Clinical trial NCT00773747: Study of Vorinostat (MK-0683) or Placebo, in Combination With Bortezomib in Participants With Multiple Myeloma (MK-0683-088 AMN)
Official title: An International, Multicenter, Randomized, Double-Blind Study of Vorinostat (MK-0683) or Placebo in Combination With Bortezomib in Patients With Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Myeloma
Keywords: 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
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2008-10-16
Enrollment: 637
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Progression-Free Survival (PFS)
timeFrame: From randomization to event of disease progression or death assessed up to 32 months (final study analysis)
Secondary outcomes:
measure: Number of Participants With Grade 3-5 Clinical or Laboratory Adverse Events (AEs)
timeFrame: Up to 722 days
measure: Overall Survival
timeFrame: From randomization up to 32 months (final study analysis)
measure: Time to Progression
timeFrame: Baseline and at the end of each 21-day Cycle assessed up to 32 months (final study analysis)
measure: Objective Response Rate
timeFrame: Baseline and at the end of each 21-day Cycle assessed up to 32 months (final study analysis)
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Dimopoulos M, Siegel DS, Lonial S, Qi J, Hajek R, Facon T, Rosinol L, Williams C, Blacklock H, Goldschmidt H, Hungria V, Spencer A, Palumbo A, Graef T, Eid JE, Houp J, Sun L, Vuocolo S, Anderson KC. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol. 2013 Oct;14(11):1129-1140. doi: 10.1016/S1470-2045(13)70398-X. Epub 2013 Sep 19.