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Multiple MyelomaPhase 3NCT00773747

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

A Phase 3 study testing Vorinostat and bortezomib in people with Multiple Myeloma, run by Merck Sharp & Dohme LLC.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Multiple Myeloma
What is being tested?
Vorinostat and bortezomib
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
637 participants
Where
No sites listed yet
Study dates
1 Dec 2008to 30 Jun 2015
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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.

About this study

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 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.

Being tested
Vorinostat, bortezomib, placebo to vorinostat
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
Medical subject headings
Multiple Myeloma, Neoplasms, Plasma Cell, Neoplasms by Histologic Type, Neoplasms, Hemostatic Disorders, Vascular Diseases, Cardiovascular Diseases, Paraproteinemias

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • VorinostatDrug

    Also called Zolinza

    Four 100 mg capsules vorinostat taken orally, once daily, on Days 1 through 14 of each 21-day treatment cycle.

  • bortezomibDrug

    Also called Velcade

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

  • placebo to vorinostatDrug

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

Study groups in NCT00773747
Study groupRoleWhat they receive
Vorinostat + BortezomibExperimentalParticipants 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.
Receives: Drug: Vorinostat; Drug: bortezomib
Placebo + BortezomibPlacebo comparatorParticipants 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.
Receives: Drug: bortezomib; Drug: placebo to vorinostat

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression-Free Survival (PFS)

    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.

    Measured: From randomization to event of disease progression or death assessed up to 32 months (final study analysis)

Secondary outcomes (4)

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

    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.

    Measured: Up to 722 days

  2. Overall Survival

    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.

    Measured: From randomization up to 32 months (final study analysis)

  3. Time to Progression

    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.

    Measured: Baseline and at the end of each 21-day Cycle assessed up to 32 months (final study analysis)

  4. Objective Response Rate

    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.

    Measured: Baseline and at the end of each 21-day Cycle assessed up to 32 months (final study analysis)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Oct 2008 (estimated)
  2. Study start1 Dec 2008
  3. Primary completion8 Sep 2011
  4. Study completion30 Jun 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
637 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00773747
Sponsor's protocol ID
0683-088
Other IDs
MK-0683-088, 2008-003752-30, 2008
Status last verified
Apr 2021
First submitted
14 Oct 2008
Last updated
30 Apr 2021
Data monitoring committee
Yes
Individual data sharing
Yes: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Publications

  • 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.

    PubMed 24055414

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Vorinostat and bortezomib in people with Multiple Myeloma, run by Merck Sharp & Dohme LLC.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 30 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 30 Apr 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression-Free Survival (PFS) (time frame: From randomization to event of disease progression or death assessed up to 32 months (final study analysis)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00773747, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Apr 2021.

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