Allogeneic Bone Marrow Transplantation Using Less Intensive Therapy

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Masonic Cancer Center, University of Minnesota
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:
NCT00303719
First received: March 15, 2006
Last updated: July 8, 2014
Last verified: July 2014
  Purpose

RATIONALE: A peripheral stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy and radiation therapy, or that have become cancer. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclophosphamide and fludarabine together with total-body irradiation followed by cyclosporine and mycophenolate mofetil before the transplant may stop this from happening.

PURPOSE: This clinical trial is studying how well giving combination chemotherapy together with radiation therapy followed by cyclosporine and mycophenolate mofetil works in treating patients who are undergoing a donor stem cell transplant for hematologic cancer, metastatic breast cancer, or kidney cancer.


Condition Intervention Phase
Kidney Cancer
Leukemia
Lymphoma
Multiple Myeloma
Plasma Cell Neoplasm
Myelodysplastic Syndromes
Biological: anti-thymocyte globulin
Drug: cyclophosphamide
Drug: cyclosporine
Drug: fludarabine
Drug: mycophenolate mofetil
Procedure: stem cell transplantation
Radiation: total body irradiation
Drug: filgrastim
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: Allogeneic Bone Marrow Transplantation Using Less Intensive Therapy

Resource links provided by NLM:


Further study details as provided by Masonic Cancer Center, University of Minnesota:

Primary Outcome Measures:
  • Neutrophil and Donor Cell Engraftment [ Time Frame: Day 42 and Day 100 ] [ Designated as safety issue: No ]

    Successful sustained engraftment is defined as primary neutrophil engraftment by day 42 and e90% donor cells at day 100, with or without DLI.

    Engraftment based on absolute neutrophil count of donor origin > 0.5 x 10e9 /L for 3 days by day 42



Secondary Outcome Measures:
  • Serious Adverse Events [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
    Safety by development of severe adverse events within 100 days of transplant

  • Transplant Related Mortality [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
    > 30% transplant related mortality at 100 days (non-relapse).

  • Overall Survival [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Acute Graft-Versus-Host Disease [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
    Grade III-IV graft versus host disease


Estimated Enrollment: 300
Study Start Date: March 2002
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: High Risk Patients
Nonmyeloablative conditioning using fludarabine, cyclophosphamide and low dose Total Body Irradiation with or without anti-thymocyte globulin followed by allogeneic hematopoietic stem cell transplantation, immunosuppressive cyclosporine and mycophenolate mofetil and post-transplant use of bone marrow-stimulating filgrastim.
Biological: anti-thymocyte globulin

ATG dose is 15 mg/kg intravenous (IV) every 12 hours for 6 doses on days -6, -5, and -4.

Those that should/will receive ATG in the preparative regimen:

  • Related donor recipients who have not had exposure to combination chemotherapy in the 6 months preceding transplant should
  • Unrelated donor recipients who have not had exposure to combination chemotherapy in the 3 months preceding transplant will
  • Unrelated donor recipients who have had only a single induction cycle for the treatment of ALL/AML or MDS or CML blast crisis should
  • Recipients with a prior autologous transplant in the year prior to second transplant do not require ATG.
Other Name: ATG
Drug: cyclophosphamide
Cyclophosphamide will be given in a two hour infusion, total dose 50 mg/kg on day -6.
Other Name: Cytoxan
Drug: cyclosporine
Patients will receive cyclosporine A (CSA) therapy beginning on day -3 maintaining a level of >200. For adults the initial dose will be 2.5 mg/kg IV over 2 hours every 12 hours. For children < 40 kg the initial dose will be 2.5 mg/kg IV over 2 hours every 8 hours. Patients will receive CSA until day +100.
Other Name: CSA
Drug: fludarabine
Fludarabine 30 mg/m^2/day intravenous (IV) on day -6 through day -2., total dose 150 mg/m^2 for 5 days.
Other Name: Fludara
Drug: mycophenolate mofetil
Mycophenolate mofetil (MMF) 1.5 gram twice a day (BID) or if < 50 kg will be given 15 mg/kg orally(po) BID,beginning on day -3, and discontinue at day +30 or 7 days after engraftment (3 consecutive days of absolute neutrophil count (ANC) > 0.5 x 109 /L).
Other Name: MMF
Procedure: stem cell transplantation
On day 0, if related donor, stem cells are infused via central line. If unrelated donor, marrow/PBSC is infused after arrival and processing on day 0.
Other Names:
  • peripheral blood stem cell transplantation
  • bone marrow transplant
Radiation: total body irradiation
The dose of TBI will be 200 cGy given in a single fraction on day -1.
Other Name: TBI
Drug: filgrastim
Patients with white blood cell (WBC) counts < 2500 any time after stem cell infusion will be started on G-CSF support at Day +5 at a dose of 5 mcg/kg intravenously or subcutaneously (IV/SQ) daily rounded to vial size until absolute neutrophil count (ANC) > 2500 for 2 consecutive days.
Other Name: G-CSF
Experimental: Standard Risk Patients
Nonmyeloablative conditioning using fludarabine, cyclophosphamide and low dose Total Body Irradiation with or without anti-thymocyte globulin followed by allogeneic hematopoietic stem cell transplantation, immunosuppressive cyclosporine and mycophenolate mofetil and post-transplant use of bone marrow-stimulating filgrastim.
Biological: anti-thymocyte globulin

ATG dose is 15 mg/kg intravenous (IV) every 12 hours for 6 doses on days -6, -5, and -4.

Those that should/will receive ATG in the preparative regimen:

  • Related donor recipients who have not had exposure to combination chemotherapy in the 6 months preceding transplant should
  • Unrelated donor recipients who have not had exposure to combination chemotherapy in the 3 months preceding transplant will
  • Unrelated donor recipients who have had only a single induction cycle for the treatment of ALL/AML or MDS or CML blast crisis should
  • Recipients with a prior autologous transplant in the year prior to second transplant do not require ATG.
Other Name: ATG
Drug: cyclophosphamide
Cyclophosphamide will be given in a two hour infusion, total dose 50 mg/kg on day -6.
Other Name: Cytoxan
Drug: cyclosporine
Patients will receive cyclosporine A (CSA) therapy beginning on day -3 maintaining a level of >200. For adults the initial dose will be 2.5 mg/kg IV over 2 hours every 12 hours. For children < 40 kg the initial dose will be 2.5 mg/kg IV over 2 hours every 8 hours. Patients will receive CSA until day +100.
Other Name: CSA
Drug: fludarabine
Fludarabine 30 mg/m^2/day intravenous (IV) on day -6 through day -2., total dose 150 mg/m^2 for 5 days.
Other Name: Fludara
Drug: mycophenolate mofetil
Mycophenolate mofetil (MMF) 1.5 gram twice a day (BID) or if < 50 kg will be given 15 mg/kg orally(po) BID,beginning on day -3, and discontinue at day +30 or 7 days after engraftment (3 consecutive days of absolute neutrophil count (ANC) > 0.5 x 109 /L).
Other Name: MMF
Procedure: stem cell transplantation
On day 0, if related donor, stem cells are infused via central line. If unrelated donor, marrow/PBSC is infused after arrival and processing on day 0.
Other Names:
  • peripheral blood stem cell transplantation
  • bone marrow transplant
Radiation: total body irradiation
The dose of TBI will be 200 cGy given in a single fraction on day -1.
Other Name: TBI
Drug: filgrastim
Patients with white blood cell (WBC) counts < 2500 any time after stem cell infusion will be started on G-CSF support at Day +5 at a dose of 5 mcg/kg intravenously or subcutaneously (IV/SQ) daily rounded to vial size until absolute neutrophil count (ANC) > 2500 for 2 consecutive days.
Other Name: G-CSF

Detailed Description:

OBJECTIVES:

  • Determine if a nonmyeloablative regimen comprising cyclophosphamide, fludarabine, and radiotherapy followed by cyclosporine and mycophenolate mofetil provides a prompt and durable donor engraftment in patients with hematologic malignancies or kidney cancer who are undergoing allogeneic stem cell transplantation.
  • Determine the safety of this nonmyeloablative transplantation regimen in these patients.
  • Determine the risk of graft-versus-host-disease in patients treated with this regimen.
  • Determine the antineoplastic potency of nonmyeloablative stem cell transplantation in patients treated with this regimen.
  • Determine the effect of lower doses of daily fludarabine on treatment-related mortality (TRM) OUTLINE: Patients are stratified according to risk (standard vs high).
  • Preparative regimen*: Patients receive cyclophosphamide intravenously (IV) over 2 hours on day -6 and fludarabine IV over 1 hour on days -6 to -2. Patients undergo total body irradiation on day -1. Some patients also receive anti-thymocyte globulin (ATG)** IV every 12 hours on days -6 to -4. Patients who receive ATG* include the following:

    • Related donor recipients who have not received combination chemotherapy within the past 6 months
    • Unrelated donor recipients who have not received combination chemotherapy within the past 3 months
    • Unrelated donor recipients who have received only 1 induction course for the treatment of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), or blastic phase chronic myelogenous leukemia (CML) NOTE: **Patients who underwent prior autologous stem cell transplantation in the past year do not receive ATG.
  • Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo allogeneic PBSCT on day 0.
  • Graft-versus-host-disease prophylaxis: Patients receive cyclosporine IV over 2 hours beginning on day -3 and continuing until at least day 100. Patients also receive mycophenolate mofetil IV or orally twice daily on days -3 to 30.
  • Donor lymphocyte infusion (DLI): Patients without active GVHD but deteriorating donor chimerism may receive DLI IV over 2 hours.

After completion of study treatment, patients are followed periodically for 2 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:

Standard patients will be enrolled into Arms 1-6. High risk patients (transplant with aplasia) will be considered separately in Arm 7.

  • Age and Graft criteria (all patients)

    • Patient's < or = 75 years old with a 5/6 or 6/6 related donor match are eligible.
    • Patient's < or = 75 years who have a 7-8/8 HLA-A,B,C,DRB1 allele matched unrelated volunteer marrow and/or peripheral blood stem cell (PBSC) donor match are eligible.
  • Disease Criteria (standard risk patients)

    • Acute myelogenous leukemia
    • Acute lymphocytic leukemia
    • Chronic myelogenous leukemia all types except blast crisis (note treated blast crisis in chronic phase is eligible).
    • Non-Hodgkins lymphoma (NHL), Hodgkins, chronic lymphocytic leukemia, multiple myeloma demonstrating chemosensitive disease
    • Acquired bone marrow failure syndromes
    • Myelodysplastic syndrome of all subtypes including refractory anemia (RA) or all IPSS categories if severe pancytopenia, transfusion requirements not responsive to therapy, or high risk cytogenetics. Blasts must be less than 5%. If >5% requires therapy (induction or Hypomethylating agents) pre-transplant to decrease disease burden.
    • Renal cell cancer,
    • Chronic myeloproliferative disorder, i.e. myelofibrosis
  • Disease Criteria (High risk patients on Arm 7)

    • Patients with refractory leukemia or MDS may be taken to transplant in aplasia after induction or re-induction chemotherapy or radiolabeled antibody. These high risk patients will be analyzed separately in Arm 7.
  • Adequate organ function and performance status (all patients)

Exclusion Criteria:

  • Pregnancy or breast feeding
  • Evidence of HIV infection or known HIV positive serology
  • Active serious infection
  • Congenital bone marrow failure syndrome
  • Previous irradiation that precludes the safe administration of an additional dose of 200 cGy of total body irradiation (TBI)
  • Chronic myelogenous leukemia (CML) in refractory blast crisis
  • Intermediate or high grade NHL, mantle cell NHL, and Hodgkins disease that is progressive on salvage therapy. Stable disease is acceptable to move forward provided it is non-bulky.
  • Multiple Myeloma progressive on salvage chemotherapy.

DONOR ELIGIBILITY

  • Related will undergo apheresis - if donor is unable to undergo apheresis, a bone marrow harvest is acceptable; unrelated volunteer donors must be able to undergo bone marrow harvest or apheresis.
  • All donors must be able to give informed consent.
  • Donors weighing less than 40 kg (children) will need evaluation by a pediatrician for suitability of the apheresis procedure. Informed consent must be obtained from parent or guardian as applicable for minors.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00303719

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
Study Chair: Erica Warlick, MD 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: NCT00303719     History of Changes
Other Study ID Numbers: 2001LS058, UMN-MT2001-10, 0108M06725
Study First Received: March 15, 2006
Last Updated: July 8, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Masonic Cancer Center, University of Minnesota:
leukemia
lymphoma
myeloma

Additional relevant MeSH terms:
Plasmacytoma
Carcinoma, Renal Cell
Kidney Neoplasms
Leukemia
Lymphoma
Multiple Myeloma
Myelodysplastic Syndromes
Neoplasms, Plasma Cell
Preleukemia
Adenocarcinoma
Blood Protein Disorders
Bone Marrow Diseases
Carcinoma
Cardiovascular Diseases
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders
Kidney Diseases
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Paraproteinemias
Precancerous Conditions
Urogenital Neoplasms
Urologic Diseases

ClinicalTrials.gov processed this record on October 21, 2014