PS-341 Alone and PS-341 Plus EPOCH Chemotherapy to Treat Non-Hodgkin's Lymphoma
Condition: B-Cell Lymphoma
MeSH terms: Lymphoma; Lymphoma, B-Cell
Intervention: PS-341; Etoposide; Doxorubicin; Vincristine; Cyclophosphamide; Prednisone; Filgrastim
Intervention description: 1.3 mg/m^2 intravenous injection days 1, 4, 8, 11 every 3 weeks; 50 mg/m^2 day continuous intravenous infusion (CIV) days 1-4, 96 hour infusion. Repeat cycle every 21 days.; 10 mg/m^2 day CIV days 1-4, 96 hour infusion. Repeat cycle every 21 days.; 0.4 mg/m^2 day CIV days 1-4, 96 hour infusion. Repeat cycle every 21 days.; 750 mg/m^2 day IV day 5 bolus. Repeat cycle every 21 days.; 60 mg/m^2 by mouth twice a day days 1-5. Repeat cycle every 21 days.; 300 micrograms subcutaneously days 6 to absolute neutrophil count recovery greater than or equal to 5000/mm^3. Repeat cycle every 21 days.
Intervention MeSH terms: Prednisone; Cyclophosphamide; Doxorubicin; Etoposide; Vincristine; Bortezomib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 50.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: BCL-2; NFK-B; Drug Resistance; Translational; Lymphoma; Large B-Cell Lymphoma

Summary:

      This study will examine the safety and effectiveness of an experimental drug called
      Bortezomib (PS-341), given alone and in combination with a chemotherapy regimen called
      Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin and Filgrastim (EPOCH), in
      treating non-Hodgkin's B-cell lymphoma. In the laboratory, PS-341 kills lymphoma cells and
      makes them more sensitive to chemotherapy. The EPOCH treatment regimen includes the drugs
      doxorubicin, etoposide, vincristine, cyclophosphamide, prednisone, and filgrastim.

      Patients 18 years of age and older with an aggressive non-Hodgkin's lymphoma that has
      relapsed after treatment or is not responding to chemotherapy may be eligible for this study.
      Candidates will be screened with a medical history and physical examination. Other tests that
      may be required include blood and urine tests; lung function studies; imaging tests such as
      magnetic resonance imaging, computed tomography and x-rays; and biopsy (surgical removal of a
      small tissue sample) of tumor, bone marrow, or other tissue.

      Upon entering the study, all participants will receive PS-341. The drug is given as a 3- to
      5-second intravenous (through a vein) injection twice a week for 2 weeks. This is followed by
      a 1-week rest. Each 3-week period comprises one treatment cycle. The number of cycles a
      patient receives depends on how well he or she responds to the drug. Patients who do not have
      a complete remission or whose tumor grows on this therapy will be offered PS-341 in
      combination with up to six cycles of EPOCH chemotherapy. The treatment for patients taking
      PS-341 plus EPOCH is as follows:

        -  PS-341, given by 3- to 5-second intravenous (IV) injection on days 1 and 4 of each
           cycle.

        -  Doxorubicin, etoposide, and vincristine, given by continuous IV infusion over 4 days,
           beginning on day 1 and ending on day 5 of each cycle. The drugs are delivered through a
           lightweight portable infusion pump to an indwelling IV catheter (plastic tube) in a
           vein.

        -  Cyclophosphamide, given by IV infusion over 15 minutes on day 5 of each cycle.

        -  Prednisone, given by mouth (pills) twice a day on days 1 through 5 of each cycle.

        -  Filgrastim, given by injection under the skin starting on day 6 of each cycle and
           continuing until the white blood cell count increases or until day 19 of the cycle.

      Patients also take a combination of antibiotics 3 days a week during EPOCH to prevent
      infection while resistance is lowered because of the chemotherapy. Etoposide, doxorubicin,
      and cyclophosphamide doses are adjusted as needed, based on white blood cell counts of the
      previous cycle. The first patients in the study will receive a low dose of PS-341. The dose
      will be increased in subsequent small groups of patients as long as the preceding dose is
      well tolerated.

      Drug therapy for patients who are candidates for bone marrow transplant will be tailored to
      permit transplantation. Patients who are not eligible for or who choose not to have a bone
      marrow transplant will be followed at the National Institutes of Health (NIH) every 3 months
      the first year, every 4 months the second year, every 6 months the third year, and then once
      a year until their disease progresses or the study ends. Patients may have tumor and bone
      marrow biopsies, blood draws, and computed tomography (CT) scans periodically to evaluate
      disease status and drug side effects.
    

Eligibility criteria:

        -  ELIGIBILITY CRITERIA:

        Large B-cell lymphoma (subtypes: DLBCL (diffuse large B-cell lymphoma);

        mediastinal (thymic) large B-cell lymphoma;

        transformed large B-cell lymphoma;

        follicular grade IIIB large B-cell lymphoma;

        intravascular large B-cell lymphoma).

        Confirmed pathological diagnosis at the treating institution.

        Prior anthracycline-based treatment.

        Age greater than or equal to 18 years.

        Available tumor tissue for biopsy.

        Eastern Cooperative Oncology Group (ECOG) performance 2 or better.

        Major organ function: Absolute neutrophil count (ANC) greater than or equal to
        1,000/microliters,

        Platelet greater than or equal to 50,000/microliters,

        creatinine less than or equal to 1.5 mg/dl or creatinine clearance greater than 60 cc/min;

        serum glutamic pyruvic transaminase (SGPT) less than 5 x upper limit of normal;

        bilirubin less than 2 mg/dl (total) except less than 5 mg/dl in patients with Gilbert's
        syndrome as defined by greater than 80 percent unconjugated; unless impairment due to organ
        involvement by lymphoma.

        Informed consent and willingness to use contraception by both men and women.

        Not pregnant or nursing because of an unknown potential for teratogenic or abortifacient
        effects.

        Both male and female patients must be willing to use adequate contraception.

        Human immunodeficiency virus (HIV) serology negative.

        HIV positive patients receiving combination anti-retroviral therapy are excluded from the
        study because of positive pharmacokinetic interactions with PS-341 or the combination of
        PS-341 and EPOCH.

        Additionally, the biology of HIV associated DLBCL's is often quite different from HIV
        negative disease due to involvement of Epstein Barr Virus (EBV).

        Hepatitis B surface antigen negative.

        No symptomatic cardiac disease or cardiac ejection fraction less than 40 percent (in
        patients receiving EPOCH).

        No active central nervous system (CNS) lymphoma.

        No systemic cytotoxic or experimental treatments within 4 weeks of treatment.