-morbidities, and attending
                  physician

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

               -  All patients must be in complete remission (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)

          -  Patients with history of prior myeloablative transplant containing full dose TBI
             (greater than 8 gray [Gy]) will not be eligible for Regimen A; however, they may still
             enroll on Regimen B if they otherwise meet inclusion and exclusion criteria

          -  Any prior myeloablative transplant within the last 6 months

          -  Patients >= 45 years: comorbidity score of 5 or higher

          -  Patients who have received Y-90 ibritumomab (Zevalin) or I-131 tostumomab (Bexxar), as
             part of their salvage therapy are not eligible for Regimen A
      
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:Change in level of chimerism at multiple time points
Time Frame:Baseline up to 2 years
Safety Issue:
Description:Cumulative incidence estimates will be used.
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: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.
Measure:Single unit umbilical cord blood (UCB) transplants with historical controls
Time Frame:Up to 2 years
Safety Issue:
Description:Single unit UCB transplants with historical controls will be compared.
Measure:Single unit UCB transplants with double unit UCB transplants
Time Frame:Up to 2 years
Safety Issue:
Description:Single unit UCB transplants with double unit UCB transplants will be compared.

Details

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

Last Updated

August 26, 2020