Clinical Trials /

Donor Umbilical Cord Blood Transplant in Treating Patients With Hematologic Cancer

NCT00723099

Description:

This phase II trial is studying how well umbilical cord blood transplant from a donor works in treating patients with hematological cancer. Giving chemotherapy and total-body irradiation (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 an unrelated donor, that do not exactly match the patient's blood, 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 (called graft-versus-host disease). Giving cyclosporine and mycophenolate mofetil before and after transplant may stop this from happening.

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

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Donor Umbilical Cord Blood Transplant in Treating Patients With Hematologic Cancer
  • Official Title: Transplantation of Umbilical Cord Blood in Patients With Hematological Malignancies Using a Reduced-Intensity Preparative Regimen (A Multi-Center Trial Coordinated by the FHCRC)

Clinical Trial IDs

  • ORG STUDY ID: 2239.00
  • SECONDARY ID: NCI-2009-01551
  • SECONDARY ID: 2239
  • SECONDARY ID: 2239.00
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT00723099

Conditions

  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Aggressive Non-Hodgkin Lymphoma
  • Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Indolent Non-Hodgkin Lymphoma
  • Lymphoma
  • Mixed Phenotype Acute Leukemia
  • Myelodysplastic Syndrome
  • Myeloproliferative Neoplasm
  • Recurrent Chronic Lymphocytic Leukemia
  • Recurrent Follicular Lymphoma
  • Recurrent Lymphoplasmacytic Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Plasma Cell Myeloma
  • Recurrent Small Lymphocytic Lymphoma
  • Recurrent T-Cell Non-Hodgkin Lymphoma
  • Refractory Chronic Lymphocytic Leukemia
  • Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Refractory Follicular Lymphoma
  • Refractory Hodgkin Lymphoma
  • Refractory Lymphoplasmacytic Lymphoma
  • Refractory Mantle Cell Lymphoma
  • Refractory Small Lymphocytic Lymphoma
  • T-Cell Non-Hodgkin 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 (chemotherapy, transplant)
Cyclosporine27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Gengraf, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCyaTreatment (chemotherapy, transplant)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Treatment (chemotherapy, transplant)
Mycophenolate MofetilCellcept, MMFTreatment (chemotherapy, transplant)

Purpose

This phase II trial is studying how well umbilical cord blood transplant from a donor works in treating patients with hematological cancer. Giving chemotherapy and total-body irradiation (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 an unrelated donor, that do not exactly match the patient's blood, 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 (called graft-versus-host disease). Giving cyclosporine and mycophenolate mofetil before and after transplant may stop this from happening.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Estimate probability of one year survival.

      II. Demonstrate equivalent or improved engraftment rates with a non-anti-thymocyte globulin
      (ATG) based conditioning regimen. Patients will be considered graft failure/rejections
      provided they meet any of the criteria listed below:

        -  Absence of 3 consecutive days with neutrophils >= 500/ul combined with host cluster of
           differentiation (CD)3 peripheral blood chimerism >= 50% at day 42

        -  Absence of 3 consecutive days with neutrophils >= 500/ul under any circumstances at day
           55

        -  Death after day 28 with neutrophil count < 100/ul without any evidence of engraftment (<
           5% donor CD3)

        -  Primary autologous count recovery with < 5% donor CD3 peripheral blood chimerism at
           count recovery and without relapse

      SECONDARY OBJECTIVES:

      I. Six month non-relapse mortality.

      II. Overall incidence of graft failure/rejection. Patients will be considered graft
      failure/rejections provided they meet any of the criteria listed below:

        -  Absence of 3 consecutive days with neutrophils >= 500/ul combined with host CD3
           peripheral blood chimerism >= 50% at day 42

        -  Absence of 3 consecutive days with neutrophils >= 500/ul under any circumstances at day
           55

        -  Death after day 28 with neutrophil count < 100/ul without any evidence of engraftment (<
           5% donor CD3)

        -  Primary autologous count recovery with < 5% donor CD3 peripheral blood chimerism at
           count recovery and without relapse

      III. Kinetics of chimeric reconstitution.

      IV. Incidence of neutrophil engraftment by day 42.

      V. Incidence of platelet engraftment by six months.

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

      VII. Incidence of one year chronic GvHD.

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

      IX. Probability of one and two year survival.

      X. Incidence of one and two year relapse or disease progression.

      XI. Fred Hutchinson Cancer Research Center (FHCRC) patients: Kinetics of immune
      reconstitution, with both functional and quantitative assays.

      XII. FHCRC patients: Examination of possible immunologic factors leading to emergence of a
      dominant unit.

      OUTLINE:

      CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 1 hour
      on days -6 to -2 and cyclophosphamide IV over 1-2 hours on day -6. Patients undergo a lower
      dose of total-body irradiation (TBI) on day -1.

      UMBILICAL CORD BLOOD TRANSPLANT: Patients undergo donor umbilical cord blood infusion on day
      0.

      IMMUNOSUPRESSIVE THERAPIES: Patients receive cyclosporine IV over 1 hour every 8-12 hours on
      days -3 to +180 and mycophenolate mofetil IV or orally (PO) every 8 hours on days 0 to +96.

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

Trial Arms

NameTypeDescriptionInterventions
Treatment (chemotherapy, transplant)ExperimentalCONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 1-2 hours on day -6. Patients undergo a lower dose of TBI on day -1. UMBILICAL CORD BLOOD TRANSPLANT: Patients undergo donor umbilical cord blood infusion on day 0. IMMUNOSUPRESSIVE THERAPIES: Patients receive cyclosporine IV over 1 hour every 8-12 hours on days 0 to +180 and mycophenolate mofetil IV or PO every 8 hours on days -3 to +96.
  • Cyclophosphamide
  • Cyclosporine
  • Fludarabine Phosphate
  • Mycophenolate Mofetil

Eligibility Criteria

        Inclusion Criteria:

          -  Patients > 70 may be considered if performance status > 80% or Eastern Cooperative
             Oncology Group (ECOG) =< 1 and comorbidity score < 3; these patients must be discussed
             with the principal investigator (PI), Rachel Salit prior to enrollment

          -  Adequate cardiac function defined as absence of decompensated congestive heart
             failure, or uncontrolled arrhythmia and:

               -  Left ventricular ejection fraction >= 35% or

               -  Fractional shortening > 22%

          -  Adequate pulmonary function defined as diffusion capacity of carbon monoxide (DLCO) >
             30% predicted, and absence of oxygen (O2) requirements

          -  Adequate hepatic function; 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

          -  Adequate renal function defined as creatinine =< 2.0 mg/dl (adults) or creatinine
             clearance > 40 ml/min (pediatrics)

          -  All adults with a creatinine > 1.2 or a history of renal dysfunction must have
             estimated creatinine clearance > 40 ml/min

          -  Performance status score: Karnofsky (for adults) >= 60 or ECOG 0-2; Lansky (for
             children) score >= 50

          -  If recent mold infection, e.g., Aspergillus, must be cleared by infectious disease

          -  Second hematopoietic cell transplant: Must be >= 3 months after prior myeloablative
             transplant

          -  Patients who have received < 2 cycles of multiagent chemotherapy and patients who have
             received no multiagent chemotherapy within the 3 months previous to umbilical cord
             blood transplant (UCBT) as well as patients experiencing graft failure following
             previous allogeneic transplant

          -  Acute myeloid leukemia/acute lymphoblastic leukemia, including biphenotypic acute
             leukemia or mixed-lineage leukemia: Must have < 5% morphologic marrow blasts in an
             evaluable marrow (> 25% of normal cellularity for age) collected less than one month
             prior to start of conditioning; patients persistently aplastic for greater than one
             month since completing last chemotherapy are also eligible with the approval of the PI
             or designee

          -  Chronic myelogenous leukemia: All types, except refractory blast crisis; chronic phase
             patients must have failed or been intolerant to Gleevec or other tyrosine kinase
             inhibitors; at time of transplant, patients must have < 5% blasts in an evaluable
             marrow (> 25% of normal cellularity for age) by morphology within the bone marrow

          -  Myelodysplastic syndrome (MDS): Any subtype; morphologic blasts must be less than 5%
             in an evaluable marrow (> 25% of normal cellularity for age); if blasts are 5% or
             more, patient requires induction chemotherapy pre-transplant to reduce blast count to
             less than 5%; patients who have a hypocellular marrow in the absence of excess blasts
             that is related to the underlying disease or as a result of treatment for MDS may also
             be eligible with the approval of the PI or designee

          -  Large-cell lymphoma and aggressive T-cell lymphoma: With chemotherapy sensitive
             disease that has failed autologous transplant or patients who are ineligible for an
             autologous transplant; chemotherapy sensitive disease is defined as >= 50% reduction
             in the size of the tumor with the chemotherapy regimen immediately preceding
             transplant

          -  Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): Must be refractory
             to fludarabine (fludarabine phosphate) or fail to have a complete or partial response
             after therapy with a regimen containing fludarabine (or another nucleoside analog,
             e.g. cladribine [2-CDA], pentostatin) or experience disease relapse within 12 months
             after completing therapy with a regimen containing fludarabine (or another nucleoside
             analog)

          -  Hodgkin disease: Must have received and failed frontline therapy

          -  Follicular lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma,
             mantle-cell lymphoma, and indolent T-cell lymphomas: Must have progressed with the
             most recent remission duration being < 6 months; patients with bulky disease should be
             considered for debulking chemotherapy before transplant; patients with refractory
             disease are eligible, unless they have bulky disease and an estimated tumor doubling
             time of less than one month

          -  Multiple myeloma: Must have received prior chemotherapy; consolidation of chemotherapy
             by autografting prior to nonmyeloablative hematopoietic cell transplant (HCT) is
             permitted

          -  Myeloproliferative syndromes

          -  DONOR: Cord blood (CB) donor selection will be based on institutional guidelines and
             in general should be selected to optimize both human leukocyte antigen (HLA) match and
             cell dose; additionally, CB grafts shall consist of one or two CB donors based on, but
             not exclusively determined by, cell dose (total nucleated cell [TNC]/kg and CD34/kg),
             HLA matching and disease status and indication for transplant; attending preference
             will be allowed for single versus double unit as well as the degree of mismatching
             based on patient specific factors, as long as the following minimum criteria are met:

               -  HLA matching

                    -  Minimum requirement: The CB graft(s) must be matched at a minimum at 4/6
                       HLA-A, B, DRB1 loci with the recipient. Therefore 0-2 mismatches at the A or
                       B or DRB1 loci based on intermediate resolution A, B antigen and DRB1 allele
                       typing for determination of HLA-match is allowed

                    -  HLA-matching determined by high-resolution typing is allowed per
                       institutional guidelines as long as the minimum criteria are met

               -  Selection of two CB units is mandatory when a single cord blood unit does not
                  meet the following criteria:

                    -  Match grade 6/6; TNC Dose >= 2.5 x 10^7/kg

                    -  Match grade 5/6 or 4/6; TNC dose >= 4.0 (+/- 0.5) x 10^7/kg

               -  If two CB units are used, the total cell dose of the combined units must be at
                  least 3.0 x 10^7 TNC per kilogram recipient weight based on pre-cryopreservation
                  numbers, with each CB unit containing a MINIMUM of 1.5 x 10^7 TNC/kg

               -  The minimum recommended CD34/kg cell dose should be 2 x 10^5 CD34/kg, total dose
                  from a single or combined double

               -  The unmanipulated CB unit(s) will be Food and Drug Administration (FDA) licensed
                  or will be obtained under a separate investigational new drug (IND), such as the
                  National Marrow Donor Program (NMDP) Protocol 10-CBA conducted under BB IND-7555
                  or another IND sponsored by (1) a participating institution or (2) an
                  investigator at FHCRC or one of the participating institutions

               -  FHCRC only: Up to 5% of cord blood product, when ready for infusion, may be
                  withheld for research purposes as long as thresholds for infused TNC dose are
                  met; threshold for double unit transplantation is >= 3.0 x 10^7/kg; these
                  products will be used to conduct studies involving the immunobiology of double
                  cord transplantation and kinetics of engraftment

        Exclusion Criteria:

          -  Patients with an available 5-6/6 HLA-A, B, DRB1 matched sibling donor

          -  Pregnancy or breastfeeding

          -  Evidence of human immunodeficiency virus (HIV) infection or known HIV positive
             serology

          -  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

          -  Active central nervous system malignancy

          -  Patients who have received >= 2 cycles of multiagent chemotherapy within the 3 months
             previous to UCBT; patients who have had previous autologous transplant within 12
             months of UCBT are excluded regardless of history of recent treatment

          -  DONOR: Any cord blood units with < 1.5 x 10^7 total nucleated cells per kilogram
             recipient weight

          -  DONOR: Any cord blood units without the full maternal testing and negative results for
             hepatitis A, B, C, HIV, and human T-lymphotropic virus (HTLV-1) viruses; any
             additional available virology results on the unit itself will be reviewed but are not
             mandated, complete or always available; cord blood units are presumed to be
             cytomegalovirus (CMV) negative regardless of serologic testing due to passive
             transmission of maternal CMV antibodies
      
Maximum Eligible Age:69 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival
Time Frame:At 1 year
Safety Issue:
Description:Kaplan-Meier and cumulative incidence estimates will be used.

Secondary Outcome Measures

Measure:Incidence of chronic GVHD for each arm
Time Frame:At 1 year
Safety Issue:
Description:Kaplan-Meier and cumulative incidence estimates will be used.
Measure:Incidence of clinically significant infections
Time Frame:Up to 2 years
Safety Issue:
Description:Kaplan-Meier and cumulative incidence estimates will be used.
Measure:Incidence of grade II-IV and III-IV acute graft versus host disease (GVHD) for each arm
Time Frame:By day 100
Safety Issue:
Description:Kaplan-Meier and cumulative incidence estimates will be used.
Measure:Incidence of graft failure/rejection
Time Frame:By day 55
Safety Issue:
Description:Kaplan-Meier and cumulative incidence estimates will be used.
Measure:Incidence of neutrophil engraftment
Time Frame:By day 42
Safety Issue:
Description:Kaplan-Meier and cumulative incidence estimates will be used.
Measure:Incidence of non-relapse mortality
Time Frame:6 months
Safety Issue:
Description:Kaplan-Meier and cumulative incidence estimates will be used
Measure:Incidence of non-relapse mortality
Time Frame:1 year
Safety Issue:
Description:Kaplan-Meier and cumulative incidence estimates will be used.
Measure:Incidence of non-relapse mortality
Time Frame:Up to 2 years
Safety Issue:
Description:Kaplan-Meier and cumulative incidence estimates will be used.
Measure:Incidence of platelet engraftment
Time Frame:By 6 months
Safety Issue:
Description:Kaplan-Meier and cumulative incidence estimates will be used.
Measure:Incidence of relapse or disease progression
Time Frame:Up to 2 years
Safety Issue:
Description:Kaplan-Meier and cumulative incidence estimates will be used.
Measure:Overall survival
Time Frame:2 years
Safety Issue:
Description:Kaplan-Meier and cumulative incidence estimates will be used
Measure:Progression-free survival
Time Frame:Up to 2 years
Safety Issue:
Description:Kaplan-Meier and cumulative incidence estimates will be used

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

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