Study of Vorinostat (MK-0683) an HDAC Inhibitor, or Placebo in Combination With Bortezomib in Patients With Multiple Myeloma (MK-0683-088 AMN)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT00773747
First received: October 14, 2008
Last updated: June 16, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Multiple Myeloma
Drug: vorinostat
Drug: bortezomib
Drug: placebo to vorinostat
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: An International, Multicenter, Randomized, Double-Blind Study of Vorinostat (MK0683) or Placebo in Combination With Bortezomib in Patients With Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • Duration of progression-free survival (PFS) in participants treated with vorinostat + bortezomib versus placebo + bortezomib [ Time Frame: From randomization to event of disease progression or death ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Number of participants with clinical and laboratory adverse events (AEs). [ Time Frame: From first dose to 30 days after last dose of study drugs ] [ Designated as safety issue: Yes ]
  • Overall survival [ Time Frame: From randomization to up to 2 years post last dose in participants treated with vorinostat + bortezomib versus placebo + bortezomib ] [ Designated as safety issue: No ]
  • Time to tumor progression (TTP) in participants treated with vorinostat + bortezomib versus placebo + bortezomib [ Time Frame: Every 21 days ] [ Designated as safety issue: No ]
  • Overall response rate (ORR) in participants treated with vorinostat + bortezomib versus placebo + bortezomib [ Time Frame: Every 21 days ] [ Designated as safety issue: No ]

Enrollment: 637
Study Start Date: December 2008
Estimated Study Completion Date: March 2015
Primary Completion Date: September 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Vorinostat + bortezomib arm Drug: vorinostat
Four 100 mg 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
Placebo Comparator: Placebo + bortezomib arm 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
Drug: placebo to vorinostat
Four placebo capsules taken orally, once daily, on Days 1-14 of each 21-day treatment cycle.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

No Contacts or Locations Provided
  More Information

Publications:
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT00773747     History of Changes
Other Study ID Numbers: 0683-088, 2008_525
Study First Received: October 14, 2008
Last Updated: June 16, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Merck Sharp & Dohme Corp.:
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

Additional relevant MeSH terms:
Multiple Myeloma
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
Antirheumatic Agents
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Vorinostat
Bortezomib
Antineoplastic Agents
Anticarcinogenic Agents
Analgesics, Non-Narcotic
Peripheral Nervous System Agents
Sensory System Agents
Histone Deacetylase Inhibitors
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Therapeutic Uses
Pharmacologic Actions
Analgesics

ClinicalTrials.gov processed this record on July 31, 2014