Study of Vorinostat (MK0683), an HDAC Inhibitor, in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma - Full Text View

Sponsor:	Merck
Information provided by:	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:	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

Resource links provided by NLM:

Genetics Home Reference related topics: aceruloplasminemia hemophilia

MedlinePlus related topics: Cancer Multiple Myeloma

Drug Information available for: Dexamethasone Dexamethasone acetate Doxiproct plus Suberoylanilide hydroxamic acid Bortezomib Dexamethasone Sodium Phosphate

U.S. FDA Resources

Further study details as provided by Merck:

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 ]

Estimated Enrollment:	142
Study Start Date:	December 2008
Estimated Study Completion Date:	October 2010
Estimated Primary Completion Date:	October 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental 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. 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. 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 .

Arms

Assigned Interventions

1: Experimental

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.

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.

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 .

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

Please refer to this study by its ClinicalTrials.gov identifier: NCT00773838

Contacts

Contact: Toll Free Number

1-888-577-8839

Show 25 Study Locations

Sponsors and Collaborators

Merck

Investigators

Study Director:

Medical Monitor

Merck

More Information

No publications provided

Responsible Party:	Merck Sharp & Dohme Corp ( Executive Vice President, Clinical and Quantitative Sciences )
Study ID Numbers:	2008_524, MK0683-095
Study First Received:	October 14, 2008
Last Updated:	January 27, 2010
ClinicalTrials.gov Identifier:	NCT00773838 History of Changes
Health Authority:	United States: Food and Drug Administration

Additional relevant MeSH terms:

Anticarcinogenic Agents
Anti-Inflammatory Agents
Dexamethasone
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Blood Protein Disorders
Physiological Effects of Drugs
Hormones, Hormone Substitutes, and Hormone Antagonists
Antiemetics
Paraproteinemias
Hemostatic Disorders
Hormones
Hemorrhagic Disorders
Sensory System Agents
Therapeutic Uses

Anti-Inflammatory Agents, Non-Steroidal
Cardiovascular Diseases
Analgesics
Dexamethasone acetate
Immunoproliferative Disorders
Neoplasms by Histologic Type
Antineoplastic Agents, Hormonal
Immune System Diseases
Hematologic Diseases
Vorinostat
Bortezomib
Gastrointestinal Agents
Vascular Diseases
Enzyme Inhibitors
Protective Agents

ClinicalTrials.gov processed this record on February 08, 2010