<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/NCT01705392</url>
  </required_header>
  <id_info>
    <org_study_id>2012/910</org_study_id>
    <nct_id>NCT01705392</nct_id>
  </id_info>
  <brief_title>Bevacizumab vs Dacarbazine in Metastatic Melanoma</brief_title>
  <official_title>A Randomized Phase II Trial Comparing Bevacizumab Monotherapy With Dacarbazine (DTIC) in Treatment of Malignant Melanoma, Focusing on Angiogenic Markers and Prevention of Hypertension.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Haukeland University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>The Norwegian Melanoma Group</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Norwegian Cancer Society</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Haukeland University Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to compare efficacy of bevacizumab monotherapy with standard&#xD;
      chemotherapy (DTIC) in patients with metastatic malignant melanoma. In addition, we want to&#xD;
      evaluate the predictive value of a set biomarkers associated with vascular endothelial growth&#xD;
      factor (VEGF) dependent angiogenesis. Also, we aim to identify mechanisms causing acquired&#xD;
      resistance to treatment with bevacizumab and escape mechanisms caused by other angiogenic&#xD;
      growth factors than VEGF. Finally, we want to analyze safety and influence on outcome&#xD;
      variables by primary prevention of bevacizumab induced hypertension by low dose beta blockers&#xD;
      in comparison with an ACE inhibitor.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Lack of financing of the study drug. Not sufficient financial support.&#xD;
  </why_stopped>
  <start_date type="Actual">January 2013</start_date>
  <completion_date type="Actual">February 20, 2017</completion_date>
  <primary_completion_date type="Actual">February 20, 2017</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression free survival</measure>
    <time_frame>Average of 6 months</time_frame>
    <description>Participants will be followed for the duration of the treatment and as long as they do not progress, an expected average of 6 months</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Response Rates according to RECIST</measure>
    <time_frame>Average 6 months</time_frame>
    <description>Participants will be followed for the duration of the treatment with CT scans for response evaluation every 2 months for an expected average of 6 months.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease control rate at 6 months</measure>
    <time_frame>6 months</time_frame>
    <description>Number of patient with complete response, partial response or stable disease at 6 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prevention of hypertension by beta blockers or ACE-inhibitors</measure>
    <time_frame>Average of 6 months</time_frame>
    <description>Safety and influence on outcome variables by primary prevention of bevacizumab induced hypertension, by low dose beta blockers (propranolol 80 mg x 1), in comparison with an ACE inhibitor (enalapril 5 mg x 1). Patients will be monitored as during active treatment with anti hypertensive drugs and bevacizumab for an average of 6 months.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>Average og 12 months</time_frame>
    <description>Participants will be followed until death for overall survival data, an expected average of 12 months</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">2</enrollment>
  <condition>Metastatic Malignant Melanoma</condition>
  <condition>Unresectable Malignant Melanoma</condition>
  <arm_group>
    <arm_group_label>Bevacizumab plus propranolol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Bevacizumab 10mg/kg q2w plus propranolol 80 mg x 1</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Bevacizumab plus enalapril</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Bevacizumab 10mg/kg q2w plus enalapril 5 mg x 1</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dacarbazine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Dacarbazine 1000mg/m2 q3w</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bevacizumab</intervention_name>
    <description>Bevacizumab 10 mg/kg q3w</description>
    <arm_group_label>Bevacizumab plus enalapril</arm_group_label>
    <arm_group_label>Bevacizumab plus propranolol</arm_group_label>
    <other_name>Avastin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Propranolol</intervention_name>
    <description>Propranolol 80 mg x 1</description>
    <arm_group_label>Bevacizumab plus propranolol</arm_group_label>
    <other_name>Inderal</other_name>
    <other_name>Inderal retard</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Enalapril</intervention_name>
    <description>Enalapril 5 mg x 1</description>
    <arm_group_label>Bevacizumab plus enalapril</arm_group_label>
    <other_name>Renitec</other_name>
    <other_name>Vasotec</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dacarbazine</intervention_name>
    <description>dacarbazine 1000 mg/m2 q3w</description>
    <arm_group_label>Dacarbazine</arm_group_label>
    <other_name>DTIC</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Previously treated or untreated, histologically confirmed, metastatic and unresectable&#xD;
             melanoma with progressive disease&#xD;
&#xD;
          -  Both BRAF wild type patients as well as BRAF mutated patients are allowed. For BRAF&#xD;
             mutated patients, BRAF targeting agents should be considered in first line if&#xD;
             otherwise indicated and no contraindications exist.&#xD;
&#xD;
          -  WHO performance status 0-1&#xD;
&#xD;
          -  Age &gt;18 years,&#xD;
&#xD;
          -  Known BRAF mutation&#xD;
&#xD;
          -  Able to undergo outpatient treatment&#xD;
&#xD;
          -  Patients must have clinically and/or radiographically documented measurable disease&#xD;
             according to RECIST.&#xD;
&#xD;
          -  All radiology studies must be performed within 28 days prior to registration (35 days&#xD;
             if negative).&#xD;
&#xD;
          -  At least 4 weeks since adjuvant interferon alpha&#xD;
&#xD;
          -  At least 4 weeks since 1st line treatment in case of metastasis&#xD;
&#xD;
          -  Major surgical procedure or significant traumatic injury &gt; 28 days prior to study&#xD;
             treatment start. Biopsy or fine needle aspiration &gt; 2 days prior to study treatment&#xD;
             start. Central venous line placement must be inserted at least 2 days prior to&#xD;
             treatment start.&#xD;
&#xD;
          -  Only patients with irradiated and asymptomatic brain metastases and off dexamethasone&#xD;
             are allowed.&#xD;
&#xD;
          -  Hematology: absolute granulocytes &gt; 1.0 x 109/L&#xD;
&#xD;
          -  Platelets &gt; 100 x 109/L&#xD;
&#xD;
          -  Bilirubin &lt; 1.5 x upper normal limit&#xD;
&#xD;
          -  Serum creatinine &lt; 1.5 x upper normal limits&#xD;
&#xD;
          -  LDH &lt; 1.5 x upper normal limit&#xD;
&#xD;
          -  INR &lt; 1.5&#xD;
&#xD;
          -  Absence of any psychological, familial, sociological or geographical condition&#xD;
             potentially hampering compliance with the study protocol and follow-up schedule; those&#xD;
             conditions should be discussed with the patient before registration in the trial&#xD;
&#xD;
          -  Before patient registration/randomization, written informed consent must be given&#xD;
             according to national and local regulations.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  No previous DTIC&#xD;
&#xD;
          -  No previous anti-VEGF targeted therapies&#xD;
&#xD;
          -  No pregnant or lactating patients can be included&#xD;
&#xD;
          -  No clinical evidence of coagulopathy&#xD;
&#xD;
          -  No unstable angina pectoris&#xD;
&#xD;
          -  No AV-block II or III without pacemaker&#xD;
&#xD;
          -  No severe congestive heart failure&#xD;
&#xD;
          -  No untreated phaeochromocytoma&#xD;
&#xD;
          -  No severe bradycardia&#xD;
&#xD;
          -  No severe hypotension&#xD;
&#xD;
          -  No severe impairment of peripheral arterial circulation&#xD;
&#xD;
          -  No uncontrolled cardiac arrhythmia&#xD;
&#xD;
          -  No severe asthma or COPD&#xD;
&#xD;
          -  No uncontrolled diabetes mellitus&#xD;
&#xD;
          -  No Angioneurotic edema&#xD;
&#xD;
          -  No severe Aortic valve stenosis&#xD;
&#xD;
          -  No severe hypertrophic cardiomyopathy&#xD;
&#xD;
          -  No severe renal dysfunction&#xD;
&#xD;
          -  No patients on beta blockers/ ACE inhibitors by inclusion unable/unwilling to&#xD;
             discontinue beta blockers/ ACE inhibitors and convert to other classes of&#xD;
             antihypertensive drugs&#xD;
&#xD;
          -  No full-dose oral coumarin-derived anticoagulants (INR&gt;1.5) or heparin, thrombolytic&#xD;
             agents, or chronic, daily treatment with aspirin (&gt;325 mg/day).&#xD;
&#xD;
          -  No uncontrolled hypertension&#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>Oddbjorn Straume, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of Oncology, Haukeland University Hospital, Bergen, Norway</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Olav Mella, MD PhD</last_name>
    <role>Study Director</role>
    <affiliation>Department of Oncology, Haukeland University Hospital, Bergen, Norway</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Haukeland University Hospital</name>
      <address>
        <city>Bergen</city>
        <zip>5021</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Norway</country>
  </location_countries>
  <verification_date>February 2017</verification_date>
  <study_first_submitted>October 8, 2012</study_first_submitted>
  <study_first_submitted_qc>October 11, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 12, 2012</study_first_posted>
  <last_update_submitted>February 23, 2017</last_update_submitted>
  <last_update_submitted_qc>February 23, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">February 24, 2017</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>Melanoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bevacizumab</mesh_term>
    <mesh_term>Dacarbazine</mesh_term>
    <mesh_term>Propranolol</mesh_term>
    <mesh_term>Enalapril</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/NCT01705392
org study id: 2012/910
nct id: NCT01705392
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
The purpose of this study is to compare efficacy of bevacizumab monotherapy with standard
      chemotherapy (DTIC) in patients with metastatic malignant melanoma. In addition, we want to
      evaluate the predictive value of a set biomarkers associated with vascular endothelial growth
      factor (VEGF) dependent angiogenesis. Also, we aim to identify mechanisms causing acquired
      resistance to treatment with bevacizumab and escape mechanisms caused by other angiogenic
      growth factors than VEGF. Finally, we want to analyze safety and influence on outcome
      variables by primary prevention of bevacizumab induced hypertension by low dose beta blockers
      in comparison with an ACE inhibitor.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression free survival
time frame: Average of 6 months
description: Participants will be followed for the duration of the treatment and as long as they do not progress, an expected average of 6 months
measure: Response Rates according to RECIST
time frame: Average 6 months
description: Participants will be followed for the duration of the treatment with CT scans for response evaluation every 2 months for an expected average of 6 months.
measure: Disease control rate at 6 months
time frame: 6 months
description: Number of patient with complete response, partial response or stable disease at 6 months
measure: Prevention of hypertension by beta blockers or ACE-inhibitors
time frame: Average of 6 months
description: Safety and influence on outcome variables by primary prevention of bevacizumab induced hypertension, by low dose beta blockers (propranolol 80 mg x 1), in comparison with an ACE inhibitor (enalapril 5 mg x 1). Patients will be monitored as during active treatment with anti hypertensive drugs and bevacizumab for an average of 6 months.
measure: Overall survival
time frame: Average og 12 months
description: Participants will be followed until death for overall survival data, an expected average of 12 months
arm group label: Bevacizumab plus propranolol
arm group type: Experimental
description: Bevacizumab 10mg/kg q2w plus propranolol 80 mg x 1
arm group label: Bevacizumab plus enalapril
arm group type: Experimental
description: Bevacizumab 10mg/kg q2w plus enalapril 5 mg x 1
arm group label: Dacarbazine
arm group type: Active Comparator
description: Dacarbazine 1000mg/m2 q3w
intervention type: Drug
intervention name: Bevacizumab
description: Bevacizumab 10 mg/kg q3w
arm group label: Bevacizumab plus enalapril
arm group label: Bevacizumab plus propranolol
other name: Avastin
intervention type: Drug
intervention name: Propranolol
description: Propranolol 80 mg x 1
arm group label: Bevacizumab plus propranolol
other name: Inderal
other name: Inderal retard
intervention type: Drug
intervention name: Enalapril
description: Enalapril 5 mg x 1
arm group label: Bevacizumab plus enalapril
other name: Renitec
other name: Vasotec
intervention type: Drug
intervention name: Dacarbazine
description: dacarbazine 1000 mg/m2 q3w
arm group label: Dacarbazine
other name: DTIC
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Oddbjorn Straume, MD PhD
role: Principal Investigator
affiliation: Department of Oncology, Haukeland University Hospital, Bergen, Norway
last name: Olav Mella, MD PhD
role: Study Director
affiliation: Department of Oncology, Haukeland University Hospital, Bergen, Norway
facility: 
country: Norway
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Bevacizumab
mesh term: Dacarbazine
mesh term: Propranolol
mesh term: Enalapril