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Fludarabine, Cyclophosphamide, and Total-Body Irradiation Followed By an Umbilical Cord Blood Transplant, Cyclosporine, and Mycophenolate Mofetil in Treating Patients With Hematologic Cancer
This study is currently recruiting participants.
Verified by National Cancer Institute (NCI), October 2008
First Received: March 21, 2006   Last Updated: June 10, 2009   History of Changes
Sponsors and Collaborators: Masonic Cancer Center, University of Minnesota
National Cancer Institute (NCI)
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00305682
  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 cyclosporine 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, cyclosporine, and mycophenolate mofetil works in treating patients with hematologic cancer.


Condition Intervention Phase
Chronic Myeloproliferative Disorders
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Diseases
Biological: anti-thymocyte globulin
Drug: cyclophosphamide
Drug: cyclosporine
Drug: fludarabine phosphate
Drug: mycophenolate mofetil
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Procedure: umbilical cord blood transplantation
Radiation: total-body irradiation
Phase II

Study Type: Interventional
Study Design: Treatment, Non-Randomized
Official Title: Transplantation of Unrelated Donor Umbilical Cord Blood in Patients With Hematological Malignancies Using a Non-Myeloablative Preparative Regimen

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Probability of survival at 1 year [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Probability of survival at 2 years [ Designated as safety issue: No ]
  • Survival at 1 and 2 years [ Designated as safety issue: No ]
  • Non-relapse mortality at 6 months after study completion [ Designated as safety issue: No ]
  • Chimerism at days 7, 14, 21, 60, 100, 180, and 365 [ Designated as safety issue: No ]
  • Incidence of neutrophil engraftment at day 42 [ Designated as safety issue: No ]
  • Incidence of platelet engraftment at 6 months [ Designated as safety issue: No ]
  • Incidence of acute graft-versus-host disease (GVHD) at day 100 [ Designated as safety issue: No ]
  • Incidence of extensive GVHD at 1 year [ Designated as safety issue: No ]
  • Probability of progression-free survival at 1 and 2 years [ Designated as safety issue: No ]
  • Incidence of relapse at 1 and 2 years [ Designated as safety issue: No ]

Estimated Enrollment: 320
Study Start Date: October 2005
Estimated Primary Completion Date: August 2013 (Final data collection date for primary outcome measure)
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 cyclosporine 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 7, 14, 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 and 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 according to disease (acute myeloid leukemia, myelodysplastic syndromes, chronic myelogenous leukemia [CML] in first chronic phase and second chronic phase [CP2] after myeloid blast crisis vs acute lymphoblastic leukemia, CML CP2 post lymphoid blast crisis, lymphoblastic lymphoma, and Burkitt's lymphoma vs large cell B- and T-cell lymphomas and mantle cell lymphoma vs chronic lymphocytic leukemia, marginal zone B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, lymphoplasmacytic lymphoma, and prolymphocytic leukemia vs Hodgkin's lymphoma and multiple myeloma).

  • Nonmyeloablative conditioning: Patients receive fludarabine IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours 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 over 4-6 hours twice daily 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: Patients receive cyclosporine IV over 1 hour 2-3 times daily beginning on day -3 and continuing until approximately day 100, followed by a taper until day 180. 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.

  Eligibility

Ages Eligible for Study:   up to 69 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Diagnosis of one of the following advanced hematologic malignancies:

    • Acute leukemia in remission by morphology (< 5% blasts) OR cytogenetic relapse or persistent disease without morphologic relapse*

      • Acute myeloid leukemia, meeting 1 of the following criteria:

        • High-risk disease as evidenced by 1 of the following criteria:

          • In first complete remission (CR) as evidenced by preceding myelodysplastic syndromes (MDS)
          • High-risk cytogenetics such as ones associated with MDS or complex karyotype
          • Required at least 2 courses to achieve CR
          • Erythroblastic and megakaryocytic
        • In second or greater CR
      • Acute lymphoblastic leukemia/lymphoma, meeting 1 of the following criteria:

        • High-risk disease in first CR, as evidenced by 1 of the following:

          • High-risk cytogenetics (e.g., t[9;22], t[1;19], t[4;11] or other mixed-lineage leukemia rearrangements)
          • More than 1 course to achieve CR
        • In second or greater CR NOTE: *Small percentage of blasts that is equivocal between marrow regeneration vs early relapse allowed provided there are no cytogenetic markers consistent with relapse
    • Chronic myelogenous leukemia

      • Patients with chronic phase disease must have failed or been intolerant to imatinib mesylate
      • No refractory blast crisis
    • Myelodysplastic syndromes (MDS)

      • Blasts must be < 5% (may achieve with induction therapy prior to transplant)
      • Any subtype including refractory anemia if severe pancytopenia or complex cytogenetics present
    • Large cell lymphoma*, Hodgkin's lymphoma*, or multiple myeloma, meeting 1 of the following criteria:

      • Chemotherapy-sensitive disease that has failed therapy
      • Patient ineligible for autologous transplantation
    • Lymphoplasmacytic lymphoma, mantle cell lymphoma*, or prolymphocytic leukemia

      • Must be chemotherapy sensitive after initial therapy NOTE: *No disease that has progressed on salvage therapy unless disease is stable and nonbulky.
    • Chronic lymphocytic leukemia/small lymphocytic lymphoma, marginal zone B-cell lymphoma, or follicular lymphoma, meeting 1 of the following criteria:

      • Disease progression after ≥ 2 prior therapies
      • Refractory disease allowed provided disease is nonbulky and an estimated tumor doubling time is ≥ 1 month
      • Patients with bulky disease (nodal areas > 5 cm) should undergo debulking chemotherapy before transplantation
    • Bone marrow failure syndromes (no Fanconi's anemia)
    • Burkitt Lymphoma

      • In CR2 or subsequent CR
    • Natural killer cell malignancy
    • Myeloproliferative syndromes
  • Stable disease allowed provided the largest residual nodal mass is approximately < 5 cm

    • Largest residual mass must represent a 50% reduction and be approximately < 7.5 cm for patients who have responded to preceding therapy
  • Disease not curable by conventional chemotherapy
  • Patients with refractory leukemia or MDS may undergo transplant in aplasia after induction or re-induction chemotherapy or radiolabeled antibody
  • Must be ineligible for autologous transplantation due to one of the following criteria:

    • Prior autologous transplantation
    • Inadequate autologous stem cell harvest
    • Inability to withstand a myeloablative preparative regimen
    • Clinically aggressive/high-risk disease
  • No evidence of progressive disease by imaging modalities or biopsy

    • Persistent PET activity is not an exclusion criteria in the absence of CT changes indicating progression
  • No available 5-6/6 HLA-A, -B, -DRB1 matched sibling donor
  • No active CNS malignancy
  • Umbilical cord blood graft must match at 4-6 HLA-A, B, DRB1 antigens

    • Antigen mismatches of 0-2 at the A, B, or DRB1 loci allowed
    • Each unit must be a 4-6 HLA-A, B, DRB1 antigen match to each other AND a 4-6 antigen match to the recipient

PATIENT CHARACTERISTICS:

  • No decompensated congestive heart failure
  • No uncontrolled arrhythmia
  • LVEF ≥ 35%
  • DLCO > 30% of predicted
  • AST and ALT < 5 times upper limit of normal (ULN)
  • Bilirubin < 3 times ULN
  • Creatinine ≤ 2.0 mg/dL (adults) OR creatinine clearance > 40 mL/min (pediatrics)

    • Adults with creatinine > 1.2 mg/dL or a history of renal dysfunction must have creatinine clearance > 40 mL/min
  • Karnofsky performance status (PS) 60-100% OR
  • Lansky PS 50-100% (pediatrics)
  • Prior mold infection (e.g., Aspergillus) must be cleared by Infectious Disease after receiving 1 month of treatment and infection controlled
  • Not pregnant or nursing
  • No evidence of HIV infection or known HIV-positive serology
  • No current active serious infection
  • Negative pregnancy test
  • Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • At least 3 months since prior myeloablative transplant if this is the patient's second bone marrow transplant
  • At least 3 months since multiagent chemotherapy (patients allowed provided they receive anti-thymocyte globulin during the preparative regimen)
  • No oxygen requirements
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00305682

Locations
United States, Minnesota
Masonic Cancer Center at University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Clinical Trials Office - Masonic Cancer Center at University o     612-624-2620        
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota
Investigators
Principal Investigator: Claudio G. Brunstein, MD, PhD Masonic Cancer Center, University of Minnesota
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by National Clinical Trials Identifier (NCT ID):
Responsible Party: Masonic Cancer Center at University of Minnesota ( Claudio G. Brunstein )
Study ID Numbers: CDR0000456202, UMN-2005LS036, UMN-MT-2005-02, UMN-0507M70121
Study First Received: March 21, 2006
Last Updated: June 10, 2009
ClinicalTrials.gov Identifier: NCT00305682     History of Changes
Health Authority: Unspecified

Keywords provided by National Cancer Institute (NCI):
accelerated phase chronic myelogenous leukemia
childhood chronic myelogenous leukemia
chronic phase chronic myelogenous leukemia
meningeal chronic myelogenous leukemia
relapsing chronic myelogenous leukemia
refractory anemia
refractory anemia with excess blasts in transformation
refractory anemia with excess blasts
refractory anemia with ringed sideroblasts
refractory cytopenia with multilineage dysplasia
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
adult acute myeloid leukemia in remission
anaplastic large cell lymphoma
childhood diffuse large cell lymphoma
childhood immunoblastic large cell lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult immunoblastic large cell lymphoma
recurrent childhood large cell lymphoma
stage III adult diffuse large cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage III childhood large cell lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult immunoblastic large cell lymphoma
stage IV childhood large cell lymphoma
recurrent adult Hodgkin lymphoma
recurrent/refractory childhood Hodgkin lymphoma
stage III adult Hodgkin lymphoma
stage III childhood Hodgkin lymphoma

Study placed in the following topic categories:
Anti-Infective Agents
Chronic Myelomonocytic Leukemia
Cyclosporine
Lymphoma, Mantle-Cell
Mycophenolic Acid
Mantle Cell Lymphoma
Cyclosporins
Follicular Lymphoma
Refractory Anemia
Acute Myelocytic Leukemia
Preleukemia
Leukemia, Prolymphocytic
Anemia, Refractory
Hemorrhagic Disorders
Acute Myeloid Leukemia, Adult
Leukemia, Lymphocytic, Chronic, B-Cell
Mycophenolate mofetil
Neoplasm Metastasis
Lymphoma, Large-Cell, Anaplastic
Hodgkin Disease
Myelodysplastic Myeloproliferative Disease
Lymphoma, Large B-Cell, Diffuse
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Immunoproliferative Disorders
Hematologic Diseases
Leukemia, Myelomonocytic, Chronic
Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
Blood Coagulation Disorders
Myeloproliferative Disorders
Juvenile Myelomonocytic Leukemia

Additional relevant MeSH terms:
Anti-Infective Agents
Antimetabolites, Antineoplastic
Cyclosporine
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Mycophenolic Acid
Cyclosporins
Preleukemia
Hemorrhagic Disorders
Pathologic Processes
Therapeutic Uses
Mycophenolate mofetil
Cardiovascular Diseases
Dermatologic Agents
Immunoproliferative Disorders
Immune System Diseases
Hematologic Diseases
Myeloproliferative Disorders
Multiple Myeloma
Neoplasms
Fludarabine
Lymphoma, Non-Hodgkin
Antimetabolites
Precancerous Conditions
Immunologic Factors
Blood Protein Disorders
Antineoplastic Agents
Paraproteinemias
Cyclophosphamide
Antibiotics, Antineoplastic

ClinicalTrials.gov processed this record on August 24, 2009