Escalating Doses of Thalidomide in Conjunction With Bortezomib and HIgh Dose Melphalan for BSCT
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The primary objective of this study is to:

      • Determine the maximum tolerated dose of thalidomide used in conjunction with dose-intense
      melphalan, bortezomib and autologous (syngeneic) HSC support in the salvage therapy of
      patients who failed a prior treatment with dose-intense melphalan

      The secondary objectives of this study are to:

        -  Determine the toxicities resulting from administration of combinations of thalidomide,
           bortezomib and melphalan

        -  Determine the complete response (CR) and very good partial response (VgPR) rate in
           patients undergoing ASCT using thalidomide, bortezomib and melphalan

        -  Evaluate the treatment-free interval after treatment with the combination of
           thalidomide, bortezomib and melphalan
    

Detailed description: 
      VELCADE™ (bortezomib) for Injection is a small molecule proteasome inhibitor developed by
      Millennium Pharmaceuticals, Inc., (Millennium) as a novel agent to treat human malignancies.
      VELCADE is currently approved by the United States Food and Drug Administration (US FDA) and
      it is registered in Europe for the treatment of multiple myeloma patients who have received
      at least one prior therapy.

      By inhibiting a single molecular target, the proteasome, bortezomib affects multiple
      signaling pathways. The anti-neoplastic effect of bortezomib likely involves several distinct
      mechanisms, including inhibition of cell growth and survival pathways, induction of
      apoptosis, and inhibition of expression of genes that control cellular adhesion, migration
      and angiogenesis. Thus, the mechanisms by which bortezomib elicits its antitumor activity may
      vary among tumor types, and the extent to which each affected pathway is critical to the
      inhibition of tumor growth could also differ. Bortezomib has a novel pattern of cytotoxicity
      in National Cancer Institute (NCI) in vitro and in vivo assays (Adams et al., 1999). In
      addition, bortezomib has cytotoxic activity in a variety of xenograft tumor models, both as a
      single agent and in combination with chemotherapy and radiation (Steiner et al., 2001;
      Teicher et al., 1999; Cusack et al., 2001; LeBlanc et al., 2002; Pink et al., 2002). Notably,
      bortezomib induces apoptosis in cells that over express bcl-2, a genetic trait that confers
      unregulated growth and resistance to conventional chemotherapeutics (McConkey et al., 1999).

      Bortezomib is thought to be efficacious in multiple myeloma via its inhibition of nuclear
      factor κB (NF-κB) activation, its attenuation of interleukin-6 (IL-6)-mediated cell growth, a
      direct apoptotic effect, and possibly anti-angiogenic and other effects.
    

Intervention name(s): Thalidomide+Melphalan +Bortezomib+stem cell transplant
Intervention type(s): Drug
Intervention description(s): Five days prior to transplant, the patient starts thalidomide. Dose range will be from 600mg for 5 days, to 1000mg for 5 days. Thalidomide dose is increased after groups of 3 to 6 patients have been treated. 4 days before the transplant and again on the day before the transplant the patient will be given bortezomib (VELCADE) intravenously at a dose of 1.6 mg/m2 (mg/m2 means that the dose will be calculated based on the patient's height and weight). 2 days before transplant the patient will be given melphalan 200 mg/m2 intravenously. Dexamethasone is given before the VELCADE and the melphalan.
Intervention MeSH terms: Thalidomide; Bortezomib; Melphalan
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: multiple myeloma; transplant; Multiple myeloma patients undergoing transplant