Study of Vorinostat (MK0683), an HDAC Inhibitor, in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma


Tracking Information

Start Date  ICMJEDecember 2008
Estimated Primary Completion DateOctober 2010   (final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE 
 (submitted: October 31, 2009)
Response rate associated with the administration of vorinostat in combination with bortezomib [ Time Frame: 21 days ] [ Designated as safety issue: No ]
Original Primary Outcome Measures  ICMJE 
 (submitted: October 15, 2008)
Response rate associated with the administration of vorinostat in combination with bortezomib [ Time Frame: 18 months ] [ Designated as safety issue: No ]
Change HistoryComplete list of historical versions of study NCT00773838 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE 
 (submitted: October 15, 2008)
Tolerability of vorinostat administered in combination with bortezomib [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
Original Secondary Outcome Measures  ICMJESame as current

Descriptive Information

Brief Title  ICMJEStudy of Vorinostat (MK0683), an HDAC Inhibitor, in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma
Official Title  ICMJEAn International, Multicenter, Open-Label Study of Vorinostat (MK0683) in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma
Brief Summary

Study of vorinostat in combination with bortezomib in patients with relapsed or refractory multiple myeloma after at least 2 prior treatment regimens.

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.

Based on the preliminary safety & efficacy presented by Weber et al and Badros et al at ASH 2007, this protocol will further evaluate the clinical activity of vorinostat in multiple myeloma.

Detailed Description 
Study PhasePhase II
Study Type  ICMJEInterventional
Study Design  ICMJETreatment, Non-Randomized, Open Label, Active Control, Single Group Assignment, Efficacy Study
Condition  ICMJERelapsed or Refractory Multiple Myeloma
Intervention  ICMJE
  • Drug: vorinostat (HDAC inhibitor)
    Four 100 mg vorinostat capsules once daily by mouth on days 1-14 of each 21 day treatment cycle. Up to 18 months of treatment.
    Other Name: Zolinza
  • Drug: bortezomib
    bortezomib 1.3 mg/m2 by IV on days 1, 4, 8, and 11 of each 21-day treatment cycle. Total treatment is up to 18 months.
    Other Name: Velcade
  • Drug: dexamethasone
    Five 4 mg Dexamethasone tablets by mouth on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day treatment cycle if disease progression is observed after 2 treatment cycles if no change to disease is observed after 4 treatment cycles .
Study Arms / Comparison Groups1: Experimental
vorinostat and bortezomib
Interventions:
  • Drug: vorinostat (HDAC inhibitor)
  • Drug: bortezomib
  • Drug: dexamethasone

Recruitment Information

Estimated Enrollment  ICMJE142
Estimated Completion DateOctober 2010
Estimated Primary Completion DateOctober 2010   (final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patient is 18 years of age or older
  • Patient has an established diagnosis of multiple myeloma based on myeloma diagnostic criteria
  • Patient must have adequate organ function
  • Patient is refractory to prior bortezomib regimen and have also been exposed to prior IMiD (thalidimide or lenalidmide)
  • Patient has relapsed and refractory multiple myeloma after at lest 2 prior treatment regimens
  • Patient is relapsed, refractory, intolerant, and/or ineligible (in the opinion of the investigator) to other therapies including an IMiD (thalidomide OR lenalidomide)
  • Patient is refractory to bortezomib (no response on prior bortezomib containing regimen or progression on or within 60 days of bortezomib containing regimen

Exclusion Criteria:

  • Patient has known hypersensitivity to any components of bortezomib or vorinostat
  • 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
GenderBoth
Ages18 Years and older
Accepts Healthy VolunteersNo
Contacts  ICMJE
Contact: Toll Free Number1-888-577-8839
Location Countries  ICMJEUnited States,   Australia,   Belgium,   Canada,   France,   Germany,   Italy,   Korea, Republic of,   Russian Federation,   Spain,   United Kingdom

Administrative Information

NCT ID  ICMJENCT00773838
Responsible PartyExecutive Vice President, Clinical and Quantitative Sciences, Merck & Co., Inc.
Study ID Numbers  ICMJE2008_524, MK0683-095
Study Sponsor  ICMJEMerck
Collaborators  ICMJE 
Investigators  ICMJE
Study Director:Medical MonitorMerck
Information Provided ByMerck