Busulfan, Fludarabine, and Total-Body Irradiation in Treating Patients Who Are Undergoing a Donor Stem Cell Transplant for Hematologic Cancer (Bu Flu TBI)

This study is currently recruiting participants.
Verified November 2013 by OHSU Knight Cancer Institute
Sponsor:
Collaborator:
Information provided by (Responsible Party):
OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier:
NCT00245037
First received: October 25, 2005
Last updated: November 18, 2013
Last verified: November 2013
  Purpose

RATIONALE: Giving low doses of chemotherapy, such as fludarabine and busulfan, before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system and help destroy any remaining cancer cells (graft-versus-tumor effect). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect. Sometimes the transplanted cells from a donor can also 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 I/II trial is studying the side effects of giving busulfan and fludarabine together with total-body irradiation and to see how well they work in treating patients who are undergoing a donor stem cell transplant for hematologic cancer.


Condition Intervention Phase
Chronic Myeloproliferative Disorders
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Neoplasms
Precancerous Condition
Biological: therapeutic allogeneic lymphocytes
Drug: busulfan
Drug: cyclosporine
Drug: fludarabine phosphate
Drug: mycophenolate mofetil
Procedure: peripheral blood stem cell transplantation
Radiation: Total Body Irradiation (TBI)
Drug: Granulocyte colony-stimulating factor (G-CSF)
Drug: Phenytoin
Drug: Methotrexate
Phase 1
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplant for the Treatment of Patients With Hematologic Malignancies Using Busulfan, Fludarabine and Total Body Irradiation

Resource links provided by NLM:

Genetic and Rare Diseases Information Center resources: Acute Lymphoblastic Leukemia Lymphoma, Small Cleaved-cell, Diffuse Leukemia, Myeloid Chronic Myeloid Leukemia Myelodysplastic Syndromes Multiple Myeloma Chronic Myeloproliferative Disorders Hodgkin Lymphoma Acute Myelocytic Leukemia Acute Non Lymphoblastic Leukemia Myelodysplastic/myeloproliferative Disease Acute Myeloid Leukemia, Adult Follicular Lymphoma B-cell Lymphomas Myelofibrosis Burkitt Lymphoma Lymphoma, Large-cell Lymphoma, Large-cell, Immunoblastic Lymphoblastic Lymphoma Chronic Lymphocytic Leukemia Leukemia, B-cell, Chronic Chronic Myelomonocytic Leukemia Chronic Neutrophilic Leukemia Hypereosinophilic Syndrome Monoclonal Gammopathy of Undetermined Significance Mantle Cell Lymphoma Cutaneous T-cell Lymphoma AL Amyloidosis Essential Thrombocythemia Anaplastic Plasmacytoma Polycythemia Vera
U.S. FDA Resources

Further study details as provided by OHSU Knight Cancer Institute:

Primary Outcome Measures:
  • Safety [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
    Evaluations at 6 months, 12 months, 18 months and subsequent yearly follow-up's for a total of 5 years.

  • Non-relapse mortality [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    Chimerisms and post-engraftment are followed on days 28, 56, and 84 post transplant with an evaluation at 180 days (6 months), then 1 year, 18 months, 2, 3, 4, & 5 years after.


Estimated Enrollment: 200
Study Start Date: June 2005
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)
Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 cGy x 1, day 0
Biological: therapeutic allogeneic lymphocytes
A population of lymphocytes therapeutically administered to a recipient individual who is genetically distinct from a donor of the same species.
Drug: busulfan

Busulfan is an alkylating chemotherapeutic agent which has been used in many high dose and reduced intensity regimens prior to allogeneic or autologous hematopoietic stem cell transplants. It is active in a wide variety of malignancies and in high-doses it is myeloablative.

IV busulfan is available and diluted and administered per package insert guidelines.

Drug: cyclosporine

Cyclosporine is a cyclic polypeptide immunosuppressive agent. It blocks the calcium-dependent calcineurin-mediated nuclear localization of NFAT following T-cell activation, thereby inhibiting transactivation of key T-cell response genes including IL-2 and IL-4.

- Starting on day -3, CSP is given at a dose of 4.0 mg/kg p.o. b.i.d.

Drug: fludarabine phosphate

Fludarabine's active metabolite 2-fluoro-ara-A is an antimetabolite that inhibits DNA primase, DNA polymerase alpha and ribonucleotide nuclease.

  • Dosing: Days -4, -3 and -2: Fludarabine 30 mg/m2/day IV. Total dose equals 90 mg/m2.
  • Monitoring: Fludarabine level is not monitored.
  • Dose Adjustments: There are no provisions for fludarabine dose adjustments.
Drug: mycophenolate mofetil

MMF is the morpholinyl ethyl ester of mycophenolic acid (MPA) and reversibly inhibits inosine monophosphate dehydrogenase, particularly the type II isoform that is more prominent in activated lymphocytes. As a result of the inhibition of de novo purine synthesis, proliferation of B- and T-lymphocytes is blocked and antibody production is inhibited.

  • Related Donors: MMF will be given daily at 15mg/kg q 12 hrs until day +28, then stop without tapering. Doses will be rounded to the nearest 250 mg (capsules are 250 mg).
  • Unrelated Donors: MMF will be given daily at 15mg/kg q 8 hrs until day +28, then given daily at 15mg/kg q 12 hours until day +56, then stop without tapering. Doses will be rounded to the nearest 250 mg (capsules are 250 mg).
Procedure: peripheral blood stem cell transplantation

Bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) are procedures that restore stem cells that have been destroyed by high doses of chemotherapy and/or radiation therapy. There are three types of transplants:

  • In autologous transplants, patients receive their own stem cells.
  • In syngeneic transplants, patients receive stem cells from their identical twin.
  • In allogeneic transplants, patients receive stem cells from their brother, sister, or parent. A person who is not related to the patient (an unrelated donor) also may be used.
Radiation: Total Body Irradiation (TBI)

TBI is a form of radiotherapy used primarily as part of the preparative regimen for haematopoietic stem cell (or bone marrow) transplantation. As the name implies, TBI involves irradiation of the entire body, though in modern practice the lungs are often partially shielded to lower the risk of radiation-induced lung injury.

  • Toxicities: At the dosage used, side effects are not expected. Nevertheless, there may be fever, alopecia, parotitis, diarrhea, reversible skin pigmentation, mucositis and late effects including cataract formation, pulmonary damage, carcinogenesis, and sterilization.
  • Dosing: TBI will be given in one 200 cGy fraction from linear accelerator at a rate of 15-19 cGy/min.
Drug: Granulocyte colony-stimulating factor (G-CSF)

Granulocyte colony-stimulating factor (G-CSF or GCSF) is a colony-stimulating factor hormone. G-CSF is also known as colony-stimulating factor 3 (CSF 3).

It is a glycoprotein, growth factor and cytokine produced by a number of different tissues to stimulate the bone marrow to produce granulocytes and stem cells. G-CSF then stimulates the bone marrow to release them into the blood.

  • Toxicities: At the dosage used, the most common side effect will be medullary bone pain.
  • Dosing: 5 mcg/kg/day given per institutional standards (on approximately days 10-15 or not at all).
Drug: Phenytoin
This drug is used to prevent seizures while on chemotherapy.
Drug: Methotrexate
Methotrexate is used to treat severe psoriasis (a skin disease in which red, scaly patches form on some areas of the body) that cannot be controlled by other treatments.

Detailed Description:

OBJECTIVES:

Primary

  • To assess safety and toxicity of the addition of busulfan added to an established fludarabine and low-dose total-body irradiation (TBI) conditioning regimen for non-myeloablative allogeneic transplantation in patients with hematologic malignancies. (Phase I)
  • To assess the non-relapse mortality 1-year after conditioning with busulfan and fludarabine/TBI in patients with hematologic malignancies at moderate to high risk for graft rejection and/or relapse of underlying disease. (Phase II)

Secondary

  • To assess overall survival 1-year survival. (Phase II)
  • To assess the incidence of graft rejection. (Phase II)
  • To assess the incidence of grade II-IV acute graft-vs-host disease (GVHD) and chronic extensive GVHD. (Phase II)
  • To assess rates of disease progression and/or relapse-related mortality. (Phase II)
  • To determine non-hematologic grade III-IV organ specific toxicity. (Phase II)

OUTLINE:

  • Nonmyeloablative-conditioning regimen: Patients receive busulfan IV on day -5 and fludarabine IV over 30 minutes on days -4 to -2. Patients undergo total body irradiation on day 0.
  • Allogeneic peripheral blood stem cell transplantation (PBSC): Patients undergo donor PBSC infusion on day 0.
  • Graft-versus-host disease prophylaxis: Patients receive oral cyclosporine twice daily on days -3 to 56 followed by a taper to day 180. Patients with a related stem cell donor receive oral mycophenolate mofetil twice daily on days 0-28. Patients with an unrelated stem cell donor receive oral mycophenolate mofetil 3 times daily on days 0-28 followed by a taper twice daily to day 56. Patients with evidence of relapse or persistent disease may also receive up to 3 donor lymphocyte infusions.

PROJECTED ACCRUAL: A total of 200 patients will be accrued for this study.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Diagnosis of a hematologic malignancy of 1 of the following high-risk types:

    • Acute lymphoblastic leukemia
    • Acute myeloid leukemia
    • Chronic myelogenous leukemia
    • Chronic lymphocytic leukemia
    • Myelodysplastic syndromes
    • Myeloproliferative disorder
    • Multiple myeloma
    • Plasma cell dyscrasias
    • Non-Hodgkin lymphoma
    • Hodgkin disease

PATIENT CHARACTERISTICS:

Performance status

  • Karnofsky 50-100%

Life expectancy

  • Not specified

Hematopoietic

  • Not specified

Hepatic

  • No liver failure
  • No cirrhosis with evidence of portal hypertension
  • No alcoholic hepatitis
  • No esophageal varices
  • No chronic hepatitis
  • No other liver disease

Renal

  • Not specified

Cardiovascular

  • LVEF > 35%
  • No symptomatic coronary artery disease or cardiac failure requiring therapy

Pulmonary

  • DLCO > 30%
  • Total lung capacity > 30%
  • FEV_1 > 30%
  • No supplementary continuous oxygen

Other

  • HIV negative
  • No active nonhematologic malignancy except localized skin cancer
  • No overt organ dysfunction

PRIOR CONCURRENT THERAPY:

  • Not specified
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00245037

Locations
United States, Oregon
Knight Cancer Institute at Oregon Health and Science University Recruiting
Portland, Oregon, United States, 97239-3098
Contact: Clinical Trials Office - Knight Cancer Institute at Oregon Hea    503-494-1080    trials@ohsu.edu   
Sponsors and Collaborators
OHSU Knight Cancer Institute
Investigators
Study Chair: Richard Maziarz, MD OHSU Knight Cancer Institute
  More Information

Additional Information:
No publications provided

Responsible Party: OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier: NCT00245037     History of Changes
Other Study ID Numbers: CDR0000447204, P30CA016058, OHSU-HEM-05011-L, OHSU-210
Study First Received: October 25, 2005
Last Updated: November 18, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by OHSU Knight Cancer Institute:
recurrent adult acute lymphoblastic leukemia
recurrent adult acute myeloid leukemia
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
atypical chronic myeloid leukemia, BCR-ABL negative
refractory chronic lymphocytic leukemia
stage III chronic lymphocytic leukemia
stage IV chronic lymphocytic leukemia
accelerated phase chronic myelogenous leukemia
blastic phase chronic myelogenous leukemia
chronic phase chronic myelogenous leukemia
relapsing chronic myelogenous leukemia
stage II multiple myeloma
stage III multiple myeloma
primary systemic amyloidosis
refractory multiple myeloma
myelodysplastic/myeloproliferative neoplasm, unclassifiable
chronic eosinophilic leukemia
primary myelofibrosis
chronic neutrophilic leukemia
essential thrombocythemia
polycythemia vera
chronic myelomonocytic leukemia
acute undifferentiated leukemia
extramedullary plasmacytoma
isolated plasmacytoma of bone
monoclonal gammopathy of undetermined significance
stage I multiple myeloma
secondary acute myeloid leukemia

Additional relevant MeSH terms:
Neoplasms
Leukemia
Lymphoma
Lymphoma, Non-Hodgkin
Multiple Myeloma
Neoplasms, Plasma Cell
Plasmacytoma
Myelodysplastic Syndromes
Preleukemia
Myeloproliferative Disorders
Precancerous Conditions
Lymphoma, Large-Cell, Immunoblastic
Myelodysplastic-Myeloproliferative Diseases
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
Phenytoin
Busulfan
Cyclosporins
Cyclosporine

ClinicalTrials.gov processed this record on April 15, 2014