EPOCH-R Chemotherapy Plus Bortezomib to Treat Mantle Cell Lymphoma
Condition: Lymphoma, Mantle Cell; Mantle Cell Lymphoma
MeSH terms: Lymphoma; Lymphoma, Mantle-Cell
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will evaluate the effectiveness of etoposide, prednisone, vincristine,
      cyclophosphamide, doxorubicin-rituximab (EPOCH-R) chemotherapy plus bortezomib for treating
      mantle cell lymphoma, a cancer of white blood cells called lymphocytes. EPOCH-R consists of
      the drugs prednisone, etoposide, doxorubicin and vincristine, with the addition of a new drug
      called rituximab. In a recent study of patients with newly diagnosed mantle cell lymphoma, 92
      percent had a complete remission of their disease after treatment with EPOCH-R. This study
      will test whether adding bortezomib as "maintenance therapy" once chemotherapy is finished
      will lengthen the time before the disease relapses and improve the overall cure rate.

      Patients 18 years of age and older with mantle cell lymphoma may be eligible for this study.
      Candidates are screened with a medical history and physical examination, blood and urine
      tests, electrocardiogram, multi-gated acquisition scan (MUGA) or echocardiogram, imaging
      studies and biopsy to determine the extent of disease, and possible colonoscopy.

      Participants undergo treatment in three parts, as follows:

        -  Part 1: Bortezomib alone: Patients receive 4 doses of bortezomib over 3 weeks. The drug
           is injected into a vein over about 30 seconds.

        -  Part 2: EPOCH-R chemotherapy plus bortezomib: This phase of treatment begins 3 to 4
           weeks after completing Part 1. Treatment is given on an outpatient basis in six 3-week
           cycles, with all drugs administered over the first 5 days of each cycle. Patients take
           prednisone by mouth on days 1 to 5 and etoposide, doxorubicin, and vincristine as a
           96-hour infusion through a vein over days 1 to 5. The infused drugs are delivered
           through a lightweight, portable infusion pump. Rituximab is given by vein over several
           hours on day 1 immediately before the chemotherapy infusion begins. Bortezomib is given
           by vein over 30 seconds on day 1 before the rituximab and again on day 4.
           Cyclophosphamide is given by vein over about 15 minutes on day 5 immediately after the
           chemotherapy infusion is completed. Patients are taught how to self inject granulocyte
           colony stimulating factor (G-CSF), a drug that helps boost white cell counts after
           chemotherapy. They inject the drug under the skin (like an insulin shot) for 10 days of
           each cycle beginning day 6. Patients also take an antibiotic to help prevent infection
           during chemotherapy.

        -  Part 3: Bortezomib alone: After completing EPOCH-R-B therapy, patients are randomly
           assigned to receive or not to receive bortezomib alone. The drug is given in 2 doses
           over 5 days, with a break of 16 days before the next dose. These 3-week cycles continue
           for up to 18 months or until the disease comes back or worsens. Patients who are
           assigned to the group that does not receive bortezomib will be offered the drug if their
           disease relapses.

      During therapy, patients have tests performed on their bone marrow, tumor tissue, blood or
      other fluids to look at different genes and proteins that may be involved in the development
      of their lymphoma or the reaction of the immune system. A tissue biopsy is done before
      treatment begins and a day after treatment starts. Disease progress is followed with computed
      tomography (CT) scans and blood tests. When treatment is completed, patients whose cancer has
      disappeared are scheduled for periodic follow-up examinations and tests. Those whose disease
      remains or recurs may be offered participation in another protocol if an appropriate one is
      available or are returned to the care of their local physician.

      ...
    

Detailed description: 
      Background:

      Mantle cell lymphoma (MCL) presents a clinical challenge because it is aggressive and
      incurable with chemotherapy. Therefore novel treatment approaches are needed.

      MCL has overexpression of NF-kappa B (NF-kappa B), a transcription factor that affects cell
      growth and survival, and cyclin D1 that affects cell cycle and growth. These proteins appear
      to be involved in the pathogenesis of MCL.

      Bortezomib, a proteasome inhibitor that inhibits NF-kappa B and cyclin D1, has demonstrated
      activity in patients with relapsed or refractory MCL.

      Dose-adjusted-etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin-rituximab
      (EPOCH-R) has excellent activity in MCL, with a complete response (CR) rate of 92%, but
      patients eventually relapse.

      Objective:

      Determine the progression free survival (PFS) and overall survival (OS) of dose-adjusted
      etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and
      rituximab,bortezomib (DA-EPOCH-RB) followed by bortezomib maintenance versus observation.

      Eligibility:

      Diagnosis of mantle cell lymphoma.

      No prior treatment except for local radiation or a short course of steroids for control of
      symptoms,

      Age greater than or equal to 18 years old.

      Adequate major organ function unless impairment is due to lymphoma.

      Study Design:

      To assess the clinical activity and biological effects of bortezomib, patients will initially
      receive one cycle of bortezomib alone with sequential tumor biopsies for microarray analysis.

      All patients will then receive Dose-adjusted (DA)-EPOCH-RB for 6 cycles, and if they have at
      least a PR, this will be followed by randomization to either immediate bortezomib maintenance
      x 18 months, or to observation, followed by bortezomib if progression occurs. This study has
      as a primary goal, to describe progression free survival (PFS) and overall survival of early
      bortezomib maintenance versus observation following induction with bortezomib followed by
      DA-EPOCH-RB. Important secondary goals are to assess response and toxicity to bortezomib
      alone or DA-EPOCH-RB, to evaluate time to progression after receiving bortezomib following
      progression on an observation arm, and to assess the biological effects of bortezomib on
      untreated MCL.
    

Intervention name(s): Rituximab (R); EPOCH; Bortezomib (B); Bortezomib; Bortezomib or observation
Intervention type(s): Drug; Biological; Drug; Drug; Drug
Intervention description(s): Rituximab is given with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) and bortezomib every 3 weeks for 6 cycles.; EPOCH is given with Rituximab and bortezomib every 3 weeks for 6 cycles.; Bortezomib is given alone for one cycle.; Bortezomib is given with EPOCH and rituximab every 6 weeks for 12 cycles.; At the beginning of Part C, patients are randomized to receive bortezomib maintenance or be observed w/o bortezomib.
Other intervention name(s): Rituxan; Velcade; Velcade; Velcade
Intervention MeSH terms: Rituximab; Bortezomib
Allocation: Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Proteasome Inhibition; NF-Kappa-B; Gene Expression Signature; Cyclin D1; Translational Studies; Lymphoma; Mantle Cell Lymphoma; MCL