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NCT00773747 · REGISTRY CONDITION SEARCH

Study of Vorinostat (MK-0683) or Placebo, in Combination With Bortezomib in Participants With Multiple Myeloma (MK-0683-088 AMN)

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase
PHASE3
Status at capture
COMPLETED
Registry last update
2021-04-30

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.

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What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Progression-Free Survival (PFS)

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outcome · POSTED

Number of Participants With Grade 3-5 Clinical or Laboratory Adverse Events (AEs)

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outcome · POSTED

Overall Survival

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outcome · POSTED

Time to Progression

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outcome · POSTED

Objective Response Rate

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part
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.
healthy Volunteers
false
minimum Age
18 Years
sex
ALL
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1-14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.
    intervention Names
    1. Drug: Vorinostat
    2. Drug: bortezomib
    label
    Vorinostat + Bortezomib
    type
    EXPERIMENTAL
  2. description
    Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1-14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.
    intervention Names
    1. Drug: bortezomib
    2. Drug: placebo to vorinostat
    label
    Placebo + Bortezomib
    type
    PLACEBO_COMPARATOR
interventions
  1. arm Group Labels
    1. Vorinostat + Bortezomib
    description
    Four 100 mg capsules vorinostat taken orally, once daily, on Days 1 through 14 of each 21-day treatment cycle.
    name
    Vorinostat
    other Names
    1. Zolinza
    type
    DRUG
  2. arm Group Labels
    1. Placebo + Bortezomib
    2. Vorinostat + Bortezomib
    description
    1.3 mg/m2 of bortezomib by IV push, on Days 1, 4, 8, and 11 of each 21-day treatment cycle.
    name
    bortezomib
    other Names
    1. Velcade
    type
    DRUG
  3. arm Group Labels
    1. Placebo + Bortezomib
    description
    Four placebo capsules taken orally, once daily, on Days 1 through 14 of each 21-day treatment cycle.
    name
    placebo to vorinostat
    type
    DRUG
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
DOUBLE
who Masked
  1. PARTICIPANT
  2. INVESTIGATOR
primary Purpose
TREATMENT
Enrollment
count
637
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. description
    Progression-free survival was measured from the start of the treatment to the time when the criteria for progression was met or death due to any cause (whichever is first recorded). Response to study therapy was assessed using European Blood and Marrow Transplantation Group (EBMT) Criteria. A stratified Cox proportional hazards model was used with Efron's likelihood approximation to account for ties in event times.
    measure
    Progression-Free Survival (PFS)
    time Frame
    From randomization to event of disease progression or death assessed up to 32 months (final study analysis)
secondary Outcomes
  1. description
    An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. Grades come from the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Per protocol, clinical and laboratory AEs are presented as a combined total for each grade.
    measure
    Number of Participants With Grade 3-5 Clinical or Laboratory Adverse Events (AEs)
    time Frame
    Up to 722 days
  2. description
    Overall survival was measured from the start of the treatment to death due to any cause. Overall Survival is represented as the number of deaths per 100-person- months and was computed by dividing the number of participants with an event of death that occurred during the study follow-up period by the total duration of follow-up (in 100 months) for all the participants in each cohort since participants had different lengths of follow-up.
    measure
    Overall Survival
    time Frame
    From randomization up to 32 months (final study analysis)
  3. description
    Time to progression was measured from the start of the treatment to the time when the criteria for progression was met or death due to myeloma (whichever is first recorded). Response to study therapy was assessed using European Blood and Marrow Transplantation Group (EBMT) Criteria. A stratified Cox proportional hazards model was used with Efron's likelihood approximation to account for ties in event times.
    measure
    Time to Progression
    time Frame
    Baseline and at the end of each 21-day Cycle assessed up to 32 months (final study analysis)
  4. description
    Objective response rate was measured as the proportion of patients who achieved a confirmed partial response or better during the course of the study. Response to study therapy was assessed using EBMT Criteria and confirmed by Independent Adjudication Review.
    measure
    Objective Response Rate
    time Frame
    Baseline and at the end of each 21-day Cycle assessed up to 32 months (final study analysis)
Full study description
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.
Source references
references
  1. 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.
    pmid
    24055414
    type
    RESULT
Source notices and limitations
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    Preserved source evidence · Not medical advice