<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/NCT01728181</url>
  </required_header>
  <id_info>
    <org_study_id>HCI59004</org_study_id>
    <nct_id>NCT01728181</nct_id>
  </id_info>
  <brief_title>A Phase I/II Study of Tivozanib and Erlotinib as Initial Treatment for Metastatic Non-small Cell Lung Cancer Assigned by VeriStrat® Serum Proteomic Evaluation</brief_title>
  <official_title>A Phase I/II Study of Tivozanib and Erlotinib as Initial Treatment for Metastatic Non-small Cell Lung Cancer Assigned by VeriStrat® Serum Proteomic Evaluation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Utah</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Utah</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The current trial &quot;A Phase I/II study of Erlotinib +/- Tivozanib as initial treatment for&#xD;
      Metastatic Non-small Cell Lung Cancer assigned by VeriStrat® Serum Proteomic Evaluation&quot; will&#xD;
      begin by evaluating toxicity for the combination of Tivozanib and Erlotinib to determine a&#xD;
      phase II dose. The phase II portion of the study will seek to duplicate the finding of the&#xD;
      BEER trial in a selected population of patients with NSCLC with a VeriStrat® Good signature&#xD;
      using two oral agents with Tivozanib substituted for bevacizumab. Phase II will be designed&#xD;
      as a selection-based randomized trial. Patients with VeriStrat® Good signature will be&#xD;
      assigned to EGFR inhibitor therapy with a randomization to Erlotinib plus/minus Tivozanib.&#xD;
      Patients with VeriStrat® Poor signature will be assigned to standard of care.&#xD;
      Standard-of-care chemotherapy as first treatment at the discretion of patient and physician&#xD;
      will be evaluated for response to treatment, survival and repeat VeriStrat® signature.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Stopped before approval due to ineffective drug&#xD;
  </why_stopped>
  <start_date>November 2013</start_date>
  <completion_date type="Anticipated">March 2016</completion_date>
  <primary_completion_date type="Anticipated">March 2016</primary_completion_date>
  <phase>Phase 1/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>Safety of combination tivozanib and erlotinib</measure>
    <time_frame>36 months</time_frame>
    <description>Phase I- To define the safety (maximum tolerated dose) of Tivozanib when administered in combination with Erlotinib in patients with NSCL cancer.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>36 months</time_frame>
    <description>Phase II - Overall survival for selection strategy of Erlotinib +/- Tivozanib</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival for entire population</measure>
    <time_frame>36 months</time_frame>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Non-small Cell Lung Cancer</condition>
  <condition>Stage IV Disease</condition>
  <condition>EGFR Unknown or Wild-type</condition>
  <arm_group>
    <arm_group_label>Phase I</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Will receive Tivozanib and Erlotinib treatment.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase II Group 1 (Standard of Care)</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Group 1: VeriStrat® predicts the chance of no benefit from erlotinib&#xD;
• The patient will get standard-of- care</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase II Group 2 (arm 1)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Group 2: VeriStrat® predicts the chance of benefit from Erlotinib&#xD;
• Arm 1: Patient will get the study drugs Erlotinib and Tivozanib</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase II Group 2 (arm 2)</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Group 2: VeriStrat® predicts the chance of benefit from Erlotinib&#xD;
• Arm 2: Patient will get the study drug erlotinib and placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tivozanib</intervention_name>
    <description>The phase I study will test two dose levels of tivozanib (dose level 1: 1.0 mg and dose level 2: 1.5 mg) given daily for 3 consecutive weeks followed by one week break. Based on the phase I results, the dose of tivozanib will be chosen for the phase II study.</description>
    <arm_group_label>Phase I</arm_group_label>
    <arm_group_label>Phase II Group 2 (arm 1)</arm_group_label>
    <other_name>AV-951</other_name>
    <other_name>KRN951</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Erlotinib</intervention_name>
    <description>150 mg/day for 28 day cycle. No rest period.</description>
    <arm_group_label>Phase I</arm_group_label>
    <arm_group_label>Phase II Group 2 (arm 1)</arm_group_label>
    <arm_group_label>Phase II Group 2 (arm 2)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Standard of Care treatment</intervention_name>
    <description>This treatment will be determined by the study doctor and is considered standard of care.</description>
    <arm_group_label>Phase II Group 1 (Standard of Care)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histological or cytological diagnosis of non-squamous, non-small cell lung cancer.&#xD;
&#xD;
          -  Stage IV disease.&#xD;
&#xD;
          -  Age &gt; 18&#xD;
&#xD;
          -  If female and of childbearing potential, documentation of negative pregnancy test&#xD;
             within 7 days prior to first dose.&#xD;
&#xD;
          -  Sexually active women of childbearing potential must agree to use adequate&#xD;
             contraceptive measures, while on study and for 30 days after the last dose of study&#xD;
             drug. All fertile female subjects (and their partners) must agree to use a highly&#xD;
             effective method of contraception. Effective birth control includes (a) intrauterine&#xD;
             device (IUD) plus one barrier method; or (b) 2 barrier methods. Effective barrier&#xD;
             methods are male or female condoms, diaphragms, and spermicides (creams or gels that&#xD;
             contain a chemical to kill sperm). (Note: Oral, implantable, or injectable&#xD;
             contraceptives may be affected by cytochrome P450 interactions, and are not considered&#xD;
             effective for this study).&#xD;
&#xD;
          -  Able to provide informed consent and have signed an approved consent form that&#xD;
             conforms to federal and institutional guidelines.&#xD;
&#xD;
        Additional Phase II Inclusion Criteria:&#xD;
&#xD;
        -No prior treatment for metastatic disease (Phase II ONLY). Patients who received adjuvant&#xD;
        systemic chemotherapy are eligible if greater than 6 months has elapsed.&#xD;
&#xD;
        Prior erlotinib treatment is allowed in phase I.&#xD;
&#xD;
          -  Performance status of 0-1.&#xD;
&#xD;
          -  One disease site meeting RECIST (version 1.1) criteria for measurable or&#xD;
             non-measurable disease. Disease sites measured from the CT portion of a combined&#xD;
             PET/CT may be used to document measurable disease (Liver or PET findings may be used&#xD;
             only for non-measurable disease).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Significant cardiovascular disease, including:&#xD;
&#xD;
               -  Active, clinically symptomatic left ventricular failure.&#xD;
&#xD;
               -  Uncontrolled hypertension: Systolic blood pressure of &gt;140 mmHg or diastolic&#xD;
                  blood pressure of &gt;90 mmHg on 2 or more antihypertensive medications, documented&#xD;
                  on 2 consecutive measurements taken at least 24 hours apart.&#xD;
&#xD;
               -  Myocardial infarction, severe angina, or unstable angina within 6 months prior to&#xD;
                  administration of first dose of study drug.&#xD;
&#xD;
               -  History of serious ventricular arrhythmia (i.e., ventricular tachycardia or&#xD;
                  ventricular fibrillation)&#xD;
&#xD;
               -  Cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial&#xD;
                  fibrillation that is well controlled with anti-arrhythmic medication)&#xD;
&#xD;
               -  Coronary or peripheral artery bypass graft within 6 months of screening.&#xD;
&#xD;
          -  Uncontrolled CNS metastases are not allowed; subjects with previously treated brain&#xD;
             metastases will be allowed if the brain metastases have been treated, toxicity of&#xD;
             radiation has resolved and steroids are no longer required. Leptomeningeal metastases&#xD;
             are not allowed.&#xD;
&#xD;
          -  Any of the following hematologic abnormalities:&#xD;
&#xD;
               -  Hemoglobin &lt; 9.0 g/dL&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) &lt; 1500 per mm3&#xD;
&#xD;
               -  Platelet count &lt; 100,000 per mm3&#xD;
&#xD;
               -  INR &gt;1.5 or PTT &gt;1.5 × ULN&#xD;
&#xD;
          -  Any of the following serum chemistry abnormalities:&#xD;
&#xD;
               -  Total bilirubin &gt; 1.5 × ULN (or &gt; 2.5 × ULN for subjects with Gilbert's syndrome)&#xD;
&#xD;
               -  AST or ALT &gt; 2.5 × ULN (or &gt; 5 × ULN for subjects with liver metastasis)&#xD;
&#xD;
               -  Creatinine &gt; 2.0 × ULN&#xD;
&#xD;
               -  Proteinuria &gt; 3+ by urinalysis or urine dipstick&#xD;
&#xD;
          -  Non-healing wound, bone fracture, or skin ulcer.&#xD;
&#xD;
          -  Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other&#xD;
             gastrointestinal condition with increased risk of perforation; history of abdominal&#xD;
             fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior&#xD;
             to administration of first dose of study drug.&#xD;
&#xD;
          -  Serious/active infection or infection requiring parenteral antibiotics.&#xD;
&#xD;
          -  Inadequate recovery from any prior surgical procedure or major surgical procedure&#xD;
             within 4 weeks prior to administration of first dose of study drug.&#xD;
&#xD;
          -  Significant thromboembolic or vascular disorders within 6 months prior to&#xD;
             administration of first dose of study drug, including but not limited to:&#xD;
&#xD;
               -  Cerebrovascular accident (CVA) or transient ischemic attack (TIA)&#xD;
&#xD;
               -  Peripheral arterial ischemia &gt; Grade 2 (per CTCAE Version 4.0)&#xD;
&#xD;
          -  Significant bleeding disorders within 6 months prior to administration of first dose&#xD;
             of study drug, including but not limited to:&#xD;
&#xD;
               -  Hematemesis, hematochezia, melena or other gastrointestinal bleeding &gt; Grade 2&#xD;
                  (per CTCAE Version 4.0)&#xD;
&#xD;
               -  Hemoptysis or other pulmonary bleeding (&gt; 1/2 tsp/event over last 3 months not&#xD;
                  associated with bronchoscopy)&#xD;
&#xD;
               -  Hematuria or other genitourinary bleeding &gt; Grade 2 (per CTCAE Version 4.0)&#xD;
&#xD;
          -  Currently active second primary malignancy, including hematologic malignancies&#xD;
             (leukemia, lymphoma, multiple myeloma, etc.), other than non-melanoma skin cancers,&#xD;
             non-metastatic prostate cancer, in situ cervical cancer, and ductal or lobular&#xD;
             carcinoma in situ of the breast. Subjects are not considered to have a currently&#xD;
             active malignancy if they have completed anti-cancer therapy and have been disease&#xD;
             free for &gt;2 years.&#xD;
&#xD;
          -  Pregnant or lactating females.&#xD;
&#xD;
          -  History of genetic or acquired immune suppression disease such as HIV; subjects on&#xD;
             immune suppressive therapy for organ transplant.&#xD;
&#xD;
          -  Life-threatening illness or organ system dysfunction compromising safety evaluation.&#xD;
&#xD;
          -  Requirement for hemodialysis or peritoneal dialysis.&#xD;
&#xD;
          -  Inability to swallow pills, malabsorption syndrome or gastrointestinal disease that&#xD;
             severely affects the absorption of tivozanib, major resection of the stomach or small&#xD;
             bowel, or gastric bypass procedure.&#xD;
&#xD;
          -  Psychiatric disorder or altered mental status precluding informed consent or protocol&#xD;
             related testing.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <removed_countries>
    <country>United States</country>
  </removed_countries>
  <verification_date>July 2013</verification_date>
  <study_first_submitted>November 12, 2012</study_first_submitted>
  <study_first_submitted_qc>November 12, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 16, 2012</study_first_posted>
  <last_update_submitted>July 23, 2013</last_update_submitted>
  <last_update_submitted_qc>July 23, 2013</last_update_submitted_qc>
  <last_update_posted type="Estimate">July 25, 2013</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>Lung Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Erlotinib Hydrochloride</mesh_term>
    <mesh_term>Tivozanib</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/NCT01728181
org study id: HCI59004
nct id: NCT01728181
lead sponsor: 
has dmc: Yes
The current trial "A Phase I/II study of Erlotinib +/- Tivozanib as initial treatment for
      Metastatic Non-small Cell Lung Cancer assigned by VeriStrat® Serum Proteomic Evaluation" will
      begin by evaluating toxicity for the combination of Tivozanib and Erlotinib to determine a
      phase II dose. The phase II portion of the study will seek to duplicate the finding of the
      BEER trial in a selected population of patients with NSCLC with a VeriStrat® Good signature
      using two oral agents with Tivozanib substituted for bevacizumab. Phase II will be designed
      as a selection-based randomized trial. Patients with VeriStrat® Good signature will be
      assigned to EGFR inhibitor therapy with a randomization to Erlotinib plus/minus Tivozanib.
      Patients with VeriStrat® Poor signature will be assigned to standard of care.
      Standard-of-care chemotherapy as first treatment at the discretion of patient and physician
      will be evaluated for response to treatment, survival and repeat VeriStrat® signature.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Safety of combination tivozanib and erlotinib
time frame: 36 months
description: Phase I- To define the safety (maximum tolerated dose) of Tivozanib when administered in combination with Erlotinib in patients with NSCL cancer.
measure: Overall Survival
time frame: 36 months
description: Phase II - Overall survival for selection strategy of Erlotinib +/- Tivozanib
measure: Overall Survival for entire population
time frame: 36 months
arm group label: Phase I
arm group type: Experimental
description: Will receive Tivozanib and Erlotinib treatment.
arm group label: Phase II Group 1 (Standard of Care)
arm group type: Other
description: Group 1: VeriStrat® predicts the chance of no benefit from erlotinib
• The patient will get standard-of- care
arm group label: Phase II Group 2 (arm 1)
arm group type: Active Comparator
description: Group 2: VeriStrat® predicts the chance of benefit from Erlotinib
• Arm 1: Patient will get the study drugs Erlotinib and Tivozanib
arm group label: Phase II Group 2 (arm 2)
arm group type: Placebo Comparator
description: Group 2: VeriStrat® predicts the chance of benefit from Erlotinib
• Arm 2: Patient will get the study drug erlotinib and placebo
intervention type: Drug
intervention name: Tivozanib
description: The phase I study will test two dose levels of tivozanib (dose level 1: 1.0 mg and dose level 2: 1.5 mg) given daily for 3 consecutive weeks followed by one week break. Based on the phase I results, the dose of tivozanib will be chosen for the phase II study.
arm group label: Phase I
arm group label: Phase II Group 2 (arm 1)
other name: AV-951
other name: KRN951
intervention type: Drug
intervention name: Erlotinib
description: 150 mg/day for 28 day cycle. No rest period.
arm group label: Phase I
arm group label: Phase II Group 2 (arm 1)
arm group label: Phase II Group 2 (arm 2)
intervention type: Other
intervention name: Standard of Care treatment
description: This treatment will be determined by the study doctor and is considered standard of care.
arm group label: Phase II Group 1 (Standard of Care)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
country: United States
responsible party type: Sponsor
mesh term: Lung Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Erlotinib Hydrochloride
mesh term: Tivozanib