Study of bortezomib administered in combination with vorinostat or placebo 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 as end-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 in patients with multiple myeloma

• Drug: vorinostat (an HDAC inhibitor)
  Four 100mg capsules Vorinostat taken orally, once daily on days 1-14 of each 21 day treatment cycle.
  Other Name: Zolinza
• Drug: bortezomib
  1.3 mg/m2 of bortezomib by IV push, on days 1, 4, 8, and 11 of each 21 day treatment cycle
  Other Name: Velcade

• 1: Experimental
  vorinostat + bortezomib
  Interventions:

  • Drug: vorinostat (an HDAC inhibitor)
  • Drug: bortezomib
• 2: Placebo Comparator
  placebo + bortezomib
  Intervention: Drug: bortezomib

Inclusion Criteria:

Patient is 18 years of age or older

• Patient has an established diagnosis of multiple myeloma based on the myeloma diagnostic criteria
• Patient has received at least 1 but not more than 3 prior anti-myeloma regimens and has progressive disease after the most recent treatment regimen
• Patient must have adequate organ function

Exclusion Criteria:

• Patient 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
• Patient has known hypersensitivity to any components of bortezomib or vorinostat
• Patient has active Hepatitis B or C, plasma cell leukemia, or is HIV positive
• Patient has had prior treatment with vorinostat or HDAC inhibitors