<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/NCT01731158</url>
  </required_header>
  <id_info>
    <org_study_id>C-II-008</org_study_id>
    <secondary_id>2011-005939-78</secondary_id>
    <nct_id>NCT01731158</nct_id>
  </id_info>
  <brief_title>Sequential Therapy in Metastatic Renal Cell Carinoma</brief_title>
  <acronym>BERAT</acronym>
  <official_title>A Prospective, Open-label, Multicenter, Randomized Phase II Trial: Sequential Therapy With BEvacizumab, RAd001 (Everolimus) and Tyrosinekinase Inhibitors (TKI) in Metastatic Renal Cell Carcinoma (mRCC) (BERAT Study)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Central European Society for Anticancer Drug Research</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Central European Society for Anticancer Drug Research</source>
  <brief_summary>
    <textblock>
      Sequential therapy with BEvacizumab, RAd001 (everolimus) and Tyrosinekinase inhibitors (TKI)&#xD;
      in metastatic renal cell carcinoma (mRCC)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This will be a prospective, open label, randomized multicenter phase-II study to evaluate&#xD;
      progression free survival (PFS) in 2nd line treatment in patients with locally advanced or&#xD;
      metastatic clear-cell renal cell cancer (cc-RCC) receiving everolimus (arm A) in comparison&#xD;
      to a tyrosine-kinase inhibitor (TKI) (arm B). Following 2nd line treatment, patients will be&#xD;
      switched to a TKI in arm A and everolimus in arm B. All patients will receive bevacizumab as&#xD;
      standardized first-line treatment.&#xD;
&#xD;
      Another key element of the study is the analysis of predictive biomarkers, which will be&#xD;
      performed in serum and tumor tissue, respectively. Serum samples will be collected at&#xD;
      prespecified timepoints throughout the study and analysed by SELDI-TOF-MS and DIGE. Candidate&#xD;
      proteins are thought to predict therapeutic outcome and candidates are subject for target&#xD;
      validation by Western Blot or ELISA. In addition, formalin-fixed paraffin-embedded (FFPE)&#xD;
      tumor tissue will be collected prospectively and analysed for micro RNA (miRNA). Candidate&#xD;
      miRNAs that predict therapeutic outcome will be validated by quantitative RT-PCR.&#xD;
      Furthermore, circulating tumor cells (CTCs) will be generated from blood drawings during&#xD;
      routine visits. The primary objective is to correlate the marker profile defined from the&#xD;
      FFPE tissue with the profile obtained from CTCs in order to validate expression based markers&#xD;
      ant their change during different treatment lines.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">September 2016</completion_date>
  <primary_completion_date type="Actual">September 2016</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>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>PFS rate of 2nd line treatment at 6 months after randomisation</measure>
    <time_frame>6 months after randomisation</time_frame>
    <description>PFS rate</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>PFS for 2nd line treatment</measure>
    <time_frame>after completion of second-line treatment (expected median treatment 1st and 2nd line: 16 months)</time_frame>
    <description>PFS</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PFS for each treatment given</measure>
    <time_frame>after completion of each treatment line (expected median treatment duration 1st line: 11 months, 2nd line: 5 months, 3rd line: 6 months)</time_frame>
    <description>PFS</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>after death of patient</time_frame>
    <description>OS</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>number and severity (CTCAE 4.0) adverse events</measure>
    <time_frame>continuously throughout trial</time_frame>
    <description>AE</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>changes in quality of life throughout the Trial using FKSI questionnaires</measure>
    <time_frame>continuously throughout trial (baseline, week 5, week 11, every 12 weeks, end of treatment for all treatment lines via FKSI-10 questionnaire)</time_frame>
    <description>quality of life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ORR for each treatment given</measure>
    <time_frame>after completion of each treatment line (expected median treatment duration 1st line: 11 months, 2nd line: 5 months, 3rd line: 6 months)</time_frame>
    <description>ORR</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">22</enrollment>
  <condition>Metastatic Renal Cell Carcinoma</condition>
  <arm_group>
    <arm_group_label>arm A</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>sequential therapy with approved drugs&#xD;
Avastin in combination with Roferon-A (first-line), Afinitor (second-line) and a TKI (Sutent, Nexavar or Votrient) (third-line)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>arm B</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>sequential therapy with approved drugs&#xD;
Avastin in combination with Roferon-A (first-line), a TKI (Sutent, Nexavar or Votrient) (second-line) and Afinitor (third-line)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Avastin in combination with Roferon-A</intervention_name>
    <arm_group_label>arm A</arm_group_label>
    <arm_group_label>arm B</arm_group_label>
    <other_name>Bevacizumab in combination with Interfereon-alfa</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Afinitor</intervention_name>
    <arm_group_label>arm A</arm_group_label>
    <arm_group_label>arm B</arm_group_label>
    <other_name>Everolimus</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TKI: Sutent, Nexavar or Votrient</intervention_name>
    <description>TKI</description>
    <arm_group_label>arm A</arm_group_label>
    <arm_group_label>arm B</arm_group_label>
    <other_name>Sunitinib, Sorafenib or Pazopanib</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed Informed Consent&#xD;
&#xD;
          -  Documented progressive disease prior to study inclusion.&#xD;
&#xD;
          -  Adult males and females: ≥ 18 years of age.&#xD;
&#xD;
          -  Metastatic or locally advanced RCC, not amendable to surgery with curative intention.&#xD;
&#xD;
          -  ECOG performance status 0-1.&#xD;
&#xD;
          -  Patients with measurable disease (at least one uni-dimensionally measurable target&#xD;
             lesion by CT-scan or MRI) according to Response Evaluation Criteria in Solid Tumors&#xD;
             (RECIST 1.1) If prior palliative radiotherapy to metastatic lesions: ≥ 1 measurable&#xD;
             lesion that has not been irradiated. Patients with bone lesions as the only measurable&#xD;
             lesion are eligible, provided that lesions consist of soft tissue, which is assessed&#xD;
             via CT or MRI.&#xD;
&#xD;
          -  Prior radiotherapy and surgery are allowed if completed 4 weeks (for minor surgery 2&#xD;
             weeks) prior to start of treatment and patient recovered from toxic effects.&#xD;
&#xD;
          -  Modified MSKCC risk (according to Heng): good or intermediate.&#xD;
&#xD;
          -  White blood cell count (WBC) ≥ 4x10*9/L with neutrophils ≥ 1.5 x 10*9/L, platelet&#xD;
             count ≥ 100x10*9/L, hemoglobin ≥ 9 g/dL.&#xD;
&#xD;
          -  Total bilirubin ≤ 2 x upper limit of normal.&#xD;
&#xD;
          -  AST and ALT ≤ 2.5 x upper limit of normal, or ≤ 5 x upper limit of normal in case of&#xD;
             liver metastases.&#xD;
&#xD;
          -  Serum creatinine ≤ 2 x upper limit of normal or calculated creatinine clearance &gt;30&#xD;
             ml/min.&#xD;
&#xD;
          -  International Normalized Ratio (INR) ≤1.5 except for patients on stable anticoagulant&#xD;
             therapy. Activated partial thromboplastin time (aPTT) ≤1.5 times upper limit of normal&#xD;
             (ULN) or greater than the lower limit of the therapeutic range. Note: The use of&#xD;
             full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is&#xD;
             within therapeutic limits (according to the medical standard in the institution) and&#xD;
             the patient has been on a stable dose of anticoagulants for at least two weeks at the&#xD;
             treatment start.&#xD;
&#xD;
          -  Adequate cardiac function (left ventricular ejection fraction ≥50% as assessed by&#xD;
             ECHO)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any investigational drug within the 30 days before inclusion.&#xD;
&#xD;
          -  Known or suspected allergy or hypersensitivity reaction to any of the components of&#xD;
             study treatments or their excipients.&#xD;
&#xD;
          -  Pregnancy (absence to be confirmed by beta-hCG test) or lactation period.&#xD;
&#xD;
          -  Men or women of child-bearing potential who are sexually active and unwilling to use a&#xD;
             highly effective method of contraception (Pearl index &lt; 1%) during the trial. Oral&#xD;
             contraceptives are acceptable if a barrier method is applied in conjunction.&#xD;
&#xD;
          -  Clinically symptomatic brain or meningeal metastasis (known or suspected), unless&#xD;
             completion of local therapy for at least 3 months with discontinuation of steroids&#xD;
             prior to start of treatment.&#xD;
&#xD;
          -  Cardiac arrhythmias requiring anti-arrhythmics (excluding beta blockers, digoxin or&#xD;
             digitoxin).&#xD;
&#xD;
          -  History of any of the following cardiac events within the past 6 months:&#xD;
&#xD;
               1. myocardial infarction (including severe/unstable angina),&#xD;
&#xD;
               2. coronary/peripheral artery bypass graft,&#xD;
&#xD;
               3. congestive heart failure (CHF) (NYHA Class III, or IV),&#xD;
&#xD;
               4. cerebrovascular accident,&#xD;
&#xD;
               5. transient ischemic attack,&#xD;
&#xD;
               6. pulmonary embolism, abdominal or tracheo-oesophageal fistula, gastrointestinal&#xD;
                  perforation, or intra-abdominal abscess&#xD;
&#xD;
          -  Hemorrhage ≥ grade 3 or clinically significant hemoptysis within the past 4 weeks&#xD;
&#xD;
          -  Uncontrolled severe hypertension (failure of diastolic blood pressure to fall below 90&#xD;
             mm Hg despite the use of ≥ 3 anti-hypertensive drugs).&#xD;
&#xD;
          -  History of relevant pulmonary hypertension or interstitial lung disease or severely&#xD;
             impaired lung function.&#xD;
&#xD;
          -  Acute or sub-acute intestinal occlusion or history of inflammatory bowel disease or&#xD;
             chronic diarrhea.&#xD;
&#xD;
          -  Previous malignancy (other than renal cell cancer) in the last 3 years, except basal&#xD;
             cell cancer of the skin, pre-invasive cancer of the cervix, T1a prostate carcinoma or&#xD;
             superficial bladder tumor [Ta, Tis and T1].&#xD;
&#xD;
          -  History of organ allograft.&#xD;
&#xD;
          -  Significant disease which, in the investigator's opinion would exclude the patient&#xD;
             from the study.&#xD;
&#xD;
          -  Medication that is known to interfere with any of the agents applied in the trial.&#xD;
&#xD;
          -  Patients with a serious non-healing wound, ulcer or bone fracture.&#xD;
&#xD;
          -  Patients with a history of seizure(s) not controlled with standard medical therapy.&#xD;
&#xD;
          -  Patients receiving chronic systemic treatment with corticosteroids (dose of &gt; 20&#xD;
             mg/day methylprednisone equivalent) or another immune-suppressive agent. Inhaled and&#xD;
             topical steroids are acceptable.&#xD;
&#xD;
          -  Legal incapacity or limited legal capacity.&#xD;
&#xD;
          -  Medical or psychological conditions that would not permit the patient to complete the&#xD;
             study or sign informed consent.&#xD;
&#xD;
          -  Significant vascular disease (e.g. aortic aneurysm, aortic dissection), or symptomatic&#xD;
             peripheral vascular disease.&#xD;
&#xD;
          -  Evidence or history of recurrent thromboembolism (&gt;1 episode of deep venous&#xD;
             thrombosis/peripheral embolism ≥ CTCAE Grade 3) during the past 2 years, bleeding&#xD;
             diathesis or coagulopathy.&#xD;
&#xD;
          -  Poorly controlled diabetes as defined by fasting serum glucose &gt; 2.0 x ULN.&#xD;
&#xD;
          -  Active (acute or chronic) or uncontrolled infection of bacterial, mycotic or viral&#xD;
             genesis.&#xD;
&#xD;
          -  Liver disease such as chronic active hepatitis or chronic persistent hepatitis.&#xD;
&#xD;
          -  Patients with a known history of HIV seropositivity.&#xD;
&#xD;
          -  QT prolongation (QTc &gt; 450 msec).&#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>Viktor Grünwald, MD</last_name>
    <role>Study Chair</role>
    <affiliation>University Hospital Hannover, Germany</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Charité Berlin</name>
      <address>
        <city>Berlin</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Bonn</name>
      <address>
        <city>Bonn</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Dresden</name>
      <address>
        <city>Dresden</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Düsseldorf</name>
      <address>
        <city>Düsseldorf</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Waldkrankenhaus St. Marien</name>
      <address>
        <city>Erlangen</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Essen</name>
      <address>
        <city>Essen</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Frankfurt</name>
      <address>
        <city>Frankfurt</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Freiburg</name>
      <address>
        <city>Freiburg</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Göttingen</name>
      <address>
        <city>Göttingen</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oncological Practice Hannover</name>
      <address>
        <city>Hannover</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Hannover</name>
      <address>
        <city>Hannover</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Magdeburg</name>
      <address>
        <city>Magdeburg</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Tübingen</name>
      <address>
        <city>Tübingen</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>February 2019</verification_date>
  <study_first_submitted>September 28, 2012</study_first_submitted>
  <study_first_submitted_qc>November 16, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 21, 2012</study_first_posted>
  <last_update_submitted>February 4, 2019</last_update_submitted>
  <last_update_submitted_qc>February 4, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">February 6, 2019</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>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Renal Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Interferon alpha-2</mesh_term>
    <mesh_term>Bevacizumab</mesh_term>
    <mesh_term>Sunitinib</mesh_term>
    <mesh_term>Everolimus</mesh_term>
    <mesh_term>Sorafenib</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/NCT01731158
org study id: C-II-008
secondary id: 2011-005939-78
nct id: NCT01731158
lead sponsor: 
Sequential therapy with BEvacizumab, RAd001 (everolimus) and Tyrosinekinase inhibitors (TKI)
      in metastatic renal cell carcinoma (mRCC)
This will be a prospective, open label, randomized multicenter phase-II study to evaluate
      progression free survival (PFS) in 2nd line treatment in patients with locally advanced or
      metastatic clear-cell renal cell cancer (cc-RCC) receiving everolimus (arm A) in comparison
      to a tyrosine-kinase inhibitor (TKI) (arm B). Following 2nd line treatment, patients will be
      switched to a TKI in arm A and everolimus in arm B. All patients will receive bevacizumab as
      standardized first-line treatment.

      Another key element of the study is the analysis of predictive biomarkers, which will be
      performed in serum and tumor tissue, respectively. Serum samples will be collected at
      prespecified timepoints throughout the study and analysed by SELDI-TOF-MS and DIGE. Candidate
      proteins are thought to predict therapeutic outcome and candidates are subject for target
      validation by Western Blot or ELISA. In addition, formalin-fixed paraffin-embedded (FFPE)
      tumor tissue will be collected prospectively and analysed for micro RNA (miRNA). Candidate
      miRNAs that predict therapeutic outcome will be validated by quantitative RT-PCR.
      Furthermore, circulating tumor cells (CTCs) will be generated from blood drawings during
      routine visits. The primary objective is to correlate the marker profile defined from the
      FFPE tissue with the profile obtained from CTCs in order to validate expression based markers
      ant their change during different treatment lines.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: PFS rate of 2nd line treatment at 6 months after randomisation
time frame: 6 months after randomisation
description: PFS rate
measure: PFS for 2nd line treatment
time frame: after completion of second-line treatment (expected median treatment 1st and 2nd line: 16 months)
description: PFS
measure: PFS for each treatment given
time frame: after completion of each treatment line (expected median treatment duration 1st line: 11 months, 2nd line: 5 months, 3rd line: 6 months)
description: PFS
measure: Overall Survival
time frame: after death of patient
description: OS
measure: number and severity (CTCAE 4.0) adverse events
time frame: continuously throughout trial
description: AE
measure: changes in quality of life throughout the Trial using FKSI questionnaires
time frame: continuously throughout trial (baseline, week 5, week 11, every 12 weeks, end of treatment for all treatment lines via FKSI-10 questionnaire)
description: quality of life
measure: ORR for each treatment given
time frame: after completion of each treatment line (expected median treatment duration 1st line: 11 months, 2nd line: 5 months, 3rd line: 6 months)
description: ORR
arm group label: arm A
arm group type: Other
description: sequential therapy with approved drugs
Avastin in combination with Roferon-A (first-line), Afinitor (second-line) and a TKI (Sutent, Nexavar or Votrient) (third-line)
arm group label: arm B
arm group type: Other
description: sequential therapy with approved drugs
Avastin in combination with Roferon-A (first-line), a TKI (Sutent, Nexavar or Votrient) (second-line) and Afinitor (third-line)
intervention type: Drug
intervention name: Avastin in combination with Roferon-A
arm group label: arm A
arm group label: arm B
other name: Bevacizumab in combination with Interfereon-alfa
intervention type: Drug
intervention name: Afinitor
arm group label: arm A
arm group label: arm B
other name: Everolimus
intervention type: Drug
intervention name: TKI: Sutent, Nexavar or Votrient
description: TKI
arm group label: arm A
arm group label: arm B
other name: Sunitinib, Sorafenib or Pazopanib
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Viktor Grünwald, MD
role: Study Chair
affiliation: University Hospital Hannover, Germany
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Germany
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Renal Cell
mesh term: Interferon alpha-2
mesh term: Bevacizumab
mesh term: Sunitinib
mesh term: Everolimus
mesh term: Sorafenib