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

Sponsor
Merck Sharp & Dohme LLC (Industry)
Overall Status
Completed
CT.gov ID
NCT00773747
Collaborator
(none)
637
Enrollment
2
Arms
78.9
Actual Duration (Months)

Study Details

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.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
637 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
An International, Multicenter, Randomized, Double-Blind Study of Vorinostat (MK-0683) or Placebo in Combination With Bortezomib in Patients With Multiple Myeloma
Actual Study Start Date :
Dec 1, 2008
Actual Primary Completion Date :
Sep 8, 2011
Actual Study Completion Date :
Jun 30, 2015

Arms and Interventions

Arm Intervention/Treatment
Experimental: Vorinostat + Bortezomib

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.

Drug: Vorinostat
Four 100 mg capsules vorinostat taken orally, once daily, on Days 1 through 14 of each 21-day treatment cycle.
Other Names:
  • Zolinza

    • Drug: bortezomib
    1.3 mg/m2 of bortezomib by IV push, on Days 1, 4, 8, and 11 of each 21-day treatment cycle.
    Other Names:
  • Velcade

    		•
    Placebo Comparator: Placebo + Bortezomib

    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.

    Drug: bortezomib
    1.3 mg/m2 of bortezomib by IV push, on Days 1, 4, 8, and 11 of each 21-day treatment cycle.
    Other Names:
  • Velcade

    • Drug: placebo to vorinostat
    Four placebo capsules taken orally, once daily, on Days 1 through 14 of each 21-day treatment cycle.

    Outcome Measures

    Primary Outcome Measures

    1. Progression-Free Survival (PFS) [From randomization to event of disease progression or death assessed up to 32 months (final study analysis)]

      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.

    Secondary Outcome Measures

    1. Number of Participants With Grade 3-5 Clinical or Laboratory Adverse Events (AEs) [Up to 722 days]

      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.

    2. Overall Survival [From randomization up to 32 months (final study analysis)]

      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.

    3. Time to Progression [Baseline and at the end of each 21-day Cycle assessed up to 32 months (final study analysis)]

      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.

    4. Objective Response Rate [Baseline and at the end of each 21-day Cycle assessed up to 32 months (final study analysis)]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No

    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.

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • Merck Sharp & Dohme LLC

    Investigators

    • Study Director: Medical Director, Merck Sharp & Dohme LLC

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Merck Sharp & Dohme LLC
    ClinicalTrials.gov Identifier:
    NCT00773747
    Other Study ID Numbers:
    • 0683-088
    • MK-0683-088
    • 2008-003752-30
    First Posted:
    Oct 16, 2008
    Last Update Posted:
    Apr 30, 2021
    Last Verified:
    Apr 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Keywords provided by Merck Sharp & Dohme LLC
    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
    Additional relevant MeSH terms:
    Multiple Myeloma
    Neoplasms, Plasma Cell
    Bortezomib
    Vorinostat

    Study Results

    Participant Flow

    Recruitment Details This study enrolled participants with an established diagnosis of multiple myeloma based on standard criteria that have received at least 1 but not more than 3 prior anti-myeloma regimens and have demonstrated progressive disease after the most recent treatment regimen. Additional inclusion and exclusion criteria applied.
    Pre-assignment Detail 637 participants were randomized to treatment and 635 participants received at least 1 dose of MK-0683 or placebo: 315 participants were treated with vorinostat + bortezomib and 320 participants were treated with placebo + bortezomib.
    Arm/Group Title Vorinostat + Bortezomib Placebo + Bortezomib
    Arm/Group Description Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 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. Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 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.
    Period Title: Overall Study
    STARTED 317 320
    Treated 315 320
    COMPLETED 20 24
    NOT COMPLETED 297 296

    Baseline Characteristics

    Arm/Group Title Vorinostat + Bortezomib Placebo + Bortezomib Total
    Arm/Group Description Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 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. Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 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. Total of all reporting groups
    Overall Participants 317 320 637
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    60.9
    (10.0)
    62.7
    (10.0)
    61.8
    (10.0)
    Age, Customized (Count of Participants)
    In utero
    0
    0%
    0
    0%
    0
    0%
    Preterm newborn infants (gestational age < 37 wks)
    0
    0%
    0
    0%
    0
    0%
    Newborns (0-27 days)
    0
    0%
    0
    0%
    0
    0%
    Infants and toddlers (28 days-23 months)
    0
    0%
    0
    0%
    0
    0%
    Children (2-11 years)
    0
    0%
    0
    0%
    0
    0%
    Adolescents (12-17 years)
    0
    0%
    0
    0%
    0
    0%
    Adults (18-64 years)
    200
    63.1%
    181
    56.6%
    381
    59.8%
    From 65-84 years
    116
    36.6%
    137
    42.8%
    253
    39.7%
    85 years and over
    1
    0.3%
    2
    0.6%
    3
    0.5%
    Sex: Female, Male (Count of Participants)
    Female
    126
    39.7%
    134
    41.9%
    260
    40.8%
    Male
    191
    60.3%
    186
    58.1%
    377
    59.2%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    32
    10.1%
    23
    7.2%
    55
    8.6%
    Not Hispanic or Latino
    285
    89.9%
    297
    92.8%
    582
    91.4%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%

    Outcome Measures

    1. Primary Outcome
    Title Progression-Free Survival (PFS)
    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.
    Time Frame From randomization to event of disease progression or death assessed up to 32 months (final study analysis)

    Outcome Measure Data

    Analysis Population Description
    The analysis population includes all randomized participants.
    Arm/Group Title Vorinostat + Bortezomib Placebo + Bortezomib
    Arm/Group Description Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 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. Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 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.
    Measure Participants 317 320
    Median (95% Confidence Interval) [Months]
    7.63
    (6.87)
    6.83
    (5.67)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Vorinostat + Bortezomib, Placebo + Bortezomib
    Comments Cox model stratified by myeloma stage at enrollment, history of a bone marrow transplant, and number of prior treatment regimens, with a single treatment covariate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.0100
    Comments
    Method Regression, Cox
    Comments
    Method of Estimation Estimation Parameter Cox Proportional Hazard
    Estimated Value 0.774
    Confidence Interval (2-Sided) 95%
    0.636 to 0.941
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Number of Participants With Grade 3-5 Clinical or Laboratory Adverse Events (AEs)
    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.
    Time Frame Up to 722 days

    Outcome Measure Data

    Analysis Population Description
    The analysis population includes all randomized participants who received ≥1 dose of study medication.
    Arm/Group Title Vorinostat + Bortezomib Placebo + Bortezomib
    Arm/Group Description Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 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. Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 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.
    Measure Participants 315 320
    Grade 3
    272
    85.8%
    240
    75%
    Grade 4
    108
    34.1%
    85
    26.6%
    Grade 5
    11
    3.5%
    17
    5.3%
    3. Secondary Outcome
    Title Overall Survival
    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.
    Time Frame From randomization up to 32 months (final study analysis)

    Outcome Measure Data

    Analysis Population Description
    The analysis population includes all randomized participants.
    Arm/Group Title Vorinostat + Bortezomib Placebo + Bortezomib
    Arm/Group Description Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 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. Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 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.
    Measure Participants 317 320
    Number (95% Confidence Interval) [Events/100-person Months]
    1.7
    (1.56)
    1.9
    (1.75)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Vorinostat + Bortezomib, Placebo + Bortezomib
    Comments Cox model stratified by myeloma stage at enrollment, history of a bone marrow transplant, and number of prior treatment regimens, with a single treatment covariate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3496
    Comments
    Method Regression, Cox
    Comments
    Method of Estimation Estimation Parameter Cox Proportional Hazard
    Estimated Value 0.858
    Confidence Interval (2-Sided) 95%
    0.622 to 1.184
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Time to Progression
    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.
    Time Frame Baseline and at the end of each 21-day Cycle assessed up to 32 months (final study analysis)

    Outcome Measure Data

    Analysis Population Description
    The analysis population includes all randomized participants.
    Arm/Group Title Vorinostat + Bortezomib Placebo + Bortezomib
    Arm/Group Description Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 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. Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 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.
    Measure Participants 317 320
    Median (95% Confidence Interval) [Months]
    7.73
    (7.00)
    7.03
    (6.33)
    5. Secondary Outcome
    Title Objective Response Rate
    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.
    Time Frame Baseline and at the end of each 21-day Cycle assessed up to 32 months (final study analysis)

    Outcome Measure Data

    Analysis Population Description
    The analysis population includes all randomized participants who received ≥1 dose of study medication.
    Arm/Group Title Vorinostat + Bortezomib Placebo + Bortezomib
    Arm/Group Description Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 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. Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 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.
    Measure Participants 315 320
    Number (95% Confidence Interval) [Percentage of Participants]
    56.2
    (50.5) 17.7%
    40.6
    (35.2) 12.7%

    Adverse Events

    Time Frame Up to 722 days.
    Adverse Event Reporting Description Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
    Arm/Group Title Vorinostat + Bortezomib Placebo + Bortezomib
    Arm/Group Description Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 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. Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 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.
    All Cause Mortality
    Vorinostat + Bortezomib Placebo + Bortezomib
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Vorinostat + Bortezomib Placebo + Bortezomib
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 130/315 (41.3%) 138/320 (43.1%)
    Blood and lymphatic system disorders
    Anaemia 4/315 (1.3%) 4 2/320 (0.6%) 2
    Bone marrow failure 1/315 (0.3%) 1 0/320 (0%) 0
    Febrile neutropenia 4/315 (1.3%) 4 0/320 (0%) 0
    Haemolysis 1/315 (0.3%) 1 0/320 (0%) 0
    Neutropenia 2/315 (0.6%) 2 1/320 (0.3%) 1
    Thrombocytopenia 9/315 (2.9%) 13 3/320 (0.9%) 3
    Cardiac disorders
    Acute myocardial infarction 1/315 (0.3%) 1 0/320 (0%) 0
    Arrhythmia 0/315 (0%) 0 1/320 (0.3%) 1
    Atrial fibrillation 1/315 (0.3%) 1 2/320 (0.6%) 3
    Cardiac failure 2/315 (0.6%) 2 0/320 (0%) 0
    Cardiac failure congestive 1/315 (0.3%) 1 0/320 (0%) 0
    Cardiopulmonary failure 1/315 (0.3%) 1 0/320 (0%) 0
    Myocardial infarction 0/315 (0%) 0 2/320 (0.6%) 2
    Supraventricular tachycardia 0/315 (0%) 0 1/320 (0.3%) 1
    Ear and labyrinth disorders
    Deafness 1/315 (0.3%) 1 0/320 (0%) 0
    Vertigo 1/315 (0.3%) 2 1/320 (0.3%) 1
    Endocrine disorders
    Hyperparathyroidism primary 0/315 (0%) 0 1/320 (0.3%) 1
    Eye disorders
    Retinal detachment 1/315 (0.3%) 1 0/320 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 1/315 (0.3%) 1 0/320 (0%) 0
    Constipation 0/315 (0%) 0 2/320 (0.6%) 3
    Diarrhoea 9/315 (2.9%) 12 10/320 (3.1%) 10
    Gastritis 1/315 (0.3%) 1 0/320 (0%) 0
    Gastrointestinal haemorrhage 1/315 (0.3%) 1 0/320 (0%) 0
    Gastrooesophageal reflux disease 1/315 (0.3%) 1 0/320 (0%) 0
    Haemorrhoids 2/315 (0.6%) 2 0/320 (0%) 0
    Ileus 0/315 (0%) 0 1/320 (0.3%) 1
    Ileus paralytic 0/315 (0%) 0 2/320 (0.6%) 2
    Melaena 0/315 (0%) 0 1/320 (0.3%) 1
    Nausea 1/315 (0.3%) 1 3/320 (0.9%) 4
    Odynophagia 1/315 (0.3%) 1 0/320 (0%) 0
    Oesophagitis 1/315 (0.3%) 1 0/320 (0%) 0
    Pancreatitis acute 0/315 (0%) 0 2/320 (0.6%) 2
    Pneumatosis intestinalis 0/315 (0%) 0 1/320 (0.3%) 1
    Vomiting 8/315 (2.5%) 8 7/320 (2.2%) 8
    General disorders
    Asthenia 2/315 (0.6%) 2 1/320 (0.3%) 1
    Death 1/315 (0.3%) 1 2/320 (0.6%) 2
    Fatigue 3/315 (1%) 3 5/320 (1.6%) 6
    General physical health deterioration 1/315 (0.3%) 1 0/320 (0%) 0
    Generalised oedema 0/315 (0%) 0 1/320 (0.3%) 1
    Influenza like illness 1/315 (0.3%) 1 0/320 (0%) 0
    Multi-organ failure 1/315 (0.3%) 1 0/320 (0%) 0
    Pelvic mass 0/315 (0%) 0 1/320 (0.3%) 1
    Pyrexia 6/315 (1.9%) 7 9/320 (2.8%) 12
    Swelling 1/315 (0.3%) 1 0/320 (0%) 0
    Hepatobiliary disorders
    Hepatic necrosis 0/315 (0%) 0 1/320 (0.3%) 1
    Immune system disorders
    Hypersensitivity 0/315 (0%) 0 1/320 (0.3%) 1
    Infections and infestations
    Bronchitis 2/315 (0.6%) 2 3/320 (0.9%) 3
    Bronchitis pneumococcal 0/315 (0%) 0 1/320 (0.3%) 1
    Bronchopneumonia 4/315 (1.3%) 4 1/320 (0.3%) 1
    Cellulitis 0/315 (0%) 0 1/320 (0.3%) 1
    Clostridial infection 0/315 (0%) 0 1/320 (0.3%) 1
    Clostridium difficile colitis 2/315 (0.6%) 3 0/320 (0%) 0
    Conjunctivitis bacterial 0/315 (0%) 0 1/320 (0.3%) 1
    Device related sepsis 1/315 (0.3%) 1 0/320 (0%) 0
    Escherichia sepsis 1/315 (0.3%) 1 0/320 (0%) 0
    Fungal infection 0/315 (0%) 0 1/320 (0.3%) 1
    Gastroenteritis 6/315 (1.9%) 9 0/320 (0%) 0
    Gastroenteritis salmonella 1/315 (0.3%) 1 0/320 (0%) 0
    Gastroenteritis viral 0/315 (0%) 0 1/320 (0.3%) 1
    Gastrointestinal infection 2/315 (0.6%) 2 0/320 (0%) 0
    Gastrointestinal viral infection 0/315 (0%) 0 1/320 (0.3%) 1
    H1N1 influenza 1/315 (0.3%) 1 0/320 (0%) 0
    Haemophilus infection 0/315 (0%) 0 1/320 (0.3%) 1
    Hepatitis B 0/315 (0%) 0 1/320 (0.3%) 1
    Herpes simplex 0/315 (0%) 0 1/320 (0.3%) 1
    Herpes zoster 0/315 (0%) 0 6/320 (1.9%) 6
    Herpes zoster ophthalmic 0/315 (0%) 0 1/320 (0.3%) 1
    Lobar pneumonia 1/315 (0.3%) 1 0/320 (0%) 0
    Lower respiratory tract infection 1/315 (0.3%) 1 0/320 (0%) 0
    Lung infection 2/315 (0.6%) 2 2/320 (0.6%) 2
    Pharyngitis 1/315 (0.3%) 1 0/320 (0%) 0
    Pneumococcal sepsis 1/315 (0.3%) 1 0/320 (0%) 0
    Pneumonia 14/315 (4.4%) 17 13/320 (4.1%) 13
    Respiratory tract infection 1/315 (0.3%) 1 1/320 (0.3%) 1
    Respiratory tract infection viral 1/315 (0.3%) 1 0/320 (0%) 0
    Sepsis 0/315 (0%) 0 5/320 (1.6%) 5
    Septic shock 1/315 (0.3%) 1 3/320 (0.9%) 4
    Skin infection 1/315 (0.3%) 1 0/320 (0%) 0
    Tracheobronchitis 0/315 (0%) 0 1/320 (0.3%) 1
    Tuberculosis 0/315 (0%) 0 1/320 (0.3%) 1
    Upper respiratory tract infection 2/315 (0.6%) 2 3/320 (0.9%) 3
    Upper respiratory tract infection bacterial 0/315 (0%) 0 1/320 (0.3%) 1
    Urinary tract infection 2/315 (0.6%) 2 4/320 (1.3%) 4
    Viral infection 1/315 (0.3%) 1 1/320 (0.3%) 1
    Injury, poisoning and procedural complications
    Accidental overdose 32/315 (10.2%) 52 27/320 (8.4%) 43
    Femur fracture 0/315 (0%) 0 1/320 (0.3%) 1
    Humerus fracture 0/315 (0%) 0 1/320 (0.3%) 1
    Rib fracture 1/315 (0.3%) 1 0/320 (0%) 0
    Road traffic accident 1/315 (0.3%) 1 0/320 (0%) 0
    Spinal compression fracture 1/315 (0.3%) 1 0/320 (0%) 0
    Tibia fracture 0/315 (0%) 0 1/320 (0.3%) 1
    Investigations
    Blood creatinine increased 0/315 (0%) 0 1/320 (0.3%) 1
    Metabolism and nutrition disorders
    Decreased appetite 1/315 (0.3%) 1 1/320 (0.3%) 1
    Dehydration 2/315 (0.6%) 2 5/320 (1.6%) 5
    Hypercalcaemia 0/315 (0%) 0 2/320 (0.6%) 2
    Hyperglycaemia 2/315 (0.6%) 2 0/320 (0%) 0
    Hyperuricaemia 0/315 (0%) 0 1/320 (0.3%) 1
    Hypoglycaemia 1/315 (0.3%) 1 0/320 (0%) 0
    Hypokalaemia 1/315 (0.3%) 1 1/320 (0.3%) 1
    Hyponatraemia 2/315 (0.6%) 2 0/320 (0%) 0
    Metabolic disorder 0/315 (0%) 0 1/320 (0.3%) 1
    Tumour lysis syndrome 0/315 (0%) 0 1/320 (0.3%) 1
    Musculoskeletal and connective tissue disorders
    Arthritis 0/315 (0%) 0 1/320 (0.3%) 1
    Back pain 1/315 (0.3%) 1 1/320 (0.3%) 1
    Bone pain 0/315 (0%) 0 1/320 (0.3%) 1
    Muscular weakness 1/315 (0.3%) 1 0/320 (0%) 0
    Musculoskeletal chest pain 0/315 (0%) 0 1/320 (0.3%) 1
    Musculoskeletal pain 0/315 (0%) 0 1/320 (0.3%) 1
    Spondylitis 0/315 (0%) 0 1/320 (0.3%) 1
    Synovial cyst 0/315 (0%) 0 1/320 (0.3%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma 1/315 (0.3%) 1 0/320 (0%) 0
    Basal cell carcinoma 0/315 (0%) 0 2/320 (0.6%) 2
    Colon cancer 0/315 (0%) 0 1/320 (0.3%) 1
    Neoplasm malignant 10/315 (3.2%) 10 13/320 (4.1%) 13
    Squamous cell carcinoma 0/315 (0%) 0 1/320 (0.3%) 1
    Nervous system disorders
    Ataxia 1/315 (0.3%) 1 0/320 (0%) 0
    Brain oedema 1/315 (0.3%) 1 0/320 (0%) 0
    Cerebral infarction 0/315 (0%) 0 1/320 (0.3%) 1
    Cerebral ischaemia 0/315 (0%) 0 1/320 (0.3%) 1
    Cerebrovascular accident 0/315 (0%) 0 1/320 (0.3%) 1
    Cognitive disorder 1/315 (0.3%) 1 0/320 (0%) 0
    Diabetic coma 0/315 (0%) 0 1/320 (0.3%) 1
    Dizziness 1/315 (0.3%) 1 0/320 (0%) 0
    Haemorrhage intracranial 0/315 (0%) 0 1/320 (0.3%) 1
    Headache 1/315 (0.3%) 1 0/320 (0%) 0
    Lethargy 0/315 (0%) 0 1/320 (0.3%) 1
    Neuralgia 0/315 (0%) 0 2/320 (0.6%) 2
    Paraplegia 0/315 (0%) 0 1/320 (0.3%) 1
    Spinal cord compression 0/315 (0%) 0 4/320 (1.3%) 4
    Syncope 2/315 (0.6%) 2 1/320 (0.3%) 1
    Psychiatric disorders
    Anxiety disorder 0/315 (0%) 0 1/320 (0.3%) 1
    Completed suicide 1/315 (0.3%) 1 0/320 (0%) 0
    Renal and urinary disorders
    Azotaemia 1/315 (0.3%) 1 0/320 (0%) 0
    Renal failure 2/315 (0.6%) 2 4/320 (1.3%) 5
    Renal failure acute 2/315 (0.6%) 2 2/320 (0.6%) 2
    Renal impairment 1/315 (0.3%) 1 1/320 (0.3%) 1
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 1/315 (0.3%) 1 0/320 (0%) 0
    Apnoea 1/315 (0.3%) 1 0/320 (0%) 0
    Bronchitis chronic 0/315 (0%) 0 1/320 (0.3%) 1
    Dyspnoea exertional 0/315 (0%) 0 1/320 (0.3%) 1
    Epistaxis 1/315 (0.3%) 1 0/320 (0%) 0
    Haemoptysis 1/315 (0.3%) 1 0/320 (0%) 0
    Interstitial lung disease 0/315 (0%) 0 2/320 (0.6%) 2
    Pleural effusion 0/315 (0%) 0 1/320 (0.3%) 1
    Pneumonia aspiration 0/315 (0%) 0 1/320 (0.3%) 1
    Pneumonitis 2/315 (0.6%) 2 0/320 (0%) 0
    Pneumothorax 1/315 (0.3%) 1 0/320 (0%) 0
    Pulmonary embolism 2/315 (0.6%) 2 2/320 (0.6%) 2
    Pulmonary hypertension 0/315 (0%) 0 1/320 (0.3%) 2
    Pulmonary oedema 1/315 (0.3%) 1 0/320 (0%) 0
    Skin and subcutaneous tissue disorders
    Angioedema 1/315 (0.3%) 1 1/320 (0.3%) 1
    Decubitus ulcer 1/315 (0.3%) 1 0/320 (0%) 0
    Rash maculo-papular 0/315 (0%) 0 1/320 (0.3%) 1
    Vascular disorders
    Circulatory collapse 1/315 (0.3%) 1 0/320 (0%) 0
    Deep vein thrombosis 1/315 (0.3%) 1 0/320 (0%) 0
    Haemorrhage 0/315 (0%) 0 1/320 (0.3%) 1
    Hypertension 1/315 (0.3%) 1 3/320 (0.9%) 3
    Hypotension 1/315 (0.3%) 1 2/320 (0.6%) 2
    Orthostatic hypotension 4/315 (1.3%) 4 0/320 (0%) 0
    Shock 0/315 (0%) 0 1/320 (0.3%) 1
    Other (Not Including Serious) Adverse Events
    Vorinostat + Bortezomib Placebo + Bortezomib
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 312/315 (99%) 306/320 (95.6%)
    Blood and lymphatic system disorders
    Anaemia 91/315 (28.9%) 198 79/320 (24.7%) 164
    Leukopenia 42/315 (13.3%) 121 32/320 (10%) 122
    Neutropenia 112/315 (35.6%) 406 95/320 (29.7%) 300
    Thrombocytopenia 172/315 (54.6%) 749 106/320 (33.1%) 384
    Gastrointestinal disorders
    Abdominal distension 8/315 (2.5%) 11 17/320 (5.3%) 21
    Abdominal pain 22/315 (7%) 37 27/320 (8.4%) 40
    Abdominal pain upper 26/315 (8.3%) 42 13/320 (4.1%) 20
    Constipation 64/315 (20.3%) 91 86/320 (26.9%) 132
    Diarrhoea 194/315 (61.6%) 604 133/320 (41.6%) 275
    Dyspepsia 24/315 (7.6%) 38 26/320 (8.1%) 40
    Nausea 193/315 (61.3%) 457 126/320 (39.4%) 247
    Vomiting 140/315 (44.4%) 280 80/320 (25%) 127
    General disorders
    Asthenia 46/315 (14.6%) 89 40/320 (12.5%) 80
    Fatigue 125/315 (39.7%) 350 96/320 (30%) 176
    Oedema peripheral 24/315 (7.6%) 28 24/320 (7.5%) 27
    Pyrexia 66/315 (21%) 114 70/320 (21.9%) 130
    Infections and infestations
    Herpes zoster 22/315 (7%) 26 19/320 (5.9%) 21
    Nasopharyngitis 16/315 (5.1%) 22 18/320 (5.6%) 20
    Upper respiratory tract infection 55/315 (17.5%) 76 38/320 (11.9%) 58
    Investigations
    Blood creatinine increased 17/315 (5.4%) 26 11/320 (3.4%) 14
    Weight decreased 22/315 (7%) 36 22/320 (6.9%) 30
    Metabolism and nutrition disorders
    Decreased appetite 75/315 (23.8%) 123 85/320 (26.6%) 139
    Hypokalaemia 35/315 (11.1%) 57 25/320 (7.8%) 40
    Musculoskeletal and connective tissue disorders
    Arthralgia 26/315 (8.3%) 34 27/320 (8.4%) 40
    Back pain 49/315 (15.6%) 67 47/320 (14.7%) 69
    Bone pain 15/315 (4.8%) 27 24/320 (7.5%) 39
    Muscle spasms 21/315 (6.7%) 25 15/320 (4.7%) 17
    Pain in extremity 16/315 (5.1%) 21 38/320 (11.9%) 52
    Nervous system disorders
    Dizziness 36/315 (11.4%) 56 27/320 (8.4%) 37
    Dysgeusia 23/315 (7.3%) 28 6/320 (1.9%) 8
    Headache 35/315 (11.1%) 45 34/320 (10.6%) 45
    Hypoaesthesia 10/315 (3.2%) 12 18/320 (5.6%) 26
    Neuralgia 82/315 (26%) 124 86/320 (26.9%) 125
    Neuropathy peripheral 62/315 (19.7%) 94 64/320 (20%) 97
    Paraesthesia 20/315 (6.3%) 27 12/320 (3.8%) 14
    Peripheral sensory neuropathy 33/315 (10.5%) 58 27/320 (8.4%) 39
    Psychiatric disorders
    Insomnia 28/315 (8.9%) 32 29/320 (9.1%) 36
    Respiratory, thoracic and mediastinal disorders
    Cough 52/315 (16.5%) 71 48/320 (15%) 61
    Dyspnoea 26/315 (8.3%) 36 28/320 (8.8%) 35
    Oropharyngeal pain 16/315 (5.1%) 17 13/320 (4.1%) 16
    Skin and subcutaneous tissue disorders
    Alopecia 24/315 (7.6%) 26 3/320 (0.9%) 3
    Rash 31/315 (9.8%) 43 40/320 (12.5%) 61
    Vascular disorders
    Hypertension 29/315 (9.2%) 37 13/320 (4.1%) 16
    Hypotension 19/315 (6%) 23 12/320 (3.8%) 15

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    An investigator may not independently publish the results for their study site until after the multicenter publication, or 24 months after completion of study. Sponsor must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the sponsor as confidential must be deleted prior to submission. Sponsor review can be expedited to meet publication guidelines.

    Results Point of Contact

    Name/Title Senior Vice President, Global Clinical Development
    Organization Merck Sharp & Dohme Corp.
    Phone 1-800-672-6372
    Email ClinicalTrialsDisclosure@merck.com
    Responsible Party:
    Merck Sharp & Dohme LLC
    ClinicalTrials.gov Identifier:
    NCT00773747
    Other Study ID Numbers:
    • 0683-088
    • MK-0683-088
    • 2008-003752-30
    First Posted:
    Oct 16, 2008
    Last Update Posted:
    Apr 30, 2021
    Last Verified:
    Apr 1, 2021