<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/NCT03290079</url>
  </required_header>
  <id_info>
    <org_study_id>MCC-19207</org_study_id>
    <nct_id>NCT03290079</nct_id>
  </id_info>
  <brief_title>Phase II Study of Pembrolizumab and Lenvatinib in Advanced Well-differentiated Neuroendocrine Tumors</brief_title>
  <official_title>Phase II Study of Pembrolizumab and Lenvatinib in Advanced Well-differentiated Neuroendocrine Tumors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>H. Lee Moffitt Cancer Center and Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>H. Lee Moffitt Cancer Center and Research Institute</source>
  <oversight_info>
    <has_dmc>No</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>
      The purpose of this study is to:&#xD;
&#xD;
        -  Assess overall radiographic response rate (ORR)&#xD;
&#xD;
        -  Assess progression-free survival (PFS)&#xD;
&#xD;
        -  Test the safety and tolerability of Pembrolizumab in combination with lenvatinib&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">December 15, 2017</start_date>
  <completion_date type="Anticipated">January 2024</completion_date>
  <primary_completion_date type="Actual">January 10, 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>
    <intervention_model_description>Simon 2-stage design</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Objective Radiographic Response Rate (ORR)</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Response Evaluation Criteria in Solid Tumors (RECIST) based response rate. Complete Response (CR): Disappearance of all extranodal target lesions. All pathological lymph nodes must have decreased to &lt;10 mm in short axis. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (SLD) of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest). The SLD must also demonstrate an absolute increase of at least 5mm. (Two lesions increasing from 2 mm to 3 mm, for example, does not qualify). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DOR)</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>DOR, defined as the time from first documented evidence of Complete Response (CR) or Partial Response (PR) until disease progression or death due to any cause, whichever occurs first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS)</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>PFS, defined as the time from initial treatment to the first documented disease progression according to RECIST 1.1, or death due to any cause, whichever occurs first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>OS defined as the time from initial treatment until death from any cause.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">28</enrollment>
  <condition>Neuroendocrine Tumors</condition>
  <condition>Neuroendocrine Carcinoma</condition>
  <condition>Neuroendocrine Cancer</condition>
  <arm_group>
    <arm_group_label>Pembrolizumab &amp; Lenvatinib treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pembrolizumab 200 mg will be administered as a 30 minute intravenous (IV) infusion every 3 weeks, in addition to 20 mg Lenvatinib by mouth every day of each 3 week cycle. Estimated average length of treatment per participant: 4 months.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>200 mg Pembrolizumab by IV on Day 1 of each 3 week cycle.</description>
    <arm_group_label>Pembrolizumab &amp; Lenvatinib treatment</arm_group_label>
    <other_name>Keytruda®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lenvatinib</intervention_name>
    <description>20 mg Lenvatinib by mouth every day of each 3 week cycle</description>
    <arm_group_label>Pembrolizumab &amp; Lenvatinib treatment</arm_group_label>
    <other_name>Lenvima®</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis/Condition for entry into the trial: Metastatic well differentiated&#xD;
             neuroendocrine tumors of primary lung, thymic, small bowel and colorectal origin&#xD;
             (including unknown primary)&#xD;
&#xD;
          -  Evidence of radiographic disease progression with scan documenting progression&#xD;
             occurring within 8 months of signing informed consent&#xD;
&#xD;
          -  At least two prior lines of systemic treatment. If the only prior line of treatment&#xD;
             was adjuvant or neoadjuvant, patient must have completed treatment within 12 months.&#xD;
             There is no limit to number of prior therapies.&#xD;
&#xD;
          -  Willing and able to provide written informed consent/assent for the trial.&#xD;
&#xD;
          -  ≥ 18 years of age on day of signing informed consent.&#xD;
&#xD;
          -  Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)&#xD;
             1.1.&#xD;
&#xD;
          -  Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)&#xD;
             Performance Scale.&#xD;
&#xD;
          -  Demonstrate adequate organ function and laboratory values. All screening labs should&#xD;
             be performed within 14 days of treatment initiation.&#xD;
&#xD;
          -  Females of childbearing potential (FOCBP) should have a negative serum pregnancy&#xD;
             within 72 hours prior to receiving the first dose of study medication.&#xD;
&#xD;
          -  FOCBP must agree to use adequate contraception as outlined in study documentation for&#xD;
             the course of the through 120 days after the last dose of study medication.&#xD;
&#xD;
          -  Male participants of childbearing potential must agree to use an adequate method of&#xD;
             contraception as outlined in study documentation, starting with the first dose of&#xD;
             study therapy through 120 days after the last dose of study therapy.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Poorly differentiated neuroendocrine carcinoma&#xD;
&#xD;
          -  Pancreatic neuroendocrine tumor&#xD;
&#xD;
          -  Currently participating and receiving study therapy or has participated in a study of&#xD;
             an investigational agent and received study therapy or used an investigational device&#xD;
             within 4 weeks of the first dose of treatment.&#xD;
&#xD;
          -  A diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other&#xD;
             form of immunosuppressive therapy within 7 days prior to the first dose of trial&#xD;
             treatment.&#xD;
&#xD;
          -  Known history of active TB (Bacillus Tuberculosis)&#xD;
&#xD;
          -  Hypersensitivity to pembrolizumab or any of its excipients.&#xD;
&#xD;
          -  Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study&#xD;
             Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events&#xD;
             due to agents administered more than 4 weeks earlier.&#xD;
&#xD;
          -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy&#xD;
             within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at&#xD;
             baseline) from adverse events due to a previously administered agent. - Note:&#xD;
             Potential participants with ≤ Grade 2 neuropathy are an exception to this criterion&#xD;
             and may qualify for the study. Note: If have received major surgery within 3 weeks,&#xD;
             must have recovered adequately from the toxicity and/or complications from the&#xD;
             intervention prior to starting therapy. Adequate wound healing after major surgery&#xD;
             must be assessed clinically, independent of time elapsed for eligibility.&#xD;
&#xD;
          -  Serious non-healing wound, ulcer or bone fracture&#xD;
&#xD;
          -  Has pre-existing &gt;/= Grade 3 gastrointestinal (GI) or non-GI fistula&#xD;
&#xD;
          -  Has significant cardiovascular impairment within 12 months of the first dose of study&#xD;
             drug&#xD;
&#xD;
          -  Known additional malignancy that is progressing or requires active treatment.&#xD;
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the&#xD;
             skin that has undergone potentially curative therapy or in situ cervical cancer.&#xD;
&#xD;
          -  Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.&#xD;
             Potential participants with previously treated brain metastases may participate&#xD;
             provided they are stable (without evidence of progression by imaging for at least four&#xD;
             weeks prior to the first dose of trial treatment and any neurologic symptoms have&#xD;
             returned to baseline), have no evidence of new or enlarging brain metastases, and are&#xD;
             not using steroids for at least 7 days prior to trial treatment. This exception does&#xD;
             not include carcinomatous meningitis which is excluded regardless of clinical&#xD;
             stability.&#xD;
&#xD;
          -  Has active autoimmune disease that has required systemic treatment in the past 2&#xD;
             years. Replacement therapy is not considered a form of systemic treatment.&#xD;
&#xD;
          -  History of (non-infectious) pneumonitis that required steroids, or current&#xD;
             pneumonitis.&#xD;
&#xD;
          -  An active infection requiring systemic therapy.&#xD;
&#xD;
          -  History or current evidence of any condition, therapy, or laboratory abnormality that&#xD;
             might confound the results of the trial, interfere with the subject's participation&#xD;
             for the full duration of the trial, or is not in the best interest of the subject to&#xD;
             participate, in the opinion of the treating investigator.&#xD;
&#xD;
          -  Known psychiatric or substance abuse disorders that would interfere with cooperation&#xD;
             with the requirements of the trial.&#xD;
&#xD;
          -  Pregnant or breastfeeding, or expecting to conceive or father children within the&#xD;
             projected duration of the trial, starting with the pre-screening or screening visit&#xD;
             through 120 days after the last dose of trial treatment.&#xD;
&#xD;
          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.&#xD;
&#xD;
          -  Has received prior therapy with a tyrosine kinase inhibitor (TKI) (e.g.; sunitinib,&#xD;
             pazopanib, cabozantinib)&#xD;
&#xD;
          -  Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).&#xD;
&#xD;
          -  Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA&#xD;
             [qualitative] is detected).&#xD;
&#xD;
          -  Has received a live vaccine within 30 days of planned start of study therapy. Note:&#xD;
             Seasonal influenza vaccines for injection are generally inactivated flu vaccines and&#xD;
             are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live&#xD;
             attenuated vaccines, and are not allowed.&#xD;
&#xD;
          -  Uncontrolled hypertension defined as systolic blood pressure &gt;150 mmHg or diastolic&#xD;
             pressure &gt;90 mmHg, despite optimal medical management&#xD;
&#xD;
          -  Thrombotic or embolic events such as a cerebrovascular accident including transient&#xD;
             ischemic, attacks, DVT within the past 6 months&#xD;
&#xD;
          -  Bleeding or thrombotic disorders or use of anticoagulants, such as warfarin, or&#xD;
             similar agents requiring therapeutic international normalized ration (INR)&#xD;
             monitoring.(Treatment with low molecular weight heparin (LMWH) is allowed)&#xD;
&#xD;
          -  Marked baseline prolongation of QT/QTc interval (QTc interval ≥ 480 msec) using the&#xD;
             Fridericia method (QTc = QT/RR0.33) for QTc analysis&#xD;
&#xD;
          -  Clinically significant bleeding within 4 weeks&#xD;
&#xD;
          -  Medical need for the continued use of potent inhibitors/inducers of CYP3A4&#xD;
&#xD;
          -  Creatinine clearance &lt;30 mL/min&#xD;
&#xD;
          -  Any condition that impairs patient's ability to swallow whole pills or&#xD;
             gastrointestinal malabsorption that, in the investigator's opinion, might affect&#xD;
             absorption of lenvatinib&#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>Jonathan Strosberg, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>H. Lee Moffitt Cancer Center and Research Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>H. Lee Moffitt Cancer Center and Research Institute</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://moffitt.org/clinical-trials-research/</url>
    <description>Moffitt Cancer Center Clinical Trials website</description>
  </link>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>September 19, 2017</study_first_submitted>
  <study_first_submitted_qc>September 19, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 21, 2017</study_first_posted>
  <last_update_submitted>April 17, 2023</last_update_submitted>
  <last_update_submitted_qc>April 17, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>well-differentiated neuroendocrine tumors</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neuroendocrine Tumors</mesh_term>
    <mesh_term>Carcinoma, Neuroendocrine</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
    <mesh_term>Lenvatinib</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/NCT03290079
org study id: MCC-19207
nct id: NCT03290079
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
The purpose of this study is to:

        -  Assess overall radiographic response rate (ORR)

        -  Assess progression-free survival (PFS)

        -  Test the safety and tolerability of Pembrolizumab in combination with lenvatinib
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Simon 2-stage design
primary purpose: Treatment
masking: None (Open Label)
measure: Objective Radiographic Response Rate (ORR)
time frame: Up to 12 months
description: Response Evaluation Criteria in Solid Tumors (RECIST) based response rate. Complete Response (CR): Disappearance of all extranodal target lesions. All pathological lymph nodes must have decreased to <10 mm in short axis. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (SLD) of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest). The SLD must also demonstrate an absolute increase of at least 5mm. (Two lesions increasing from 2 mm to 3 mm, for example, does not qualify). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
measure: Duration of Response (DOR)
time frame: Up to 12 months
description: DOR, defined as the time from first documented evidence of Complete Response (CR) or Partial Response (PR) until disease progression or death due to any cause, whichever occurs first.
measure: Progression Free Survival (PFS)
time frame: Up to 12 months
description: PFS, defined as the time from initial treatment to the first documented disease progression according to RECIST 1.1, or death due to any cause, whichever occurs first.
measure: Overall Survival (OS)
time frame: Up to 12 months
description: OS defined as the time from initial treatment until death from any cause.
arm group label: Pembrolizumab & Lenvatinib treatment
arm group type: Experimental
description: Pembrolizumab 200 mg will be administered as a 30 minute intravenous (IV) infusion every 3 weeks, in addition to 20 mg Lenvatinib by mouth every day of each 3 week cycle. Estimated average length of treatment per participant: 4 months.
intervention type: Drug
intervention name: Pembrolizumab
description: 200 mg Pembrolizumab by IV on Day 1 of each 3 week cycle.
arm group label: Pembrolizumab & Lenvatinib treatment
other name: Keytruda®
intervention type: Drug
intervention name: Lenvatinib
description: 20 mg Lenvatinib by mouth every day of each 3 week cycle
arm group label: Pembrolizumab & Lenvatinib treatment
other name: Lenvima®
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jonathan Strosberg, M.D.
role: Principal Investigator
affiliation: H. Lee Moffitt Cancer Center and Research Institute
facility: 
country: United States
url: https://moffitt.org/clinical-trials-research/
description: Moffitt Cancer Center Clinical Trials website
responsible party type: Sponsor
mesh term: Neuroendocrine Tumors
mesh term: Carcinoma, Neuroendocrine
mesh term: Pembrolizumab
mesh term: Lenvatinib