Fludarabine, Cyclophosphamide, and Total-Body Irradiation Followed By an Umbilical Cord Blood Transplant, Sirolimus, and Mycophenolate Mofetil in Treating Patients With Hematologic Cancer

This study is currently recruiting participants.
Verified October 2013 by Masonic Cancer Center, University of Minnesota
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:
NCT00305682
First received: March 21, 2006
Last updated: October 9, 2013
Last verified: October 2013
  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.


Condition Intervention Phase
Myeloproliferative Disorders
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Biological: anti-thymocyte globulin
Drug: cyclophosphamide
Drug: fludarabine phosphate
Drug: mycophenolate mofetil
Procedure: umbilical cord blood transplantation
Radiation: total-body irradiation
Drug: Sirolimus
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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 Masonic Cancer Center, University of Minnesota:

Primary Outcome Measures:
  • Overall Survival [ Time Frame: 1 Year, 2 Years ] [ Designated as safety issue: No ]
    Number of patients alive at 1 and 2 years post transplant


Secondary Outcome Measures:
  • Incidence of Non-relapse mortality [ Time Frame: Month 6 ] [ Designated as safety issue: No ]
    Number of Patients Dead at 6 Months after study completion

  • Chimerism Values [ Time Frame: Days 21, 60, 100, 180, and 365 ] [ Designated as safety issue: No ]
    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.

  • Incidence of neutrophil engraftment [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    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).

  • Incidence of platelet engraftment [ Time Frame: Day 100 ] [ Designated as safety issue: No ]
    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.

  • Incidence of acute graft-versus-host disease (GVHD) [ Time Frame: Day 100 ] [ Designated as safety issue: No ]

    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


  • Incidence of Chronic Graft-Versus-Host Disease [ Time Frame: 1 Year ] [ Designated as safety issue: Yes ]

    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


  • Progression-free survival [ Time Frame: 1 Year, 2 Years ] [ Designated as safety issue: No ]
    Number of patients who were alive and did not have disease progression.

  • Incidence of relapse [ Time Frame: Year 1, Year 2 ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 300
Study Start Date: October 2005
Estimated Study Completion Date: August 2015
Estimated Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm 1-Previous Autologous Transplant
Arm 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).
Drug: cyclophosphamide
Cyclophosphamide 50mg/kg x 1 to be administered with high volume fluid flush and mesna (MT(S) 1996-02) on day -6.
Other Name: Cytoxan
Drug: fludarabine phosphate
Fludarabine 40 mg/m2/day intravenously (IV) x 5 days, total dose 200 mg/m2
Other Name: Fludara
Drug: mycophenolate mofetil
Mycophenolate mofetil (MMF) 3 gram/day for patients who are ≥ 40 kg divided in 2 or 3 doses. Pediatric patient (<40 kilograms) will receive MMF at the dose of 15 mg/kg/dose every 8 hours.
Other Name: MMF
Procedure: umbilical cord blood transplantation
One or 2 UCB units may be infused to achieve the required cell dose.
Other Name: UCBT
Radiation: total-body irradiation
Administered Day -1, 200 cGy
Other Name: TBI
Drug: Sirolimus
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.
Other Name: rapamycin
Active Comparator: Arm 2 - No Previous Autologous Transplant
Arm 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 (ATG) as part of their conditioning regimen.
Biological: anti-thymocyte globulin
Equine ATG dose is 15 mg/kg intravenously (IV) every 12 hours for 6 doses on days -6, - 5, and -4.
Other Name: ATGAM(R)
Drug: cyclophosphamide
Cyclophosphamide 50mg/kg x 1 to be administered with high volume fluid flush and mesna (MT(S) 1996-02) on day -6.
Other Name: Cytoxan
Drug: fludarabine phosphate
Fludarabine 40 mg/m2/day intravenously (IV) x 5 days, total dose 200 mg/m2
Other Name: Fludara
Drug: mycophenolate mofetil
Mycophenolate mofetil (MMF) 3 gram/day for patients who are ≥ 40 kg divided in 2 or 3 doses. Pediatric patient (<40 kilograms) will receive MMF at the dose of 15 mg/kg/dose every 8 hours.
Other Name: MMF
Procedure: umbilical cord blood transplantation
One or 2 UCB units may be infused to achieve the required cell dose.
Other Name: UCBT
Radiation: total-body irradiation
Administered Day -1, 200 cGy
Other Name: TBI
Drug: Sirolimus
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.
Other Name: rapamycin
Active Comparator: Arm 3 - Refractory Leukemia/Lymphoma
Arm 3 - patients with refractory leukemia or lymphoma who have been rendered aplastic either by induction chemotherapy or radioimmunoconjugated monoclonal antibody therapy.
Drug: cyclophosphamide
Cyclophosphamide 50mg/kg x 1 to be administered with high volume fluid flush and mesna (MT(S) 1996-02) on day -6.
Other Name: Cytoxan
Drug: fludarabine phosphate
Fludarabine 40 mg/m2/day intravenously (IV) x 5 days, total dose 200 mg/m2
Other Name: Fludara
Drug: mycophenolate mofetil
Mycophenolate mofetil (MMF) 3 gram/day for patients who are ≥ 40 kg divided in 2 or 3 doses. Pediatric patient (<40 kilograms) will receive MMF at the dose of 15 mg/kg/dose every 8 hours.
Other Name: MMF
Procedure: umbilical cord blood transplantation
One or 2 UCB units may be infused to achieve the required cell dose.
Other Name: UCBT
Radiation: total-body irradiation
Administered Day -1, 200 cGy
Other Name: TBI
Drug: Sirolimus
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.
Other Name: rapamycin

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 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 intravenously (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: 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 300 patients will be accrued for this study.

  Eligibility

Ages Eligible for Study:   up to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Age, Graft Cell Dose and Graft HLA Criteria (all patients: Arms 1, 2, 3)

  • 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.
  • Umbilical cord blood (UCB) units will be selected according to current University of Minnesota 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 HLA-A, B, DRB1 antigens with the recipient. This may include 0-2 antigen mismatches at the A or B or DRB1 loci. If 2 UCB units are required to reach the target cell dose, each unit must be a 4-6 HLA-A, B, DRB1 antigen match to each other, as well as a 4-6 antigen match to 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: All diseases listed below are advanced hematologic malignancies not curable by conventional chemotherapy. Responses to conventional treatment range from zero to 30% but are typically short lived.

  • Acute Leukemias: Must be in remission by morphology (<5% blasts). Note cytogenetic relapse or persistent disease without morphologic relapse is acceptable. Also a small percentage of blasts that is equivocal between marrow regeneration vs. early relapse are acceptable provided there are no associated cytogenetic markers consistent with relapse.

    • 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: any subtype including refractory anemia (RA) if severe pancytopenia or complex cytogenetics. Blasts must be less than 5%. If 5% or more requires induction therapy pre-transplant to reduce blast count to

    ≤5%.

  • 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. These patients may be taken to transplant in aplasia after induction or re-induction chemotherapy or radiolabeled antibody. These high risk patients will be analyzed separately (Arm 3).
  • Bone marrow failure syndromes, except for Fanconi Anemia
  • Myeloproliferative syndromes Patients who have undergone an autologous transplant >12 months prior to allogeneic transplantation and who have not received multi-agent or immunosuppressive chemotherapy within the preceding 3 months must receive ATG as part of the preparative regimen (Arm 2).

Organ Function and Performance Status Criteria (all patients)

  • Adequate organ function is defined as:

    • Cardiac: Absence of decompensated congestive heart failure, or uncontrolled arrhythmia and left ventricular ejection fraction > 35%. For children that are not able to cooperate with multigated acquisition scan (MUGA) and echocardiography, such should be clearly stated in the physician's note
    • Pulmonary: Carbon Monoxide Diffusing Capacity (DLCO) > 30% predicted, and absence of oxygen (O2) requirements. For children that are not able to cooperate with pulmonary function tests (PFTs), a pulse oximetry with exercise should be attempted. If nether test can be obtained it should be clearly stated in the physician's note.
    • Liver: Transaminases < 5 x upper limit of normal and bilirubin < 3 x upper limit of normal
    • Renal: Creatinine < 2.0 mg/dl (adults) and creatinine clearance > 40 ml/min (pediatrics). Adults with a creatinine > 1.2 or a history of renal dysfunction must have estimated creatinine clearance > 40 ml/min.
    • Adequate performance status is defined as Karnofsky score > or = 60% or Lansky score > or = 50 (pediatrics)

Other Inclusion Criteria (all patients)

  • If recent mold infection (e.g. Aspergillus) - must have minimum of 30 days of appropriate treatment before bone marrow transplant (BMT) and infection controlled and be cleared by Infectious Disease.
  • Second BMT: Must be > 3 months after prior myeloablative transplant.
  • Patients must be ineligible for autologous transplantation due to prior autologous transplant, an inadequate autologous stem cell harvest, inability to withstand a myeloablative preparative regimen, or clinically aggressive/high risk disease.
  • Patients are eligible for transplantation if there is no evidence of progressive disease by imaging modalities or biopsy. Persistent positron emission tomography scan (PET) activity, though possibly related to lymphoma, is not an exclusion criterion in the absence of computated tomography scan (CT) changes indicating progression.
  • Patients with stable disease are eligible for transplantation if the largest residual nodal mass is < 5 cm (approximately). For patients who have responded to preceding therapy, the largest residual mass must represent a 50% reduction and be < 7.5 cm (approximately).

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00305682

Contacts
Contact: Claudio Brunstein, MD 612-625-3918 bruns072@umn.edu
Contact: Timothy Krepski 612-273-2800 tkrepsk1@fairview.org

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 ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT00305682     History of Changes
Other Study ID Numbers: 2005LS036, UMN-MT-2005-02, UMN-0507M70121
Study First Received: March 21, 2006
Last Updated: October 9, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Neoplasms
Leukemia
Lymphoma
Multiple Myeloma
Neoplasms, Plasma Cell
Plasmacytoma
Myelodysplastic Syndromes
Preleukemia
Myeloproliferative Disorders
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Bone Marrow Diseases
Precancerous Conditions
Antilymphocyte Serum
Cyclophosphamide
Mycophenolate mofetil
Fludarabine monophosphate
Sirolimus
Everolimus
Fludarabine

ClinicalTrials.gov processed this record on April 15, 2014