Allogeneic Bone Marrow Transplantation Using Less Intensive Therapy

This study is currently recruiting participants.
Verified December 2013 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: December 18, 2013
Last verified: December 2013
  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 phosphate
Drug: mycophenolate mofetil
Procedure: stem cell transplantation
Radiation: total-body irradiation
Drug: methylprednisolone
Drug: allopurinol
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
This treatment protocol will study the efficacy of a nonmyeloablative preparative regimen consisting of fludarabine and low dose TBI, with cytoxan to promote engraftment after allogeneic hematopoietic stem cell transplant.
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 08.
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 phosphate
Fludarabine 30 mg/m^2/day intravenous (IV) x 5 days, 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, adjust to tablet size; intravenous (IV) route can be used if po not tolerated (same dosing as PO).

Begin day -3.

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: methylprednisolone
Methylprednisolone 1 mg/kg intravenous (IV) will be administered immediately prior to each dose of ATG (6 doses).
Other Name: Medrol
Drug: allopurinol
Allopurinol 300 mg/day starting at day -6 through day 0
Other Name: Zyloprim
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
This treatment protocol will study the efficacy of a nonmyeloablative preparative regimen consisting of fludarabine and low dose TBI, with cytoxan to promote engraftment after allogeneic hematopoietic stem cell transplant.
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 08.
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 phosphate
Fludarabine 30 mg/m^2/day intravenous (IV) x 5 days, 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, adjust to tablet size; intravenous (IV) route can be used if po not tolerated (same dosing as PO).

Begin day -3.

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: methylprednisolone
Methylprednisolone 1 mg/kg intravenous (IV) will be administered immediately prior to each dose of ATG (6 doses).
Other Name: Medrol
Drug: allopurinol
Allopurinol 300 mg/day starting at day -6 through day 0
Other Name: Zyloprim
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— high risk CR1 (as evidenced by preceding myelodysplastic syndrome [MDS], high risk cytogenetics such as those associated with MDS or complex karyotype, or > 2 cycles to obtain CR); second or greater complete remission (CR). Must be in remission by morphology. Patients in morphologic relapse/ persistent disease defined as > 5% blasts in normocellular bone marrow OR any % blasts if blasts have unique morphologic markers (eg auer rods) or associated cytogenetic markers that allows morphologic relapse to be distinguished are not eligible for arms 2 or 3.

Note cytogenetic evidence of disease alone without morphologic relapse is acceptable. Also a small percentage of blasts that is equivocal between marrow regeneration vs early relapse is acceptable provided there are no associated cytogenetic markers consistent with relapse.

  • Acute lymphocytic leukemia-- high risk CR1 as evidenced by high risk cytogenetics (eg t(9;22) or complex cytogenetic abnormalities) or > 1 cycle to obtain CR; second or greater CR. Must be in remission by morphology. Patients in morphologic relapse/ persistent disease defined as > 5% blasts in normocellular bone marrow OR any % blasts if blasts have unique morphologic markers or associated cytogenetic markers that allows morphologic relapse to be distinguished are not eligible for arms 2 or 3. 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 is acceptable provided there are no associated cytogenetic markers consistent with relapse.
  • 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):
  • Cardiac: No decompensated congestive heart failure (CHF), or uncontrolled arrythmia; ejection fraction > 35%
  • Pulmonary: DLCO > 30% predicted, No oxygen requirements
  • Liver: Transaminases < 5.0 x upper limit of normal (ULN); Bilirubin < 3 x ULN
  • Renal: Creatinine < 2.0 mg/dl (adults) or creatinine clearance > 40 ml/min. ). All adults with a creatinine > 1.2 or a history of renal dysfunction must have creatinine clearance (must be > 40 ml/min).
  • Second bone marrow transplant (BMT): must be > 3 months after prior myeloablative transplant
  • Defined as Karnofsky > 60 (adults) or Lansky >/= 50.
  • If recent mold infection (e.g. aspergillus) must have minimum of 30 days of therapy and responsive disease and be cleared by Infectious Disease.
  • Albumin > 2.5

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
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: December 18, 2013
Health Authority: United States: Food and Drug Administration

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

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

ClinicalTrials.gov processed this record on April 17, 2014