<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/NCT03839498</url>
  </required_header>
  <id_info>
    <org_study_id>AAAR5314</org_study_id>
    <nct_id>NCT03839498</nct_id>
  </id_info>
  <brief_title>Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Pheochromocytoma/Paraganglioma</brief_title>
  <official_title>Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Metastatic, Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Columbia University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Pfizer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Columbia University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Primary Objective:&#xD;
&#xD;
      To determine the response rate (RR) of metastatic or locally advanced&#xD;
      pheochromocytoma/paraganglioma to axitinib administered daily.&#xD;
&#xD;
      Secondary Objectives:&#xD;
&#xD;
        -  Determine the progression-free survival.&#xD;
&#xD;
        -  In an exploratory manner examine the extent of activation of the VEGFR pathway in&#xD;
           pheochromocytoma/paraganglioma using a semi-quantitative immunohistochemistry assay and&#xD;
           examine the relationship with response to therapy.&#xD;
&#xD;
        -  Perform pharmacogenomics analyses of drug metabolism and transport proteins through&#xD;
           germline DNA examination.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The long-term survival for malignant pheochromocytoma/paraganglioma (PHEO/PGL) may be limited&#xD;
      because of its hormonal effects as well as its aggressive behavior and dissemination,&#xD;
      particularly in some hereditary PHEO/PGL. Although several therapeutic modalities have been&#xD;
      used to palliate malignant PHEO/PGL, a continued search for new agents to address the&#xD;
      malignancy is needed to improve outcomes. One approach is to utilize drugs that target&#xD;
      signaling pathways leading to decreased proliferation and survival of cancer cells. Some data&#xD;
      in the literature suggests that in malignant PHEO/PGL, VEGF seems to play a role in the&#xD;
      biology of the cancer and thus, its inhibition could reduce tumor growth. Sunitinib and&#xD;
      imatinib has been used in a limited number of malignant pheochromocytomas with varying&#xD;
      responses. Axitinib was designed to inhibit VEGFR that participates in tumor angiogenesis. In&#xD;
      order to determine the activity of axitinib in tumor and hormonal responses in malignant&#xD;
      PHEO/PGL, it will be used as a single agent in this study. The combination of&#xD;
      cyclophosphamide; vincristine and dacarbazine have been shown to produce partial responses in&#xD;
      malignant PHEO/PGL. The majority of the patients may have already received this combination&#xD;
      or will receive this combination chemotherapy in the future. The goal is to develop multiple&#xD;
      lines of effective treatments for this disease.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 22, 2019</start_date>
  <completion_date type="Anticipated">January 2024</completion_date>
  <primary_completion_date type="Anticipated">December 2023</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>Response Rate (RR)</measure>
    <time_frame>Up to 16 weeks</time_frame>
    <description>This study is designed to determine the percentage of patients whose cancer shrinks or disappears after treatment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival</measure>
    <time_frame>Duration of time from start of treatment to time of progression or death, whichever occurs first; an average of up to 12 months</time_frame>
    <description>The length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">25</enrollment>
  <condition>Pheochromocytoma</condition>
  <condition>Paraganglioma</condition>
  <arm_group>
    <arm_group_label>Axitinib (AG-013736)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects with Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma will receive 16 weeks of therapy (Axitinib), and be seen in clinic every 4 weeks to monitor therapy.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Axitinib</intervention_name>
    <description>Axitinib (AG-013736) is an oral, potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3.&#xD;
Starting dose level 1: 5 mg every morning; 5 mg every evening. Dose level 2: 7 mg every morning; 7 mg every evening. Dose level 3: 10 mg every morning; 10 mg every evening. Dose level -1: 3 mg every morning; 3 every evening. Dose level -2: 2 mg every morning; 2 mg every evening.&#xD;
Axitinib is supplied as 1 and 5-mg tablets and is administered orally twice a day with or without food, each morning and evening (i.e., every 12 hours). Axitinib will be given as self-administered.</description>
    <arm_group_label>Axitinib (AG-013736)</arm_group_label>
    <other_name>AG-013736</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
        Adults with a confirmed pathologic diagnosis of pheochromocytoma/paraganglioma by a&#xD;
        CUMC/NYPH laboratory when such tissue is available to confirm.&#xD;
&#xD;
        In the event that outside tissue is not available:&#xD;
&#xD;
        An outside pathology report confirms the diagnosis of Pheo/PGL, AND the patient has nuclear&#xD;
        medicine imaging studies that would only be positive in an adult patient with a diagnosis&#xD;
        of Pheo/PGL (F-DOPA, Dotatate, F-Dopamine or MIBG)&#xD;
&#xD;
          -  Imaging confirmation of metastatic disease&#xD;
&#xD;
          -  Measurable disease at the time of enrollment as per RECIST 1.1.&#xD;
&#xD;
          -  A life expectancy of at least 3 months and ECOG performance status ≤ 2&#xD;
&#xD;
          -  Age ≥ 18 years&#xD;
&#xD;
          -  Information available or pending regarding possible genetic alterations that can&#xD;
             explain the patient's pheochromocytoma/paraganglioma (mutations in SDHB, SDHV or VHL&#xD;
             genes)&#xD;
&#xD;
          -  Last dose of chemotherapy or experimental therapy more than 4 weeks (6 weeks in the&#xD;
             case of nitrosourea) prior to enrollment date; 2 weeks if the last therapy was&#xD;
             received as part of a &quot;phase 0&quot; or &quot;exploratory IND&quot; trial. Last surgery more than 4&#xD;
             weeks prior to enrollment, to allow for wound healing. Core biopsies or FNA will not&#xD;
             require any waiting period&#xD;
&#xD;
          -  Last radiotherapy treatment ≥ 4 weeks prior to starting treatment with this protocol&#xD;
             and there must be sites of measurable disease that did not receive radiation&#xD;
&#xD;
          -  Prior therapeutic MIBG is allowed&#xD;
&#xD;
          -  Organ and marrow function as defined below:&#xD;
&#xD;
          -  Total bilirubin ≤ 1.5 x ULN (upper limit of normal), unless the patient meets the&#xD;
             criteria for Gilbert's Syndrome. The upper limit value for bilirubin for subjects with&#xD;
             Gilbert's Syndrome is less than 3 mg/dl.&#xD;
&#xD;
             o Note: A diagnosis of Gilbert's disease will be made in the presence of (1)&#xD;
             unconjugated hyperbilirubinemia noted on several occasions; (2) normal results from&#xD;
             CBC count, reticulocyte count, and blood smear; (3) normal liver function test&#xD;
             results; and (4) an absence of other disease processes that can explain the&#xD;
             unconjugated hyperbilirubinemia.&#xD;
&#xD;
          -  AST ≤ 2.5 x ULN, ALT ≤ 2.5 x ULN&#xD;
&#xD;
          -  Amylase and lipase equal to, or less than, the institutional ULN.&#xD;
&#xD;
          -  Creatinine clearance ≥ 40 ml/min (estimated or measured creatinine clearance) or serum&#xD;
             creatinine ≤ 1.6 mg/dl&#xD;
&#xD;
             o Random urine protein &lt; 20 mg/dL. If ≥ 20 mg/dL then a 24-hour urine protein&#xD;
             collection will be performed to accurately demonstrate that the 24-hour total is &lt;1000&#xD;
             mg, the level acceptable for enrollment on study&#xD;
&#xD;
          -  Absolute neutrophil count ≥ 500/mm3&#xD;
&#xD;
          -  Platelet count ≥ 50,000/ mm3&#xD;
&#xD;
          -  Ability to understand and sign an informed consent document.&#xD;
&#xD;
          -  Ability and willingness to follow the guidelines of the clinical protocol.&#xD;
&#xD;
          -  Because the effects of chemotherapy on the developing human fetus are potentially&#xD;
             harmful, women of childbearing potential and men who participate in the study must&#xD;
             agree to use adequate contraception (hormonal or barrier methods) before, during the&#xD;
             study and for a period of 3 months after the last dose of chemotherapy.&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          -  Patients with pheochromocytoma/paraganglioma tumors potentially curable by surgical&#xD;
             excision alone as determined by the Principal Investigator in discussions with the&#xD;
             surgical consultants&#xD;
&#xD;
          -  Patients who have large abdominal masses impinging on bowel or pulmonary masses with&#xD;
             encroached vessels and a potential to bleed will be considered on case by case basis&#xD;
             after careful consultation with multiple disciplines such as radiologists and surgeons&#xD;
             with main intent being patient safety.&#xD;
&#xD;
          -  Unstable hypertension defined as a systolic blood pressure &gt;150 mm Hg or diastolic&#xD;
             pressure &gt; 90 mmHg despite optimal medical management.&#xD;
&#xD;
          -  Untreated brain metastases (or local treatment of brain metastases within the last 3&#xD;
             months) due to the poor prognosis of these patients and difficulty ascertaining the&#xD;
             cause of neurologic adverse events.&#xD;
&#xD;
          -  Pregnancy, due to the possible adverse effects on the developing fetus.&#xD;
&#xD;
          -  Lactating women who are breast-feeding due to the possibility of transmitting axitinib&#xD;
             to the child.&#xD;
&#xD;
          -  The presence of a second malignancy, other than squamous cell carcinoma of the skin or&#xD;
             in situ cervical cancer because it will complicate the primary objective of the study.&#xD;
             Cancer survivors who have been free of disease for at least one year can be enrolled&#xD;
             in this study.&#xD;
&#xD;
          -  Patients with evidence of a bleeding diathesis&#xD;
&#xD;
          -  Patients must not have received prior therapy with a TKI. Prior TKI usage in&#xD;
             pheochromocytoma affects the same pathway as axitinib.&#xD;
&#xD;
          -  Gastrointestinal abnormalities including:&#xD;
&#xD;
               -  Inability to take oral medications&#xD;
&#xD;
               -  Requirement for intravenous alimentation&#xD;
&#xD;
               -  Prior surgical procedure affecting absorption including total gastric resection&#xD;
&#xD;
               -  Treatment for active peptic ulcer disease in the past 6 months&#xD;
&#xD;
               -  Active gastrointestinal bleeding, unrelated to cancer, as evidenced by&#xD;
                  hematemesis, hematochezia or melena in the past 3 months without evidence of&#xD;
                  resolution documented by endoscopy or colonoscopy.&#xD;
&#xD;
               -  Malabsorption syndrome&#xD;
&#xD;
          -  Current use or anticipated need for treatment with drugs that are known potent CYP3A4&#xD;
             inhibitors (i.e., grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole,&#xD;
             erythromycin, telithromycin, clarithromycin, indinavir, saquinavir, ritonavir,&#xD;
             nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, and delavirdine).&#xD;
&#xD;
          -  Current use or anticipated need for treatment with drugs that are known CYP3A4 or&#xD;
             CYP1A2 inducers (i.e., carbamazepine, dexamethasone, felbamate, omeprazole,&#xD;
             phenobarbital, phenytoin, amobarbital, nevirapine, primidone, rifabutin, rifampin, and&#xD;
             St. John's wort).&#xD;
&#xD;
          -  Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose&#xD;
             anticoagulants for maintenance of patency of central venous access devices or&#xD;
             prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular&#xD;
             weight heparin is allowed.&#xD;
&#xD;
          -  Active seizure disorder or evidence of brain metastases, spinal cord compression, or&#xD;
             carcinomatous meningitis.&#xD;
&#xD;
          -  Any of the following within 12 months prior to study drug administration: myocardial&#xD;
             infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic&#xD;
             congestive heart failure, cerebrovascular accident or transient ischemic attack and&#xD;
             within 6 months before study drug administration for deep vein thrombosis or pulmonary&#xD;
             embolism.&#xD;
&#xD;
          -  Other severe acute or chronic medical or psychiatric condition, or laboratory&#xD;
             abnormality that may increase the risk associated with study participation or study&#xD;
             drug administration, or may interfere with the interpretation of study results, and in&#xD;
             the judgment of the investigator would make the patient inappropriate for entry into&#xD;
             this 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>Antonio Fojo, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Columbia University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Research Nurse Navigator</last_name>
    <phone>(212) 342-5162</phone>
    <email>cancerclinicaltrials@cumc.columbia.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Alexandria Rodriguez</last_name>
    <email>ar3954@cumc.columbia.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Columbia University Irving Medical Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10031</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Antonio Fojo, MD, PhD</last_name>
      <phone>212-305-5098</phone>
    </contact>
    <investigator>
      <last_name>Antonio Fojo, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>January 31, 2019</study_first_submitted>
  <study_first_submitted_qc>February 11, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 15, 2019</study_first_posted>
  <last_update_submitted>October 5, 2022</last_update_submitted>
  <last_update_submitted_qc>October 5, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 7, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Columbia University</investigator_affiliation>
    <investigator_full_name>Antonio Fojo</investigator_full_name>
    <investigator_title>Professor of Medicine at the Columbia University Medical Center, Dept of Med Hematology &amp; Onc</investigator_title>
  </responsible_party>
  <keyword>Axitinib</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pheochromocytoma</mesh_term>
    <mesh_term>Paraganglioma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Axitinib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03839498
org study id: AAAR5314
nct id: NCT03839498
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Primary Objective:

      To determine the response rate (RR) of metastatic or locally advanced
      pheochromocytoma/paraganglioma to axitinib administered daily.

      Secondary Objectives:

        -  Determine the progression-free survival.

        -  In an exploratory manner examine the extent of activation of the VEGFR pathway in
           pheochromocytoma/paraganglioma using a semi-quantitative immunohistochemistry assay and
           examine the relationship with response to therapy.

        -  Perform pharmacogenomics analyses of drug metabolism and transport proteins through
           germline DNA examination.
The long-term survival for malignant pheochromocytoma/paraganglioma (PHEO/PGL) may be limited
      because of its hormonal effects as well as its aggressive behavior and dissemination,
      particularly in some hereditary PHEO/PGL. Although several therapeutic modalities have been
      used to palliate malignant PHEO/PGL, a continued search for new agents to address the
      malignancy is needed to improve outcomes. One approach is to utilize drugs that target
      signaling pathways leading to decreased proliferation and survival of cancer cells. Some data
      in the literature suggests that in malignant PHEO/PGL, VEGF seems to play a role in the
      biology of the cancer and thus, its inhibition could reduce tumor growth. Sunitinib and
      imatinib has been used in a limited number of malignant pheochromocytomas with varying
      responses. Axitinib was designed to inhibit VEGFR that participates in tumor angiogenesis. In
      order to determine the activity of axitinib in tumor and hormonal responses in malignant
      PHEO/PGL, it will be used as a single agent in this study. The combination of
      cyclophosphamide; vincristine and dacarbazine have been shown to produce partial responses in
      malignant PHEO/PGL. The majority of the patients may have already received this combination
      or will receive this combination chemotherapy in the future. The goal is to develop multiple
      lines of effective treatments for this disease.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Response Rate (RR)
time frame: Up to 16 weeks
description: This study is designed to determine the percentage of patients whose cancer shrinks or disappears after treatment.
measure: Progression-free survival
time frame: Duration of time from start of treatment to time of progression or death, whichever occurs first; an average of up to 12 months
description: The length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse.
arm group label: Axitinib (AG-013736)
arm group type: Experimental
description: Subjects with Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma will receive 16 weeks of therapy (Axitinib), and be seen in clinic every 4 weeks to monitor therapy.
intervention type: Drug
intervention name: Axitinib
description: Axitinib (AG-013736) is an oral, potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3.
Starting dose level 1: 5 mg every morning; 5 mg every evening. Dose level 2: 7 mg every morning; 7 mg every evening. Dose level 3: 10 mg every morning; 10 mg every evening. Dose level -1: 3 mg every morning; 3 every evening. Dose level -2: 2 mg every morning; 2 mg every evening.
Axitinib is supplied as 1 and 5-mg tablets and is administered orally twice a day with or without food, each morning and evening (i.e., every 12 hours). Axitinib will be given as self-administered.
arm group label: Axitinib (AG-013736)
other name: AG-013736
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Antonio Fojo, MD
role: Principal Investigator
affiliation: Columbia University
last name: Research Nurse Navigator
phone: (212) 342-5162
email: cancerclinicaltrials@cumc.columbia.edu
last name: Alexandria Rodriguez
email: ar3954@cumc.columbia.edu
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Columbia University
investigator full name: Antonio Fojo
investigator title: Professor of Medicine at the Columbia University Medical Center, Dept of Med Hematology & Onc
mesh term: Pheochromocytoma
mesh term: Paraganglioma
mesh term: Axitinib
sharing ipd: No