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Sponsored by: |
Merck |
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Information provided by: | Merck |
ClinicalTrials.gov Identifier: | NCT00773838 |
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 ubiquinated 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
Condition | Intervention | Phase |
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Relapsed or Refractory Multiple Myeloma |
Drug: Comparator: vorinostat (HDAC inhibitor) Drug: Comparator: bortezomib Drug: Comparator: dexamethasone |
Phase II |
Study Type: | Interventional |
Study Design: | Treatment, Non-Randomized, Open Label, Active Control, Single Group Assignment, Efficacy Study |
Official Title: | An International, Multicenter, Open-Label Study of Vorinostat (MK0683) in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma |
Estimated Enrollment: | 142 |
Study Start Date: | October 2008 |
Estimated Study Completion Date: | June 2010 |
Estimated Primary Completion Date: | June 2010 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
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1: Experimental
vorinostat and bortezomib
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Drug: Comparator: 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.
Drug: Comparator: 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.
Drug: Comparator: 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 .
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Ages Eligible for Study: | 18 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
Contact: Toll Free Number | 1-888-577-8839 |
United States, California | |
Call for Information | Recruiting |
Los Angeles, California, United States, 90095 | |
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Duarte, California, United States, 91010 | |
United States, Georgia | |
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Atlanta, Georgia, United States, 30322 | |
United States, Indiana | |
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Indianapolis, Indiana, United States, 46254 | |
United States, Massachusetts | |
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Boston, Massachusetts, United States, 02115 | |
United States, New Jersey | |
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Hackensack, New Jersey, United States, 07601 | |
United States, New York | |
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Syracuse, New York, United States, 13210-0000 | |
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New York, New York, United States, 10011 | |
United States, Pennsylvania | |
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Philadelphia, Pennsylvania, United States, 19107 | |
United States, South Carolina | |
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Greenville, South Carolina, United States, 29615 | |
United States, Tennessee | |
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Knoxville, Tennessee, United States, 37920 | |
United States, Texas | |
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Houston, Texas, United States, 77030-0000 | |
United States, Utah | |
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Salt Lake City, Utah, United States, 84132 | |
United States, Wisconsin | |
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Milwaukee, Wisconsin, United States, 53226 |
Study Director: | Medical Monitor | Merck |
Responsible Party: | Merck & Co., Inc. ( Executive Vice President, Clinical and Quantitative Sciences ) |
Study ID Numbers: | 2008_524, MK0683-095 |
Study First Received: | October 14, 2008 |
Last Updated: | January 8, 2009 |
ClinicalTrials.gov Identifier: | NCT00773838 |
Health Authority: | United States: Food and Drug Administration |
Dexamethasone Immunoproliferative Disorders Blood Protein Disorders Hematologic Diseases Blood Coagulation Disorders Bortezomib Vorinostat Vascular Diseases |
Paraproteinemias Hemostatic Disorders Multiple Myeloma Hemorrhagic Disorders Multiple myeloma Lymphoproliferative Disorders Dexamethasone acetate Neoplasms, Plasma Cell |
Anticarcinogenic Agents Anti-Inflammatory Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Physiological Effects of Drugs Hormones, Hormone Substitutes, and Hormone Antagonists Antiemetics Hormones Sensory System Agents Therapeutic Uses Cardiovascular Diseases Anti-Inflammatory Agents, Non-Steroidal Analgesics Neoplasms by Histologic Type |
Immune System Diseases Antineoplastic Agents, Hormonal Gastrointestinal Agents Enzyme Inhibitors Protective Agents Glucocorticoids Pharmacologic Actions Protease Inhibitors Neoplasms Autonomic Agents Analgesics, Non-Narcotic Peripheral Nervous System Agents Antirheumatic Agents Central Nervous System Agents |