<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/NCT02971410</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00040660</org_study_id>
    <secondary_id>NCI-2016-01465</secondary_id>
    <secondary_id>CCCWFU 26216</secondary_id>
    <secondary_id>P30CA012197</secondary_id>
    <nct_id>NCT02971410</nct_id>
  </id_info>
  <brief_title>Simvastatin in Overcoming Chemotherapy Resistance in Patients With Relapsed or Refractory Multiple Myeloma</brief_title>
  <official_title>Overcoming Chemotherapy Resistance in Refractory Multiple Myeloma With Simvastatin, A Pilot Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Wake Forest University Health Sciences</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Wake Forest University Health Sciences</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This pilot clinical trial studies how well simvastatin works in overcoming chemotherapy&#xD;
      resistance in patients with multiple myeloma that has come back or does not respond to&#xD;
      treatment. Simvastatin may stop the growth of cancer cells by blocking some of the enzymes&#xD;
      needed for cell growth.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To examine the effect of simvastatin on myeloma (M)-protein and/or free light chains ratio&#xD;
      when added to conventional chemotherapy for the treatment of multiple myeloma patients who&#xD;
      have received up to 3 (=&lt; 3) and &gt; 3 different chemotherapy regimens. (group A and group B)&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To estimate the progression-free survival (PFS), time to progression (TTP), and duration&#xD;
      of response (DOR) in group A, group B, and both groups combined.&#xD;
&#xD;
      II. To describe toxicities (frequency and severity during the treatment) in group A, group B,&#xD;
      and both groups combined.&#xD;
&#xD;
      III. To estimate overall response (OR) in group A, group B, and both groups combined.&#xD;
&#xD;
      IV. To evaluate the quality of life (QoL) of patients on the combined treatment in group A,&#xD;
      group B, and both groups combined.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive standard of care chemotherapy for up to 3 courses and simvastatin orally&#xD;
      (PO) daily 2 days before the first dose of chemotherapy for up to 2 days after the last dose&#xD;
      of chemotherapy. Treatment with simvastatin continues in the absence of disease progression&#xD;
      or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 30 days, every 3-5 weeks for&#xD;
      the first 6 months, and every 1-3 months thereafter.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    PI no longer interested in pursuing study.&#xD;
  </why_stopped>
  <start_date type="Anticipated">April 2017</start_date>
  <completion_date type="Anticipated">November 2021</completion_date>
  <primary_completion_date type="Anticipated">November 2021</primary_completion_date>
  <phase>Early Phase 1</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>Change in free light chain ratios</measure>
    <time_frame>Up to 126 Days</time_frame>
    <description>The success rate will be estimated overall and within the strata groups and 95% confidence intervals will be calculated around the estimate. Will also estimate the change in free light chain ratios and provide confidence intervals for those estimates, both overall and within groups.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in M-protein level measured using electrophoresis</measure>
    <time_frame>Up to 126 Days</time_frame>
    <description>The success rate will be estimated overall and within the strata groups and 95% confidence intervals will be calculated around the estimate. Will also estimate the change in M-proteins and provide confidence intervals for those estimates, both overall and within groups.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>DOR</measure>
    <time_frame>Up to 28 months</time_frame>
    <description>Will estimate the mean duration of response and provide confidence intervals in the subset of patients who respond. The proportion (with confidence interval) of subjects achieving a clinical benefit response will be calculated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of toxicities evaluated according to National Cancer Institute CTCAE version 4.0</measure>
    <time_frame>Up to 28 months</time_frame>
    <description>Toxicity data (both frequency and severity) will be summarized descriptively by showing the number of subjects experiencing each type of toxicity by grade for those with a grade 2 or higher.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>OR including stringent complete remission (CR), CR, Partial Remission (PR), and very good PR</measure>
    <time_frame>Up to 28 months</time_frame>
    <description>The proportion (with confidence interval) of subjects achieving a clinical benefit response will be calculated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>Up to 28 months</time_frame>
    <description>Will be analyzed initially using Kaplan-Meier estimation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PFS</measure>
    <time_frame>Up to 28 months</time_frame>
    <description>Will be analyzed initially using Kaplan-Meier estimation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>QoL assessed using a survey designed by European Organization for Research and Treatment of Cancer (EORTC)</measure>
    <time_frame>Up to 126 Days</time_frame>
    <description>Quality of life outcomes from the EORTC survey will be summarized descriptively.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response in patients who did and did not receive zoledronic acid with therapy</measure>
    <time_frame>Up to 28 months</time_frame>
    <description>Subset analysis will be done on patients who received zoledronic acid as part of their treatment while on study vs those who did not receive zoledronic acid to assess differences in response.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to first response</measure>
    <time_frame>Up to 28 months</time_frame>
    <description>Will be analyzed initially using Kaplan-Meier estimation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to next therapy</measure>
    <time_frame>Up to 28 months</time_frame>
    <description>Will be analyzed initially using Kaplan-Meier estimation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>TTP</measure>
    <time_frame>Up to 28 months</time_frame>
    <description>Will be analyzed initially using Kaplan-Meier estimation.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Recurrent Plasma Cell Myeloma</condition>
  <condition>Refractory Plasma Cell Myeloma</condition>
  <arm_group>
    <arm_group_label>Treatment (simvastatin)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive standard of care chemotherapy for up to 3 courses and simvastatin (PO) daily 2 days before the first dose of chemotherapy for up to 2 days after the last dose of chemotherapy. Treatment with simvastatin continues in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (simvastatin)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Quality-of-Life Assessment</intervention_name>
    <description>Ancillary studies</description>
    <arm_group_label>Treatment (simvastatin)</arm_group_label>
    <other_name>Quality of Life Assessment</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Simvastatin</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (simvastatin)</arm_group_label>
    <other_name>MK 733</other_name>
    <other_name>Synvinolin</other_name>
    <other_name>Zocor</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have a definitive diagnosis of multiple myeloma (using the International&#xD;
             Myeloma Working Group Guidelines)&#xD;
&#xD;
          -  Patients must meet one of the following two requirements:&#xD;
&#xD;
               -  Have achieved minimal response (MR) or stable disease (SD) in current treatment&#xD;
                  regimen after receiving a minimum of two cycles&#xD;
&#xD;
               -  Have a partial response but show a decrease less than 25% or an increase less&#xD;
                  than 25% in measurable disease over a two month period&#xD;
&#xD;
                    -  NOTE: Patients may be refractory to primary therapy or relapsed and have&#xD;
                       measurable or assessable disease; (refractory disease is defined as anything&#xD;
                       less than partial response [PR] or progression within 60 days of completing&#xD;
                       therapy)&#xD;
&#xD;
          -  Patients with multiple myeloma must have measurable disease; measurable disease may be&#xD;
             paraprotein in serum or urine or the presence of free light chains in serum or urine&#xD;
             defined by one or more of the following criteria:&#xD;
&#xD;
               -  Presence of serum M-protein concentration &gt; 1 g/dL&#xD;
&#xD;
               -  Urine M-protein excretion &gt; 200 mg in 24-hour urine collection&#xD;
&#xD;
               -  Serum free light chain concentration &gt;= 10 mg/dL and abnormal kappa/lambda ratio&#xD;
&#xD;
               -  Urine free light chain concentration &gt;= 100 mg/L and abnormal kappa/lambda ratio&#xD;
&#xD;
          -  If female patient with reproductive capacity: on effective means of barrier birth&#xD;
             control during the entire duration of the treatment&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) or Karnofsky performance status of 0, 1, or&#xD;
             2 (Karnofsky &gt;= 60%)&#xD;
&#xD;
          -  Life expectancy of greater than 8 weeks&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 500/ul&#xD;
&#xD;
          -  Platelets &gt;= 30,000/ul&#xD;
&#xD;
          -  Total bilirubin &lt; 2 times the upper limit of normal&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]),&#xD;
             alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) &lt; 3 x&#xD;
             upper limit of normal&#xD;
&#xD;
          -  Patients must have adequate renal function as defined by a creatinine clearance &gt;= 40&#xD;
             mL/min (measured or estimated by the Cockcroft-Gault formula)&#xD;
&#xD;
          -  Patients must have no signs of significant rhabdomyolysis determined by creatine&#xD;
             phosphokinase (CPK) levels with a creatine kinase (CK) &lt; 5 times the upper limit of&#xD;
             normal&#xD;
&#xD;
          -  Patients must have recovered from acute toxicities resulting from therapy administered&#xD;
             prior to entering this study to grade 1 or less (Common Terminology Criteria for&#xD;
             Adverse Events [CTCAE] 4); alopecia may be unresolved&#xD;
&#xD;
          -  Ability to understand and the willingness to sign an Institutional Review Board&#xD;
             (IRB)-approved informed consent document&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who have not received any chemotherapy treatment for multiple myeloma prior&#xD;
             to being enrolled in the study&#xD;
&#xD;
          -  Patients who have no measureable disease by serologic or urine markers (detectable&#xD;
             disease only by bone marrow or imaging scans)&#xD;
&#xD;
          -  Patients who show progressive disease or are not tolerating the current chemotherapy&#xD;
             regimen&#xD;
&#xD;
          -  Patients who were receiving simvastatin (dose &gt; 40 mg/day) while receiving current&#xD;
             chemotherapy regimen for multiple myeloma&#xD;
&#xD;
          -  Patients receiving any other investigational agent(s)&#xD;
&#xD;
          -  Active second malignancy in the last 3 years except for non-melanoma skin cancer or&#xD;
             carcinoma-in-situ&#xD;
&#xD;
          -  History of hypersensitivity reactions attributed to simvastatin&#xD;
&#xD;
          -  Patients receiving medications that may increase risk of rhabdomyolysis such as&#xD;
             itraconazole, ketoconazole, erythromycin, cyclosporine, amiodarone, verapamil,&#xD;
             clarithromycin, nefazodone, ranolazine, human immunodeficiency virus (HIV) protease&#xD;
             inhibitors, gemfibrozil, posaconazole, danazol, amiodarone, diltiazem, and amlodipine&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, myopathy, untreated hypothyroidism,&#xD;
             hereditary myopathy in the family history, unstable angina pectoris, liver disease not&#xD;
             due to multiple myeloma, cardiac arrhythmia that is symptomatic or not rate&#xD;
             controlled, active connective tissue disease, active autoimmune disease, or&#xD;
             psychiatric illness/social situations that would limit compliance with study&#xD;
             requirements&#xD;
&#xD;
          -  Pregnant women are ineligible, as treatment involves unforeseeable risks to the embryo&#xD;
             or fetus; female patients with reproductive capacity are required to use effective&#xD;
             means of birth control during the entire duration of the treatment&#xD;
&#xD;
          -  Patients who have been on a statin other than simvastatin within 2 weeks of starting&#xD;
             treatment on current study; these include atorvastatin, fluvastatin, lovastatin,&#xD;
             pitavastatin, pravastatin, and rosuvastatin; if patient is on statin, will need to&#xD;
             stop treatment 2 weeks prior to starting treatment on study&#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>Cesar Rodriguez</last_name>
    <role>Principal Investigator</role>
    <affiliation>Wake Forest University Health Sciences</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Comprehensive Cancer Center of Wake Forest University</name>
      <address>
        <city>Winston-Salem</city>
        <state>North Carolina</state>
        <zip>27157</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2018</verification_date>
  <study_first_submitted>October 4, 2016</study_first_submitted>
  <study_first_submitted_qc>November 18, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 23, 2016</study_first_posted>
  <last_update_submitted>June 29, 2018</last_update_submitted>
  <last_update_submitted_qc>June 29, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">July 2, 2018</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>Simvastatin</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/NCT02971410
org study id: IRB00040660
secondary id: NCI-2016-01465
secondary id: CCCWFU 26216
secondary id: P30CA012197
nct id: NCT02971410
lead sponsor: 
collaborator: 
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This pilot clinical trial studies how well simvastatin works in overcoming chemotherapy
      resistance in patients with multiple myeloma that has come back or does not respond to
      treatment. Simvastatin may stop the growth of cancer cells by blocking some of the enzymes
      needed for cell growth.
PRIMARY OBJECTIVES:

      I. To examine the effect of simvastatin on myeloma (M)-protein and/or free light chains ratio
      when added to conventional chemotherapy for the treatment of multiple myeloma patients who
      have received up to 3 (=< 3) and > 3 different chemotherapy regimens. (group A and group B)

      SECONDARY OBJECTIVES:

      I. To estimate the progression-free survival (PFS), time to progression (TTP), and duration
      of response (DOR) in group A, group B, and both groups combined.

      II. To describe toxicities (frequency and severity during the treatment) in group A, group B,
      and both groups combined.

      III. To estimate overall response (OR) in group A, group B, and both groups combined.

      IV. To evaluate the quality of life (QoL) of patients on the combined treatment in group A,
      group B, and both groups combined.

      OUTLINE:

      Patients receive standard of care chemotherapy for up to 3 courses and simvastatin orally
      (PO) daily 2 days before the first dose of chemotherapy for up to 2 days after the last dose
      of chemotherapy. Treatment with simvastatin continues in the absence of disease progression
      or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, every 3-5 weeks for
      the first 6 months, and every 1-3 months thereafter.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in free light chain ratios
time frame: Up to 126 Days
description: The success rate will be estimated overall and within the strata groups and 95% confidence intervals will be calculated around the estimate. Will also estimate the change in free light chain ratios and provide confidence intervals for those estimates, both overall and within groups.
measure: Change in M-protein level measured using electrophoresis
time frame: Up to 126 Days
description: The success rate will be estimated overall and within the strata groups and 95% confidence intervals will be calculated around the estimate. Will also estimate the change in M-proteins and provide confidence intervals for those estimates, both overall and within groups.
measure: DOR
time frame: Up to 28 months
description: Will estimate the mean duration of response and provide confidence intervals in the subset of patients who respond. The proportion (with confidence interval) of subjects achieving a clinical benefit response will be calculated.
measure: Incidence of toxicities evaluated according to National Cancer Institute CTCAE version 4.0
time frame: Up to 28 months
description: Toxicity data (both frequency and severity) will be summarized descriptively by showing the number of subjects experiencing each type of toxicity by grade for those with a grade 2 or higher.
measure: OR including stringent complete remission (CR), CR, Partial Remission (PR), and very good PR
time frame: Up to 28 months
description: The proportion (with confidence interval) of subjects achieving a clinical benefit response will be calculated.
measure: Overall survival
time frame: Up to 28 months
description: Will be analyzed initially using Kaplan-Meier estimation.
measure: PFS
time frame: Up to 28 months
description: Will be analyzed initially using Kaplan-Meier estimation.
measure: QoL assessed using a survey designed by European Organization for Research and Treatment of Cancer (EORTC)
time frame: Up to 126 Days
description: Quality of life outcomes from the EORTC survey will be summarized descriptively.
measure: Response in patients who did and did not receive zoledronic acid with therapy
time frame: Up to 28 months
description: Subset analysis will be done on patients who received zoledronic acid as part of their treatment while on study vs those who did not receive zoledronic acid to assess differences in response.
measure: Time to first response
time frame: Up to 28 months
description: Will be analyzed initially using Kaplan-Meier estimation.
measure: Time to next therapy
time frame: Up to 28 months
description: Will be analyzed initially using Kaplan-Meier estimation.
measure: TTP
time frame: Up to 28 months
description: Will be analyzed initially using Kaplan-Meier estimation.
arm group label: Treatment (simvastatin)
arm group type: Experimental
description: Patients receive standard of care chemotherapy for up to 3 courses and simvastatin (PO) daily 2 days before the first dose of chemotherapy for up to 2 days after the last dose of chemotherapy. Treatment with simvastatin continues in the absence of disease progression or unacceptable toxicity.
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Treatment (simvastatin)
intervention type: Other
intervention name: Quality-of-Life Assessment
description: Ancillary studies
arm group label: Treatment (simvastatin)
other name: Quality of Life Assessment
intervention type: Drug
intervention name: Simvastatin
description: Given PO
arm group label: Treatment (simvastatin)
other name: MK 733
other name: Synvinolin
other name: Zocor
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Cesar Rodriguez
role: Principal Investigator
affiliation: Wake Forest University Health Sciences
facility: 
country: United States
responsible party type: Sponsor
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Simvastatin