<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01720875</url>
  </required_header>
  <id_info>
    <org_study_id>HM11/10041</org_study_id>
    <secondary_id>ISRCTN08577602</secondary_id>
    <secondary_id>2011-005361-20</secondary_id>
    <nct_id>NCT01720875</nct_id>
  </id_info>
  <brief_title>Vorinostat, Bortezomib and Dexamethasone in Multiple Myeloma (MUKFour)</brief_title>
  <acronym>MUKfour</acronym>
  <official_title>A Phase II Trial of Combination Treatment With Vorinostat, Bortezomib and Dexamethasone in Patients With Relapsed and Relapsed Refractory Multiple Myeloma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Leeds</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Myeloma UK</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Leeds</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Bortezomib is an established treatment in multiple myeloma; it is common practice in the UK&#xD;
      to administer bortezomib with dexamethasone. This practice is based on data that supports&#xD;
      improved response rates with this combination.&#xD;
&#xD;
      Recent trial data indicates that the addition of vorinostat to bortezomib treatment overcomes&#xD;
      treatment resistance to bortezomib. As such this current trial is designed to investigate the&#xD;
      efficacy, safety and tolerability of combination treatment with vorinostat, bortezomib and&#xD;
      dexamethasone in patients with relapsed and relapsed refractory myeloma.&#xD;
&#xD;
      A comparison of this Phase II trial with the pivotal Phase III trial conducted by MSD (using&#xD;
      the labelled bortezomib indication without dexamethasone) will address the impact of&#xD;
      dexamethasone in regards to tolerability and additional efficacy in myeloma patients.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 9, 2013</start_date>
  <completion_date type="Actual">August 29, 2018</completion_date>
  <primary_completion_date type="Actual">August 2015</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall response rate to vorinostat, bortezomib and dexamethasone.</measure>
    <time_frame>up to 24 weeks</time_frame>
    <description>To assess the number and proportion of participants with at least a partial response (PR) or better within 8 cycles of protocol treatment with vorinostat, bortezomib and dexamethasone.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of dose reductions during treatment with vorinostat, bortezomib and dexamethasone.</measure>
    <time_frame>up to 24 weeks</time_frame>
    <description>To assess the dose reduction profile of combination treatment with vorinostat, bortezomib and dexamethasone. The proportion of participants experiencing a dose reduction or terminating treatment early due to toxicity will be assessed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall numbers and rates of adverse events</measure>
    <time_frame>Up to 18 months</time_frame>
    <description>Safety and toxicity analyses will summarise the overall serious adverse event and adverse events rates including the number and proportion of participants with at least one safety event. SAEs will be additionally presented by the relationship to study treatment, seriousness criteria, event outcome, duration and by MedDRA body system coding.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival</measure>
    <time_frame>Up to 18 months</time_frame>
    <description>A progression-free survival curve will be calculated using the Kaplan Meier method and median PFS estimates will be presented</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum response to treatment</measure>
    <time_frame>Up to 24 weeks</time_frame>
    <description>The overall number and proportion of participants in each response category within 8 cycles of treatment and overall across all treatment including the maintenance phase</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to maximum response</measure>
    <time_frame>Up to 18 months</time_frame>
    <description>The time to maximum response will be calculated from the date of registration to the date of maximum response. Participant's who progress and do not achieve a maximum response will be censored at the time of progression. Median time to maximum response will be presented.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Matched pairs analysis</measure>
    <time_frame>Up to 24 months</time_frame>
    <description>A matched pairs analysis will be carried out looking at overall response, PFS, dose reductions and toxicity in participants treated with vorinostat in combination with bortezomib and dexamethasone (VVD) in this current study compared to participants randomised to the bortezomib/vorinostat (VV) arm in the pivotal MSD phase III study.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">16</enrollment>
  <condition>Multiple Myeloma</condition>
  <arm_group>
    <arm_group_label>Vorinostat Velcade Dexamethasone (VVD)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Up to 8 cycles of VVD followed by vorinostat maintenance until disease progression.&#xD;
Cycles 1-8 (21-day cycle)&#xD;
Velcade: 1.3mg/m2 (subcutaneous) on days 1, 4, 8 and 11&#xD;
Dexamethasone: 20 mg (PO) on days 1, 2, 4, 5, 8, 9, 11 and 12&#xD;
Vorinostat: 400mg (PO) on days 1-4, 8-11, 15-18 Maintenance (28-day cycle)&#xD;
Vorinostat: 400mg PO on 1-4 and 15-18</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vorinostat Velcade Dexamethasone</intervention_name>
    <arm_group_label>Vorinostat Velcade Dexamethasone (VVD)</arm_group_label>
    <other_name>Bortezomib (velcade)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Able to give informed consent - Aged 18 years or over&#xD;
&#xD;
          -  Participants with relapsed myeloma who have received 1-3 prior lines of treatment and&#xD;
             now require further treatment&#xD;
&#xD;
          -  ECOG Performance Status ≤ 2&#xD;
&#xD;
          -  Required laboratory values within 14 days of registration:&#xD;
&#xD;
               -  Absolute neutrophil count ≥1.0 x 10^9/L.&#xD;
&#xD;
               -  Platelet count ≥75x10^9/L.&#xD;
&#xD;
               -  Haemoglobin &gt; 9 g/dL.&#xD;
&#xD;
               -  Bilirubin ≤1.5 x upper limit of normal&#xD;
&#xD;
               -  ALT and / or AST ≤2.5 x upper limit of normal&#xD;
&#xD;
               -  Serum creatinine ≤ 2.0 x upper limit of normal&#xD;
&#xD;
               -  Corrected calcium ≤ 2.8 mmol/L&#xD;
&#xD;
          -  Life expectancy of at least 3 months&#xD;
&#xD;
          -  Female participants of child-bearing potential must have a negative pregnancy test at&#xD;
             baseline and agree to use dual methods of contraception for the duration of the study&#xD;
             and must continue to do so for 3 months after the end of treatment. Male participants&#xD;
             must agree to use a barrier method of contraception for the duration of the study if&#xD;
             sexually active with a female of child-bearing potential and must continue to do so&#xD;
             for 3 months after the end of treatment&#xD;
&#xD;
          -  Participant is able to swallow capsules and is able to take or tolerate oral&#xD;
             medications on a continuous basis.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previous anti-tumour therapies, including prior experimental agents or approved&#xD;
             anti-tumour small molecules and biologics, within 28 days before the start of protocol&#xD;
             treatment. Steroid therapy to stop rapid relapse during this period is permitted, but&#xD;
             must be stopped 7 days prior to study drug administration.&#xD;
&#xD;
          -  Prior HDAC inhibitor treatment.&#xD;
&#xD;
          -  Previous or concurrent active malignancies (&lt;12 months post end of treatment) at other&#xD;
             sites with the exception of appropriately treated localised epithelial skin or&#xD;
             cervical cancer.&#xD;
&#xD;
          -  Participants considered to be refractory to prior bortezomib treatment or unable to&#xD;
             tolerate treatment with bortezomib.&#xD;
&#xD;
          -  Peripheral neuropathy of ≥ grade 2 severity&#xD;
&#xD;
          -  Participants who have received growth factor support or platelet support within 14&#xD;
             days prior to registration&#xD;
&#xD;
          -  Participants with uncontrolled concurrent illness or circumstances that could limit&#xD;
             compliance with the study.&#xD;
&#xD;
          -  Patients with significant cardiovascular or pulmonary disease&#xD;
&#xD;
          -  Active symptomatic fungal, bacterial, and/or viral infection including known active&#xD;
             HIV or known viral (A, B, or C) hepatitis.&#xD;
&#xD;
          -  Pregnant or breast feeding females&#xD;
&#xD;
          -  Unable to take corticosteroid therapy at study entry&#xD;
&#xD;
          -  Participants with known hypersensitivity to any components of bortezomib, (such as&#xD;
             boron, mannitol), vorinostat or dexamethasone.&#xD;
&#xD;
          -  Participant has known CNS metastases and/or carcinomatous meningitis.&#xD;
&#xD;
          -  Participants with a history of a gastrointestinal surgery or other procedures that&#xD;
             might, in the opinion of the Investigator, interfere with the absorption or swallowing&#xD;
             of the study drug(s)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Matthew Jenner</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Hospital of Southampton</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Nottingham University Hospital</name>
      <address>
        <city>Nottingham</city>
        <state>Nottinghamshire</state>
        <zip>NG5 1PB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Southampton</name>
      <address>
        <city>Southampton</city>
        <zip>SO16 6YD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <results_reference>
    <citation>Brown S, Pawlyn C, Tillotson AL, Sherratt D, Flanagan L, Low E, Morgan GJ, Williams C, Kaiser M, Davies FE, Jenner MW; Myeloma UK Early Phase Clinical Trial Network. Bortezomib, Vorinostat, and Dexamethasone Combination Therapy in Relapsed Myeloma: Results of the Phase 2 MUK four Trial. Clin Lymphoma Myeloma Leuk. 2021 Mar;21(3):154-161.e3. doi: 10.1016/j.clml.2020.11.019. Epub 2020 Dec 3.</citation>
    <PMID>33478922</PMID>
  </results_reference>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>October 31, 2012</study_first_submitted>
  <study_first_submitted_qc>November 1, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 2, 2012</study_first_posted>
  <last_update_submitted>August 9, 2021</last_update_submitted>
  <last_update_submitted_qc>August 9, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 16, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Myeloma</mesh_term>
    <mesh_term>Neoplasms, Plasma Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Bortezomib</mesh_term>
    <mesh_term>Vorinostat</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01720875
org study id: HM11/10041
secondary id: ISRCTN08577602
secondary id: 2011-005361-20
nct id: NCT01720875
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
Bortezomib is an established treatment in multiple myeloma; it is common practice in the UK
      to administer bortezomib with dexamethasone. This practice is based on data that supports
      improved response rates with this combination.

      Recent trial data indicates that the addition of vorinostat to bortezomib treatment overcomes
      treatment resistance to bortezomib. As such this current trial is designed to investigate the
      efficacy, safety and tolerability of combination treatment with vorinostat, bortezomib and
      dexamethasone in patients with relapsed and relapsed refractory myeloma.

      A comparison of this Phase II trial with the pivotal Phase III trial conducted by MSD (using
      the labelled bortezomib indication without dexamethasone) will address the impact of
      dexamethasone in regards to tolerability and additional efficacy in myeloma patients.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall response rate to vorinostat, bortezomib and dexamethasone.
time frame: up to 24 weeks
description: To assess the number and proportion of participants with at least a partial response (PR) or better within 8 cycles of protocol treatment with vorinostat, bortezomib and dexamethasone.
measure: Number of dose reductions during treatment with vorinostat, bortezomib and dexamethasone.
time frame: up to 24 weeks
description: To assess the dose reduction profile of combination treatment with vorinostat, bortezomib and dexamethasone. The proportion of participants experiencing a dose reduction or terminating treatment early due to toxicity will be assessed.
measure: Overall numbers and rates of adverse events
time frame: Up to 18 months
description: Safety and toxicity analyses will summarise the overall serious adverse event and adverse events rates including the number and proportion of participants with at least one safety event. SAEs will be additionally presented by the relationship to study treatment, seriousness criteria, event outcome, duration and by MedDRA body system coding.
measure: Progression free survival
time frame: Up to 18 months
description: A progression-free survival curve will be calculated using the Kaplan Meier method and median PFS estimates will be presented
measure: Maximum response to treatment
time frame: Up to 24 weeks
description: The overall number and proportion of participants in each response category within 8 cycles of treatment and overall across all treatment including the maintenance phase
measure: Time to maximum response
time frame: Up to 18 months
description: The time to maximum response will be calculated from the date of registration to the date of maximum response. Participant's who progress and do not achieve a maximum response will be censored at the time of progression. Median time to maximum response will be presented.
measure: Matched pairs analysis
time frame: Up to 24 months
description: A matched pairs analysis will be carried out looking at overall response, PFS, dose reductions and toxicity in participants treated with vorinostat in combination with bortezomib and dexamethasone (VVD) in this current study compared to participants randomised to the bortezomib/vorinostat (VV) arm in the pivotal MSD phase III study.
arm group label: Vorinostat Velcade Dexamethasone (VVD)
arm group type: Experimental
description: Up to 8 cycles of VVD followed by vorinostat maintenance until disease progression.
Cycles 1-8 (21-day cycle)
Velcade: 1.3mg/m2 (subcutaneous) on days 1, 4, 8 and 11
Dexamethasone: 20 mg (PO) on days 1, 2, 4, 5, 8, 9, 11 and 12
Vorinostat: 400mg (PO) on days 1-4, 8-11, 15-18 Maintenance (28-day cycle)
Vorinostat: 400mg PO on 1-4 and 15-18
intervention type: Drug
intervention name: Vorinostat Velcade Dexamethasone
arm group label: Vorinostat Velcade Dexamethasone (VVD)
other name: Bortezomib (velcade)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Matthew Jenner
role: Principal Investigator
affiliation: University Hospital of Southampton
facility: 
facility: 
country: United Kingdom
citation: Brown S, Pawlyn C, Tillotson AL, Sherratt D, Flanagan L, Low E, Morgan GJ, Williams C, Kaiser M, Davies FE, Jenner MW; Myeloma UK Early Phase Clinical Trial Network. Bortezomib, Vorinostat, and Dexamethasone Combination Therapy in Relapsed Myeloma: Results of the Phase 2 MUK four Trial. Clin Lymphoma Myeloma Leuk. 2021 Mar;21(3):154-161.e3. doi: 10.1016/j.clml.2020.11.019. Epub 2020 Dec 3.
PMID: 33478922
responsible party type: Sponsor
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Dexamethasone
mesh term: Bortezomib
mesh term: Vorinostat