Study of Vorinostat (MK-0683) an HDAC Inhibitor, or Placebo in Combination With Bortezomib in Patients With Multiple Myeloma (MK-0683-088 AMN)
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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 |
- 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 ]
- 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: | September 2013 |
| 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 |
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 More Information
No publications provided
| Responsible Party: | Merck |
| ClinicalTrials.gov Identifier: | NCT00773747 History of Changes |
| Other Study ID Numbers: | MK-0683-088, 2008_525 |
| Study First Received: | October 14, 2008 |
| Last Updated: | May 9, 2013 |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by Merck:
|
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 June 17, 2013