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

Sponsor:	Masonic Cancer Center, University of Minnesota
Information provided by (Responsible Party):	Masonic Cancer Center, University of Minnesota
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
Myeloproliferative Disorders Leukemia Lymphoma Multiple Myeloma and Plasma Cell Neoplasm Myelodysplastic Syndromes	Biological: anti-thymocyte globulin Drug: cyclophosphamide Drug: cyclosporine Drug: fludarabine phosphate Drug: mycophenolate mofetil Procedure: umbilical cord blood transplantation Radiation: total-body irradiation	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:

Genetics Home Reference related topics: aceruloplasminemia hemophilia

MedlinePlus related topics: Cancer Leukemia Lymphoma Multiple Myeloma Myelodysplastic Syndromes

Drug Information available for: Cyclophosphamide Fludarabine Cyclosporine Fludarabine phosphate Mycophenolate mofetil hydrochloride Mycophenolate mofetil Antilymphocyte Serum

U.S. FDA Resources

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:

Number of Patients Dead at 6 Months [ Time Frame: Month 6 ] [ Designated as safety issue: No ]
Incidence of Non-relapse mortality at 6 months after study completion
Chimerism Values days 7, 14, 21, 60, 100, 180, and 365 [ Time Frame: Days 7, 14, 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 2014
Estimated Primary Completion Date:	August 2013 (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: cyclosporine Patients will receive cyclosporine A (CSA) therapy beginning on day -3 maintaining a trough level between 200 and 400 ng/mL. For adults the initial dose will be 2.5 mg/kg IV over 1 hour every 12 hours. For children < 40 kg the initial dose will be 2.5 mg/kg IV over 1 hour every 8 hours. Other Name: CSA 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
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: cyclosporine Patients will receive cyclosporine A (CSA) therapy beginning on day -3 maintaining a trough level between 200 and 400 ng/mL. For adults the initial dose will be 2.5 mg/kg IV over 1 hour every 12 hours. For children < 40 kg the initial dose will be 2.5 mg/kg IV over 1 hour every 8 hours. Other Name: CSA 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
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: cyclosporine Patients will receive cyclosporine A (CSA) therapy beginning on day -3 maintaining a trough level between 200 and 400 ng/mL. For adults the initial dose will be 2.5 mg/kg IV over 1 hour every 12 hours. For children < 40 kg the initial dose will be 2.5 mg/kg IV over 1 hour every 8 hours. Other Name: CSA 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

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 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: 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 300 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

Inclusion Criteria:

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
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
Negative pregnancy test
Fertile patients must use effective contraception

Exclusion Criteria:

Decompensated congestive heart failure
Uncontrolled arrhythmia
Pregnant or nursing
Evidence of HIV infection or known HIV-positive serology
Current active serious infection
Less than 3 months since prior myeloablative transplant if this is the patient's second bone marrow transplant
Less than 3 months since multiagent chemotherapy (patients allowed provided they receive anti-thymocyte globulin during the preparative regimen)
Oxygen requirements

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:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Publications:

Brunstein CG, Cantero S, Cao Q, Majhail N, McClune B, Burns LJ, Tomblyn M, Miller JS, Blazar BR, McGlave PB, Weisdorf DJ, Wagner JE. Promising progression-free survival for patients low and intermediate grade lymphoid malignancies after nonmyeloablative umbilical cord blood transplantation. Biol Blood Marrow Transplant. 2009 Feb;15(2):214-22.

Bachanova V, Verneris MR, DeFor T, Brunstein CG, Weisdorf DJ. Prolonged survival in adults with acute lymphoblastic leukemia after reduced-intensity conditioning with cord blood or sibling donor transplantation. Blood. 2009 Mar 26;113(13):2902-5. Epub 2009 Jan 28.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Bachanova V, Sandhu K, Yohe S, Cao Q, Burke MJ, Verneris MR, Weisdorf D. Allogeneic hematopoietic stem cell transplantation overcomes the adverse prognostic impact of CD20 expression in acute lymphoblastic leukemia. Blood. 2011 May 12;117(19):5261-3. Epub 2011 Mar 14.

MacMillan ML, Weisdorf DJ, Brunstein CG, Cao Q, DeFor TE, Verneris MR, Blazar BR, Wagner JE. Acute graft-versus-host disease after unrelated donor umbilical cord blood transplantation: analysis of risk factors. Blood. 2009 Mar 12;113(11):2410-5. Epub 2008 Nov 7.

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:	December 6, 2011
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
Cyclosporins
Cyclosporine
Fludarabine monophosphate
Mycophenolate mofetil
Fludarabine

ClinicalTrials.gov processed this record on May 21, 2012