Study of Vorinostat (MK-0683) or Placebo, in Combination With Bortezomib in Participants With Multiple Myeloma (MK-0683-088 AMN)
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Vorinostat; bortezomib; placebo to vorinostat
Intervention description: Four 100 mg capsules vorinostat taken orally, once daily, on Days 1 through 14 of each 21-day treatment cycle.; 1.3 mg/m2 of bortezomib by IV push, on Days 1, 4, 8, and 11 of each 21-day treatment cycle.; Four placebo capsules taken orally, once daily, on Days 1 through 14 of each 21-day treatment cycle.
Intervention MeSH terms: Bortezomib; Vorinostat
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 637.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Vorinostat; Bortezomib; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Pharmacologic Actions; Anti-Inflammatory Agents; Therapeutic Uses; Antirheumatic Agents; Antineoplastic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anticarcinogenic Agents

Summary:

      Study of the efficacy and safety of bortezomib administered in combination with vorinostat in
      patients with relapsed or refractory multiple myeloma. Histone deacetylases (HDAC) facilitate
      gene transcription by modulating the uncoiling of chromatin. HDAC function is dysregulated in
      hematologic and solid malignancies, and this dysregulation may result in over-expression of
      oncogenes. Thus, inhibition of HDACs may result in anti-cancer effects. HDAC inhibitors, like
      vorinostat, represent a new class of antitumor agents that have the ability to induce
      antiproliferative effects including cyto-differentiation, cell cycle growth arrest or
      apoptosis in various cancer cell lines. Several studies have investigated the in vitro
      antimyeloma activity of vorinostat in combination with bortezomib and have demonstrated that
      vorinostat may act synergistically with bortezomib to modulate tumor cell growth. Mitsiades
      et al have shown that vorinostat enhances the sensitivity of bortezomib. Pei et al found that
      exposure of human multiple myeloma cell lines & patient-derived multiple myeloma cells to
      bortezomib and vorinostat resulted in synergistic interactions as a result of: (1)
      Interruption of NF-kB & related signaling pathways (JNK, XIAP, Mcl-1, etc.) (2) Inhibition of
      Hsp90 (3)Induction of ER stress signal and (4) acetylation of Dynein/disruption of aggresome
      function/formation, salvage for ubiquitinated proteins. In addition a marked increase in
      mitochondrial injury, caspase activation, and apoptosis was also observed. Bortezomib is
      indicated for the treatment of patients with multiple myeloma. Two Phase I dose-ranging
      studies of a regimen combining vorinostat and bortezomib among patients with relapsed as well
      asend-stage, refractory multiple myeloma have been conducted. These studies enrolled a total
      of 57 patients. In these studies, administration of vorinostat with standard doses of
      bortezomib resulted in responses in 20/45 (44%) evaluable patients (Weber et al 2007, Badros
      et al 2007). The purpose of the present study is to definitively evaluate the clinical
      activity of vorinostat in combination with bortezomib inpatients with multiple myeloma.
    

Eligibility criteria:

        Inclusion criteria

          -  Participant has an established diagnosis of multiple myeloma based on the myeloma
             diagnostic criteria.

          -  Participant has received at least 1 but not more than 3 prior anti-myeloma regimens
             and has progressive disease after the most recent treatment regimen.

          -  Participant must have adequate organ function.

        Exclusion criteria:

          -  Participant has had a prior allogeneic bone marrow transplant or plans to undergo any
             type of bone marrow transplantation within 4 weeks of the initiation of study therapy.

          -  Participant has known hypersensitivity to any components of bortezomib or vorinostat.

          -  Participant has active Hepatitis B or C, plasma cell leukemia, or is human
             immunodeficiency virus (HIV) positive.

          -  Participant has had prior treatment with vorinostat or histone deacetylase (HDAC)
             inhibitors.