Clinical Trials /

Non-Myeloablative Conditioning for Unrelated Donor Umbilical Cord Blood Transplant

NCT00305682

Description:

RATIONALE: Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill cancer cells. An umbilical cord blood transplant may be able to replace blood-forming cells that were destroyed by chemotherapy and radiation therapy. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving sirolimus and mycophenolate mofetil after the transplant may stop this from happening. PURPOSE: This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation followed by an umbilical cord blood transplant, sirolimus, and mycophenolate mofetil works in treating patients with hematologic cancer.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Anaplastic Large Cell Lymphoma
  • B-Cell Prolymphocytic Leukemia
  • Burkitt Lymphoma
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
  • Chronic Myeloid Leukemia
  • Follicular Lymphoma
  • Hodgkin Lymphoma
  • Lymphoplasmacytic Lymphoma
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
  • Mature T-Cell and NK-Cell Neoplasm
  • Multiple Myeloma
  • Myelodysplastic Syndromes
  • Myeloproliferative Neoplasm
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Non-Myeloablative Conditioning for Unrelated Donor Umbilical Cord Blood Transplant
  • Official Title: Transplantation of Unrelated Donor Umbilical Cord Blood in Patients With Hematological Malignancies Using a Non-Myeloablative Preparative Regimen

Clinical Trial IDs

  • ORG STUDY ID: 2005LS036
  • SECONDARY ID: UMN-MT-2005-02
  • SECONDARY ID: UMN-0507M70121
  • NCT ID: NCT00305682

Conditions

  • Myeloproliferative Disorders
  • Leukemia
  • Lymphoma
  • Myelodysplastic Syndromes

Interventions

DrugSynonymsArms
anti-thymocyte globulinATGAM, ATGArm 2 - No Prior Autologous Transplant
cyclophosphamideCytoxanArm 1-Previous Autologous Transplant
FludarabineFludaraArm 1-Previous Autologous Transplant
mycophenolate mofetilMMFArm 1-Previous Autologous Transplant
SirolimusrapamycinArm 1-Previous Autologous Transplant

Purpose

RATIONALE: Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill cancer cells. An umbilical cord blood transplant may be able to replace blood-forming cells that were destroyed by chemotherapy and radiation therapy. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving sirolimus and mycophenolate mofetil after the transplant may stop this from happening. PURPOSE: This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation followed by an umbilical cord blood transplant, sirolimus, and mycophenolate mofetil works in treating patients with hematologic cancer.

Detailed Description

      OBJECTIVES:

      Primary

        -  Determine the one- and two-year survival of patients with hematologic malignancies
           treated with a nonmyeloablative conditioning regimen comprising fludarabine,
           cyclophosphamide, and total-body irradiation followed by umbilical cord blood
           transplantation and post-transplant immunosuppression comprising sirolimus and
           mycophenolate mofetil.

      Secondary

        -  Determine the six-month nonrelapse mortality of patients treated with this regimen.

        -  Determine the presence of chimerism in patients treated with this regimen at days 21,
           60, 100, 180, and 365.

        -  Determine the incidence of neutrophil engraftment by day 42 in patients treated with
           this regimen.

        -  Determine the incidence of platelet engraftment by six months in patients treated with
           this regimen.

        -  Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease
           (GVHD) at day 100 in patients treated with this regimen.

        -  Determine the incidence of chronic GVHD at one year in patients treated with this
           regimen.

        -  Determine the probability of overall survival within one or two years in patients
           treated with this regimen.

        -  Determine the probability of progression-free survival within one or two years in
           patients treated with this regimen.

        -  Determine the incidence of relapse or disease progression within one or two years in
           patients treated with this regimen.

      OUTLINE: This is a nonrandomized study. Patients are stratified into five disease groups: 1.
      acute myeloid leukemia, myelodysplastic syndromes, chronic myelogenous leukemia [CML] in
      first chronic phase and second chronic phase [CP2] after myeloid blast crisis; 2. acute
      lymphoblastic leukemia, Burkitt's lymphoma, CML CP2 post lymphoid blast crisis, 3. large-cell
      B and T-cell lymphoma, mantle cell lymphoma; 4. chronic lymphocytic leukemia/small
      lymphocytic lymphoma, prolymphocytic leukemia, marginal zone B-cell lymphoma, follicular
      lymphoma; 5. Hodgkin's lymphoma and multiple myeloma.

        -  Nonmyeloablative conditioning: Patients receive fludarabine intravenously on days -6 to
           -2 and cyclophosphamide IV on day -6. Patients who did not undergo prior autologous
           transplant or who received ≤ 1 course of prior multiagent chemotherapy or no severely
           immunosuppressive therapy in the past 3 months also receive anti-thymocyte globulin IV
           on days -6 to -4. All patients also undergo total-body irradiation on day -1.

        -  Umbilical cord blood transplant: Patients undergo umbilical cord blood transplantation
           on day 0.

        -  Post-transplant immunosuppression: Sirolimus will be administered starting at day -3
           with 8mg-12mg mg oral loading dose followed by single dose 4 mg/day with a target serum
           concentration of 3 to 12 mg/mL. Levels are to be monitored 3 times/week in the first 2
           weeks, weekly until day +60, and as clinically indicated until day +100
           post-transplantation. In the absence of acute GVHD sirolimus may be tapered starting at
           day +100 and eliminated by day +180 post-transplantation. Patients also receive
           mycophenolate mofetil IV on days -3 to 5 and then orally on days 6-30.

      After completion of study treatment, patients are followed periodically for 5 years.

      PROJECTED ACCRUAL: A total of 320 patients will be accrued for this study.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1-Previous Autologous TransplantActive ComparatorArm 1 - hematologic malignancy patients who have received a previous autologous transplant or ≥ 2 cycle of multiagent chemotherapy within the last 3 months previous to umbilical cord blood transplant (UCBT). Conditioning Fludarabine dose of 40 mg/m2/day x 5, cyclophosphamide and total body irradiation without anti-thymocyte globulin followed by umbilical cord blood transplantation, and peri-transplant Mycophenolate Mofetil and Sirolimus.
  • cyclophosphamide
  • Fludarabine
  • mycophenolate mofetil
  • Sirolimus
Arm 2 - No Prior Autologous TransplantActive ComparatorArm 2 - hematologic malignancy patients who have not been treated with prior autologous transplant or ≤ 1 cycle of chemotherapy in the 3 months previous to umbilical cord blood transplant (UCBT), and who should receive anti-thymocyte globulin as conditioning regimen. Conditioning Fludarabine dose of 40 mg/m2/day x 5, cyclophosphamide and total body irradiation with anti-thymocyte globulin followed by umbilical cord blood transplantation, and peri-transplant Mycophenolate Mofetil and Sirolimus.
  • cyclophosphamide
  • Fludarabine
  • mycophenolate mofetil
  • Sirolimus
Arm 3 - Refractory Leukemia/LymphomaActive ComparatorArm 3 - patients with refractory leukemia or lymphoma who have been rendered aplastic either by induction chemotherapy or radioimmunoconjugated monoclonal antibody therapy. Conditioning Fludarabine dose of 40 mg/m2/day x 5, cyclophosphamide and total body irradiation with anti-thymocyte globulin followed by umbilical cord blood transplantation, and peri-transplant Mycophenolate Mofetil and Sirolimus.
  • cyclophosphamide
  • Fludarabine
  • mycophenolate mofetil
  • Sirolimus
Arm 4: MT2006-01 coenrolling patientsActive ComparatorArm 4 - hematologic malignancy patients enrolled in MT2006-01. Conditioning Fludarabine dose of 40 mg/m2/day x 5, cyclophosphamide and total body irradiation with or without anti-thymocyte globulin followed by umbilical cord blood transplantation, and peri-transplant Mycophenolate Mofetil and Sirolimus.
  • cyclophosphamide
  • Fludarabine
  • mycophenolate mofetil
  • Sirolimus
Arm 5 - Previous Autologous TransplantActive ComparatorArm 5 - hematologic malignancy patients who have received a previous autologous transplant or ≥ 2 cycle of multiagent chemotherapy within the last 3 months previous to umbilical cord blood transplant (UCBT). Conditioning Fludarabine dose of 30 mg/m2/day x 5, cyclophosphamide and total body irradiation without anti-thymocyte globulin followed by umbilical cord blood transplantation, and peri-transplant Mycophenolate Mofetil and Sirolimus.
  • cyclophosphamide
  • Fludarabine
  • mycophenolate mofetil
  • Sirolimus
Arm 6 - No prior autologous transplantActive ComparatorArm 6 - hematologic malignancy patients who have not been treated with prior autologous transplant or ≤ 1 cycle of chemotherapy in the 3 months previous to umbilical cord blood transplant (UCBT), and who should receive anti-thymocyte globulin as conditioning regimen. Conditioning Fludarabine dose of 30 mg/m2/day x 5, cyclophosphamide and total body irradiation with anti-thymocyte globulin followed by umbilical cord blood transplantation, and peri-transplant Mycophenolate Mofetil and Sirolimus.
  • cyclophosphamide
  • Fludarabine
  • mycophenolate mofetil
  • Sirolimus

Eligibility Criteria

        Inclusion Criteria:

        Age, Graft Cell Dose and Graft HLA Criteria

          -  Subjects must be <70 years old. Subjects ages ≥ 70 and ≤ 75 may be eligible if they
             have a Co-Morbidity Scoring (HCT-CI) score ≤ 2.

          -  The UCB graft is matched at 4-6 HLA-A, B, DRB1 antigens with the recipient.

          -  Patients co-enrolled in MT-2006-01 Phase I Study of Infusion of Umbilical Cord Blood
             Derived CD25+CD4+ T-Regulatory (Treg) Cells after Non-Myeloablative Cord\Blood
             Transplantation will receive grafts composed of 2 UCB units.

        Disease Criteria:

          -  Acute Leukemias:

               -  Acute myeloid leukemia: high risk complete remission 1 (CR1) (as evidenced by
                  preceding myelodysplastic syndrome (MDS), high risk cytogenetics such as those
                  associated with MDS or complex karyotype, > 2 cycles to obtain CR or
                  erythroblastic and megakaryocytic); second or greater CR.

               -  Acute lymphoblastic leukemia/lymphoma: high risk CR1 as evidenced by high risk
                  cytogenetics (e.g. t(9;22), t(1;19),t(4;11), other myeloid/lymphoid or mixed
                  lineage leukemia [MLL] rearrangements, hypodiploidy or Ikaros family zinc finger
                  1 [IKZF1]), > 1 cycle to obtain CR or evidence of minimal residual disease (MRD).
                  Patients in second or greater CR are also eligible.

          -  Burkitt's lymphoma in CR2 or subsequent CR

          -  Natural Killer cell malignancies

          -  Chronic myelogenous leukemia: all types except refractory blast crisis. Chronic phase
             patients must have failed or been intolerant to Gleevec

          -  Myelodysplastic syndrome:

          -  Large-cell lymphoma, Hodgkin lymphoma and multiple myeloma with chemotherapy sensitive
             disease that has failed or patients who are ineligible for an autologous transplant.

          -  Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone
             B-cell lymphoma, follicular lymphoma, which have progressed within 12 months of
             achieving a partial or complete remission. Patients who had remissions lasting > 12
             months, are eligible after at least two prior therapies. Patients with bulky disease
             should be considered for debulking chemotherapy before transplant. Patients with
             refractory disease are eligible, unless has bulky disease and an estimated tumor
             doubling time of less than one month.

          -  Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are eligible
             after initial therapy if chemotherapy sensitive.

          -  Refractory leukemia or MDS.

          -  Bone marrow failure syndromes, except for Fanconi Anemia

          -  Myeloproliferative syndromes Patients who have undergone an autologous transplant >12
             months prior to allogeneic transplantation

        Adequate Organ Function and Performance Status

        Exclusion Criteria:

          -  < 70 years 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

          -  Current active serious infection

          -  Unless in post-chemotherapy and radioimmunoconjugated antibody induced aplasia, when
             he/she would be eligible for Arm 3, patients with acute leukemia in morphologic
             relapse/ persistent disease defined as > 5% blasts in normocellular bone marrow OR any
             % blasts if blasts have unique morphologic markers (e.g. Auer rods) or associated
             cytogenetic markers that allows morphologic relapse to be distinguished are not
             eligible.

          -  Chronic myelogenous leukemia (CML) in refractory blast crisis

          -  Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that is progressive on
             salvage therapy. Stable disease is acceptable to move forward provided it is
             non-bulky.

          -  Active central nervous system malignancy
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Survival
Time Frame:1 Year, 2 Years
Safety Issue:
Description:Number of patients alive at 1 and 2 years post transplant

Secondary Outcome Measures

Measure:Incidence of Non-relapse mortality
Time Frame:Month 6
Safety Issue:
Description:Number of Patients Dead at 6 Months after study completion
Measure:Chimerism Values
Time Frame:Days 21, 60, 100, 180, and 365
Safety Issue:
Description:Chimerism studies will be performed on the blood and bone marrow (BM). BM chimerism days 21 and 100, at 6 months and 1 year to determine the relative contribution of donor and recipient hematopoiesis. If the patient's peripheral blood counts are slow to recover, absolute neutrophil count (ANC) <5 x 10^8/L by day 28, or the peripheral blood counts drop below <1.0 x 10^8/L after an initial recovery, the peripheral blood and bone marrow will be evaluated at that time unless a cause has been determined.
Measure:Incidence of neutrophil engraftment
Time Frame:Day 42
Safety Issue:
Description:Time to 1st 3 consecutive days with absolute neutrophil count (ANC) > 5 x 10^8/L and percentage of patients with neutrophil recovery by day 42 (Cumulative incidence).
Measure:Incidence of platelet engraftment
Time Frame:Day 180
Safety Issue:
Description:Time to platelets > 20,000 (first of 3 consecutive days) with no platelet transfusions for seven days and percentage of patients with platelet engraftment >50,000 by day 100.
Measure:Incidence of acute graft-versus-host disease (GVHD)
Time Frame:Day 100
Safety Issue:
Description:Patients will be staged weekly between days 0 and 100 after transplantation using standard criteria. Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level
Measure:Incidence of Chronic Graft-Versus-Host Disease
Time Frame:1 Year
Safety Issue:
Description:Patients will be staged weekly between days 0 and 100 after transplantation using standard criteria. Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level
Measure:Progression-free survival
Time Frame:1 Year, 2 Years
Safety Issue:
Description:Number of patients who were alive and did not have disease progression.
Measure:Incidence of relapse
Time Frame:Year 1, Year 2
Safety Issue:
Description:Patients with leukemia and lymphoma involving the BM and multiple myeloma will have this done by BM biopsy and additional special studies such as cytogenetics or flow cytometry as appropriate. Patients with lymphoma and myeloma will have radiology studies such as plain X-rays or CT scans and/or other studies such as blood tumor markers to document presence or absence of disease as clinically indicated.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Masonic Cancer Center, University of Minnesota

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