<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/NCT03014297</url>
  </required_header>
  <id_info>
    <org_study_id>MCC-16-GI-99-PMC</org_study_id>
    <nct_id>NCT03014297</nct_id>
  </id_info>
  <brief_title>Fosbretabulin With Everolimus in Neuroendocrine Tumors With Progression</brief_title>
  <official_title>A Phase 1 Study of Fosbretabulin in Combination With Everolimus in Neuroendocrine Tumors (Grades 1-3) That Have Progressed After at Least One Prior Regimen for Metastatic Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lowell Anthony, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Kentucky</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>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a single center, open label, phase I study involving grade I-III&#xD;
      gastroenteropancreatic neuroendocrine tumors, consisting of a dose escalation Part A followed&#xD;
      by an expansion cohort Part B. On Part A Patients will be treated with daily oral everolimus.&#xD;
      Fosbretabulin will be administered IV either q3 weekly or q weekly based on PO CRM cohort.&#xD;
      Part B: Once the investigators have established an MTD in Part A, the investigators will be&#xD;
      treating 15 more patients at that dose combination. The primary and secondary objectives of&#xD;
      the expansion cohort will be similar to Part A of the study, i.e., to establish a safety&#xD;
      profile of the experimental drug combination and to collect and assess efficacy data.&#xD;
      Patients will be treated with concurrent everolimus and fosbretabulin for 12 weeks.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A variety of treatment options are available for NETs with carcinoid syndrome including&#xD;
      surgical and medical therapies. Most subjects require somatostatin analogs to control the&#xD;
      symptoms of carcinoid syndrome. Subjects who no longer respond to somatostatin and other&#xD;
      liver-directed therapies, who experience progression of disease and increasing symptoms have&#xD;
      limited options, including participation in a clinical trial. Recently everolimus and&#xD;
      sunitinib have been approved for the treatment of subjects with progressive locally advanced&#xD;
      or metastatic neuroendocrine tumors. Based on the preclinical data in models of NETs and the&#xD;
      clinical activity seen in NETS and other tumor types that have existing tumor vascculature,&#xD;
      this study will examine the effectiveness of fosbretabulin given in combination with&#xD;
      everolimus in subjects with GI-NETs and PNETs.The vasoconstrictive effect of fosbretabulin is&#xD;
      potent, though short-lived (4-8 hours), with no cumulative adverse effect. Everolimus&#xD;
      inhibits angiogenesis, slows tumor growth and has a prolonged half-life (30 hours). Combining&#xD;
      these two agents with distinctly different mechanisms of action may improve tumor control&#xD;
      without additional toxicities, and has the potential of reducing drug resistance.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Part I completed. Part 2 will not be done due to sponsor decision.&#xD;
  </why_stopped>
  <start_date type="Actual">March 6, 2017</start_date>
  <completion_date type="Actual">November 16, 2018</completion_date>
  <primary_completion_date type="Actual">June 5, 2018</primary_completion_date>
  <phase>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>Maximum Tolerated Dose (MTD)</measure>
    <time_frame>12 weeks</time_frame>
    <description>To establish the maximum tolerated dose of the combination of everolimus plus fosbretabulin in neuroendocrine tumors (Grades 1-3) who have progressed after at least one prior regimen for metastatic disease.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of Toxicities</measure>
    <time_frame>12 weeks</time_frame>
    <description>Incidence of patients reporting at least one adverse event per NCI CTCAE v4.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Anti-tumor activity</measure>
    <time_frame>12 weeks</time_frame>
    <description>Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">17</enrollment>
  <condition>Neuroendocrine Tumors</condition>
  <condition>Everolimus</condition>
  <arm_group>
    <arm_group_label>everolimus + fosbretabulin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>everolimus + fosbretabulin</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>everolimus</intervention_name>
    <description>everolimus</description>
    <arm_group_label>everolimus + fosbretabulin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>fosbretabulin</intervention_name>
    <description>fosbretabulin</description>
    <arm_group_label>everolimus + fosbretabulin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have histologically confirmed neuroendocrine tumor (grades 1-3) that is&#xD;
             metastatic or unresectable, and for which standard curative or palliative measures do&#xD;
             not exist or are no longer effective.&#xD;
&#xD;
          -  Prior treatment with fosbretabulin is allowed, if not given in combination with&#xD;
             everolimus.&#xD;
&#xD;
          -  Prior treatment with everolimus is allowed, if the patient was able to tolerate 10 mg&#xD;
             daily everolimus with acceptable side effects, and if everolimus was not given in&#xD;
             combination with fosbretabulin. A 1 week washout period will be required if patient&#xD;
             was previously on everolimus.&#xD;
&#xD;
          -  Age ≥18 years.&#xD;
&#xD;
          -  ECOG performance status ≤2.&#xD;
&#xD;
          -  Life expectancy greater than 6 months.&#xD;
&#xD;
          -  Progressive disease based on radiological imaging within 12 months. RECIST 1.1 would&#xD;
             be used to assess measurable disease burden.&#xD;
&#xD;
          -  Patients must have normal organ and marrow function as defined below:&#xD;
&#xD;
               -  absolute neutrophil count ≥1,000/mcL&#xD;
&#xD;
               -  platelets ≥75,000/mcL&#xD;
&#xD;
               -  total bilirubin ≤2.5 × institutional upper limit of normal&#xD;
&#xD;
               -  AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal&#xD;
&#xD;
               -  creatinine within normal institutional limits OR&#xD;
&#xD;
               -  creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above&#xD;
                  institutional normal&#xD;
&#xD;
          -  Women of childbearing potential and men must agree to use adequate contraception&#xD;
             (hormonal or barrier method of birth control; abstinence) prior to study entry and for&#xD;
             the duration of study participation. Should a woman become pregnant or suspect she is&#xD;
             pregnant while she or her partner is participating in this study, she should inform&#xD;
             her treating physician immediately.&#xD;
&#xD;
          -  Men treated or enrolled on this protocol must also agree to use adequate contraception&#xD;
             prior to the study, for the duration of study participation, and 4 months after&#xD;
             completion of fosbretabulin and everolimus administration.&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who have had prior everolimus but were not able to tolerate a 10 mg daily&#xD;
             dose.&#xD;
&#xD;
          -  Prior chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or&#xD;
             mitomycin C) prior to entering the study or those who have not recovered from adverse&#xD;
             events due to agents administered more than 4 weeks earlier.&#xD;
&#xD;
          -  Child Pugh Class B or greater hepatic dysfunction.&#xD;
&#xD;
          -  Patients who are receiving any other investigational agents.&#xD;
&#xD;
          -  Patients with known brain metastases because of their poor prognosis and likelihood to&#xD;
             develop progressive neurologic dysfunction that would confound the evaluation of&#xD;
             neurologic and other adverse events.&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to fosbretabulin&#xD;
&#xD;
          -  Uncontrolled hypertension (HTN); sustained blood pressure (BP) greater than 150/100&#xD;
             mmHg&#xD;
&#xD;
          -  Must not have had any unstable angina or myocardial infarction within 4 months prior&#xD;
             to enrollment to treatment, NYHA Class III or IV heart failure, uncontrolled angina,&#xD;
             history of severe coronary artery disease, severe uncontrolled ventricular&#xD;
             arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia&#xD;
             or Grade 3 conduction system abnormalities unless subject has a pacemaker.&#xD;
&#xD;
          -  Must not have any evidence of other clinically active cancer and have no history of&#xD;
             prior malignancy within the past 3 years with the exception of: a) adequately treated&#xD;
             basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in&#xD;
             situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less and with&#xD;
             stable prostatespecific antigen levels; or d) cancer considered cured by surgical&#xD;
             resection or unlikely to impact survival for the duration of the study, such as&#xD;
             localized transitional cell carcinoma of the bladder or benign tumors of the adrenal&#xD;
             glands or pancreas.&#xD;
&#xD;
          -  Patients receiving any medications or substances that are strong inhibitors or&#xD;
             inducers of CYP3A4 are ineligible. Because the lists of these agents are constantly&#xD;
             changing, it is important to regularly consult a frequently-updated list such as&#xD;
             http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as&#xD;
             the Physicians' Desk Reference may also provide this information. As part of the&#xD;
             enrollment/informed consent procedures, the patient will be counseled on the risk of&#xD;
             interactions with other agents, and what to do if new medications need to be&#xD;
             prescribed or if the patient is considering a new over-the-counter medicine or herbal&#xD;
             product.&#xD;
&#xD;
          -  Pregnant women are excluded from this study because everolimus and fosbretabulin have&#xD;
             the potential for teratogenic or abortifacient effects. Because there is an unknown&#xD;
             but potential risk for adverse events to nursing infants secondary to treatment of the&#xD;
             mother with these agents, breastfeeding should be discontinued if the mother is&#xD;
             treated with everolimus and fosbretabulin.&#xD;
&#xD;
          -  HIV-positive patients on combination antiretroviral therapy are ineligible because of&#xD;
             the potential for pharmacokinetic interactions with everolimus and fosbretabulin. In&#xD;
             addition, these patients are at increased risk of lethal infections when treated with&#xD;
             marrowsuppressive therapy. Appropriate studies will be initiated for patients&#xD;
             receiving combination antiretroviral therapy when indicated.&#xD;
&#xD;
          -  History of prior cerebrovascular event, (including transient ischemic attack) within 6&#xD;
             months of start of screening.&#xD;
&#xD;
          -  Current thrombotic or hemorrhagic disorder/event or history of prior event within 6&#xD;
             months of start of Screening&#xD;
&#xD;
          -  Corrected QT interval ([QTc] Fridericia) &gt; 480 ms&#xD;
&#xD;
          -  Significant vascular disease or recent peripheral arterial thrombosis&#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>Lowell Anthony, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Kentucky</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Kentucky Markey Cancer Center</name>
      <address>
        <city>Lexington</city>
        <state>Kentucky</state>
        <zip>40502</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2019</verification_date>
  <study_first_submitted>December 21, 2016</study_first_submitted>
  <study_first_submitted_qc>January 6, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 9, 2017</study_first_posted>
  <last_update_submitted>August 6, 2019</last_update_submitted>
  <last_update_submitted_qc>August 6, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">August 8, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Kentucky</investigator_affiliation>
    <investigator_full_name>Lowell Anthony, MD</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neuroendocrine Tumors</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Everolimus</mesh_term>
    <mesh_term>Fosbretabulin</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/NCT03014297
org study id: MCC-16-GI-99-PMC
nct id: NCT03014297
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This is a single center, open label, phase I study involving grade I-III
      gastroenteropancreatic neuroendocrine tumors, consisting of a dose escalation Part A followed
      by an expansion cohort Part B. On Part A Patients will be treated with daily oral everolimus.
      Fosbretabulin will be administered IV either q3 weekly or q weekly based on PO CRM cohort.
      Part B: Once the investigators have established an MTD in Part A, the investigators will be
      treating 15 more patients at that dose combination. The primary and secondary objectives of
      the expansion cohort will be similar to Part A of the study, i.e., to establish a safety
      profile of the experimental drug combination and to collect and assess efficacy data.
      Patients will be treated with concurrent everolimus and fosbretabulin for 12 weeks.
A variety of treatment options are available for NETs with carcinoid syndrome including
      surgical and medical therapies. Most subjects require somatostatin analogs to control the
      symptoms of carcinoid syndrome. Subjects who no longer respond to somatostatin and other
      liver-directed therapies, who experience progression of disease and increasing symptoms have
      limited options, including participation in a clinical trial. Recently everolimus and
      sunitinib have been approved for the treatment of subjects with progressive locally advanced
      or metastatic neuroendocrine tumors. Based on the preclinical data in models of NETs and the
      clinical activity seen in NETS and other tumor types that have existing tumor vascculature,
      this study will examine the effectiveness of fosbretabulin given in combination with
      everolimus in subjects with GI-NETs and PNETs.The vasoconstrictive effect of fosbretabulin is
      potent, though short-lived (4-8 hours), with no cumulative adverse effect. Everolimus
      inhibits angiogenesis, slows tumor growth and has a prolonged half-life (30 hours). Combining
      these two agents with distinctly different mechanisms of action may improve tumor control
      without additional toxicities, and has the potential of reducing drug resistance.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum Tolerated Dose (MTD)
time frame: 12 weeks
description: To establish the maximum tolerated dose of the combination of everolimus plus fosbretabulin in neuroendocrine tumors (Grades 1-3) who have progressed after at least one prior regimen for metastatic disease.
measure: Incidence of Toxicities
time frame: 12 weeks
description: Incidence of patients reporting at least one adverse event per NCI CTCAE v4.0
measure: Anti-tumor activity
time frame: 12 weeks
description: Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes.
arm group label: everolimus + fosbretabulin
arm group type: Experimental
description: everolimus + fosbretabulin
intervention type: Drug
intervention name: everolimus
description: everolimus
arm group label: everolimus + fosbretabulin
intervention type: Drug
intervention name: fosbretabulin
description: fosbretabulin
arm group label: everolimus + fosbretabulin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Lowell Anthony, MD
role: Principal Investigator
affiliation: University of Kentucky
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Kentucky
investigator full name: Lowell Anthony, MD
investigator title: Principal Investigator
mesh term: Neuroendocrine Tumors
mesh term: Everolimus
mesh term: Fosbretabulin
sharing ipd: No