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| Sponsor: | Merck |
|---|---|
| Collaborators: |
University of Colorado, Denver Duke University |
| Information provided by (Responsible Party): | Merck |
| ClinicalTrials.gov Identifier: | NCT00773838 |
Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Relapsed or Refractory Multiple Myeloma |
Drug: vorinostat (HDAC inhibitor) Drug: bortezomib Drug: dexamethasone |
Phase II |
| Study Type: | Interventional |
| Study Design: | Allocation: Non-Randomized Endpoint Classification: Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| 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: | December 2008 |
| Estimated Study Completion Date: | April 2012 |
| Primary Completion Date: | May 2011 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: 1
vorinostat and bortezomib
|
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 .
|
The protocol has been amended to incorporate language to indicate the end of the study. The end of the study is designated as the time when the primary endpoint of 29 responders has been met, or the time when all patients have discontinued treatment or have been enrolled in the study for at least 6 months (if the primary endpoint is not reached by this time). Patients will be allowed to continue on protocol as long as they have not met the criteria for discontinuation.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
Contacts and Locations More Information
| Responsible Party: | Merck |
| ClinicalTrials.gov Identifier: | NCT00773838 History of Changes |
| Other Study ID Numbers: | MK-0683-095, 2008_524 |
| Study First Received: | October 14, 2008 |
| Last Updated: | September 7, 2011 |
| Health Authority: | United States: Food and Drug Administration |
|
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 Dexamethasone acetate |
Dexamethasone Dexamethasone 21-phosphate Vorinostat Bortezomib BB 1101 Histone Deacetylase Inhibitors Anti-Inflammatory Agents Therapeutic Uses Pharmacologic Actions Antiemetics Autonomic Agents Peripheral Nervous System Agents Physiological Effects of Drugs Central Nervous System Agents Gastrointestinal Agents |
