Study of Vorinostat (MK0683), an HDAC Inhibitor, in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma (0683-095 AMJ)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT00773838
First received: October 14, 2008
Last updated: April 17, 2012
Last verified: April 2012
  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 2

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

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Response rate associated with the administration of vorinostat in combination with bortezomib [ Time Frame: 21 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Tolerability of vorinostat administered in combination with bortezomib [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]

Enrollment: 143
Study Start Date: December 2008
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 .

Detailed Description:

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
Criteria

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
  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

No publications provided

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT00773838     History of Changes
Other Study ID Numbers: MK-0683-095, 2008_524
Study First Received: October 14, 2008
Last Updated: April 17, 2012
Health Authority: United States: Food and Drug Administration

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
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

ClinicalTrials.gov processed this record on July 24, 2014