<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/NCT02973997</url>
  </required_header>
  <id_info>
    <org_study_id>ACCRU-ITOG-1504</org_study_id>
    <secondary_id>NCI-2016-01752</secondary_id>
    <secondary_id>ACCRU-ITOG-1504</secondary_id>
    <secondary_id>P30CA015083</secondary_id>
    <nct_id>NCT02973997</nct_id>
  </id_info>
  <brief_title>Lenvatinib and Pembrolizumab in Differentiated Thyroid Cancers (DTC)</brief_title>
  <official_title>Combination Targeted Therapy With Pembrolizumab and Lenvatinib in Progressive, Radioiodine-Refractory Differentiated Thyroid Cancers: A Phase II Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Academic and Community Cancer Research United</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Academic and Community Cancer Research United</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase II trial studies how well pembrolizumab and lenvatinib work in treating patients&#xD;
      with differentiated thyroid cancer that has spread to other places in the body or has come&#xD;
      back and cannot be removed by surgery. Immunotherapy with monoclonal antibodies, such as&#xD;
      pembrolizumab, may help the body's immune system attack the cancer, and may interfere with&#xD;
      the ability of tumor cells to grow and spread.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To investigate the clinical efficacy, as indicated by the rate of complete response (CR)&#xD;
      per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, of combination therapy with&#xD;
      pembrolizumab and lenvatinib in lenvatinib-naive patients with progressive&#xD;
      radioiodine-refractory differentiated thyroid cancers (DTC). (Cohort 1) II. To determine the&#xD;
      overall response rate (ORR) by the addition of pembrolizumab to patients with&#xD;
      radioiodine-refractory DTC who have progressive disease on lenvatinib alone. (Cohort 2)&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the safety profile and toxicity of combination therapy with pembrolizumab and&#xD;
      lenvatinib in patients with progressive DTC. (Cohort 1 and cohort 2) II. To determine&#xD;
      progression-free survival (PFS) and overall survival (OS). (Cohort 1 and cohort 2)&#xD;
&#xD;
      CORRELATIVE RESEARCH OBJECTIVES:&#xD;
&#xD;
      I. To correlate tumor response (RECIST 1.1) with pretreatment frequency of CD8+ T cells in&#xD;
      the primary and/or metastatic tumor. (Cohort 1 and cohort 2) II. To correlate tumor response&#xD;
      (RECIST 1.1) with pretreatment PD-L1 and PD-L2 levels in the primary and/or metastatic tumor.&#xD;
      (Cohort 1 and cohort 2) III. To correlate tumor response (RECIST 1.1) with pretreatment&#xD;
      frequency of lymphocytes expressing CD3, CD4, PD-1, FoxP3, or CD20, and of CD163+&#xD;
      macrophages. (Cohort 1 and cohort 2) IV. To correlate tumor response (RECIST 1.1) with the&#xD;
      phenotype and frequency of key leukocyte subsets (i.e., PD-1+ T cells, regulatory T cells&#xD;
      [Tregs], myeloid subsets) in the peripheral blood before, at 6 and 18 weeks on therapy, and&#xD;
      at 54 weeks (study completion), progressive disease (PD), or study withdrawal. (Cohort 1) V.&#xD;
      To correlate tumor response (RECIST 1.1) with PD-1+ T cell functional capacity. (Cohort 1)&#xD;
      VI. To correlate tumor response (RECIST 1.1) with serum anti-thyroglobulin antibody levels&#xD;
      assessed before, and at 18 weeks on therapy. (Cohort 1 and 2) VII. To correlate tumor&#xD;
      response (RECIST 1.1) with tumor mutation status. (Cohort 1) VIII. To broadly investigate&#xD;
      mechanisms of response and resistance to combination therapy, gene expression profiles will&#xD;
      be generated from frozen biopsies for analysis by ribonucleic acid-sequencing (RNA-Seq).&#xD;
      (Cohort 1)&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive lenvatinib orally (PO) once daily (QD) on days 1-21 and pembrolizumab&#xD;
      intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 19&#xD;
      cycles in the absence of disease progression or unacceptable toxicity. Patients may continue&#xD;
      treatment for up to 35 cycles.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 3 months for up to 3&#xD;
      years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">February 7, 2018</start_date>
  <completion_date type="Anticipated">October 8, 2023</completion_date>
  <primary_completion_date type="Actual">August 15, 2022</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>Complete response rate (Cohort 1)</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Will use a one-stage binomial design.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Confirmed response rate (Cohort 2)</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Assessed by RECIST 1.1. Will use a 2-stage Simon Optimal MinMax design.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. All patients that have initiated treatment will be considered evaluable for assessing adverse events. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine adverse event patterns. Only the grade 2+ adverse events will be assessed, regardless of relationship to the study treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival (PFS)</measure>
    <time_frame>From registration to the first of either death due to any cause or progression, assessed up to 3 years</time_frame>
    <description>The distribution of PFS will be estimated using the method of Kaplan-Meier.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>From registration to death due to any cause, assessed up to 3 years</time_frame>
    <description>The distribution of survival time will be estimated using the method of Kaplan-Meier.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Biomarker levels analysis following pembrolizumab and lenvatinib combination therapy</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>All analyses with respect to the translational component of this study are intended to be hypothesis-generating and descriptive in manner. Clinical data (i.e. CR rates confirmed response rates, PFS, OS, etc.) will be correlated with tumor marker data of interest (CD8+, PD-L1, PD-L2, T cell functional capacity markers, anti-thyroglobulin antibody levels, tumor mutation status, and other markers). The Chi-Square (or Fisher's Exact test) will be used to assess the association of categorical clinical data with categorical biomarker data. Time-to-event clinical data (PFS, OS) will be correlated with biomarker data using Kaplan-Meier methodology and Cox regression models. Logistic regression models will also be used to predict binary clinical data with baseline biomarker data. Finally, graphical methods and descriptive statistics will be used to summarize the data as well. Two-sided p-values &lt; 0.05 will be considered statistically significant.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Columnar Cell Variant Thyroid Gland Papillary Carcinoma</condition>
  <condition>Follicular Variant Thyroid Gland Papillary Carcinoma</condition>
  <condition>Metastatic Thyroid Gland Follicular Carcinoma</condition>
  <condition>Metastatic Thyroid Gland Papillary Carcinoma</condition>
  <condition>Poorly Differentiated Thyroid Gland Carcinoma</condition>
  <condition>Recurrent Differentiated Thyroid Gland Carcinoma</condition>
  <condition>Recurrent Thyroid Gland Follicular Carcinoma</condition>
  <condition>Recurrent Thyroid Gland Papillary Carcinoma</condition>
  <condition>Stage III Differentiated Thyroid Gland Carcinoma AJCC v7</condition>
  <condition>Stage III Thyroid Gland Follicular Carcinoma AJCC v7</condition>
  <condition>Stage III Thyroid Gland Papillary Carcinoma AJCC v7</condition>
  <condition>Stage IV Thyroid Gland Follicular Carcinoma AJCC v7</condition>
  <condition>Stage IV Thyroid Gland Papillary Carcinoma AJCC v7</condition>
  <condition>Stage IVA Differentiated Thyroid Gland Carcinoma AJCC v7</condition>
  <condition>Stage IVA Thyroid Gland Follicular Carcinoma AJCC v7</condition>
  <condition>Stage IVA Thyroid Gland Papillary Carcinoma AJCC v7</condition>
  <condition>Stage IVB Differentiated Thyroid Gland Carcinoma AJCC v7</condition>
  <condition>Stage IVB Thyroid Gland Follicular Carcinoma AJCC v7</condition>
  <condition>Stage IVB Thyroid Gland Papillary Carcinoma AJCC v7</condition>
  <condition>Stage IVC Differentiated Thyroid Gland Carcinoma AJCC v7</condition>
  <condition>Stage IVC Thyroid Gland Follicular Carcinoma AJCC v7</condition>
  <condition>Stage IVC Thyroid Gland Papillary Carcinoma AJCC v7</condition>
  <condition>Tall Cell Variant Thyroid Gland Papillary Carcinoma</condition>
  <condition>Thyroid Gland Hurthle Cell Carcinoma</condition>
  <condition>Unresectable Differentiated Thyroid Gland Carcinoma</condition>
  <condition>Unresectable Thyroid Gland Carcinoma</condition>
  <arm_group>
    <arm_group_label>Treatment (lenvatinib, pembrolizumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive lenvatinib PO QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 19 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment for up to 35 cycles.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (lenvatinib, pembrolizumab)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lenvatinib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (lenvatinib, pembrolizumab)</arm_group_label>
    <other_name>E7080</other_name>
    <other_name>ER-203492-00</other_name>
    <other_name>Multi-Kinase Inhibitor E7080</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lenvatinib Mesylate</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (lenvatinib, pembrolizumab)</arm_group_label>
    <other_name>4-[3-Chloro-4-(N''-cyclopropylureido)phenoxy]7-methoxyquinoline-6-carboxamide Mesylate</other_name>
    <other_name>E7080</other_name>
    <other_name>Lenvima</other_name>
    <other_name>Multi-Kinase Inhibitor E7080</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (lenvatinib, pembrolizumab)</arm_group_label>
    <other_name>Keytruda</other_name>
    <other_name>Lambrolizumab</other_name>
    <other_name>MK-3475</other_name>
    <other_name>SCH 900475</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Locally recurrent and unresectable and/or distant metastatic differentiated thyroid&#xD;
             cancer (DTC), histologically or cytologically confirmed; the diagnosis of DTC includes&#xD;
             the following subtypes: papillary thyroid cancer (PTC) (including but not limited to&#xD;
             variants such as follicular variant, tall cell, columnar cell, Hurthle cell variant of&#xD;
             papillary carcinoma, and poorly differentiated), follicular thyroid cancer (FTC),&#xD;
             including insular variant, Hurthle cell carcinoma and poorly differentiated thyroid&#xD;
             cancer&#xD;
&#xD;
          -  Measurable disease meeting the following criteria:&#xD;
&#xD;
               -  At least 1 lesion of &gt;= 1.0 cm in the longest diameter for a non-lymph node or &gt;=&#xD;
                  1.5 cm in the short-axis diameter for a lymph node which is serially measurable&#xD;
                  according to RECIST 1.1 using computerized tomography/magnetic resonance imaging&#xD;
                  (CT/MRI); if there is only one target lesion and it is a non-lymph node, it&#xD;
                  should have a longest diameter of &gt;= 1.5 cm&#xD;
&#xD;
               -  Lesions that have had external beam radiotherapy (EBRT) or loco-regional&#xD;
                  therapies such as radiofrequency (RF) ablation must show evidence of progressive&#xD;
                  disease based on RECIST 1.1 to be deemed a target lesion&#xD;
&#xD;
          -  For cohort 1 only: evidence of disease progression =&lt; 14 months prior to registration&#xD;
             according to RECIST 1.1, as confirmed by the site study principal investigator (PI)&#xD;
&#xD;
          -  For cohort 2 only: progressive disease (PD) on lenvatinib per RECIST 1.1 =&lt; 60 days&#xD;
             prior to registration, as confirmed by the site study PI; patients need to have&#xD;
             documented imaging and measurement of RECIST target lesions within 30 days of starting&#xD;
             pembrolizumab&#xD;
&#xD;
          -  Radioiodine (RAI)-resistant disease as defined by one or more of the following&#xD;
             criteria:&#xD;
&#xD;
               -  One or more measurable lesions that do not demonstrate RAI uptake&#xD;
&#xD;
               -  One or more measurable lesions progressive by RECIST 1.1 =&lt; 14 months of prior&#xD;
                  RAI therapy&#xD;
&#xD;
               -  One or more measurable lesions present after cumulative RAI dose of &gt;= 600 mCi&#xD;
&#xD;
               -  One or more measurable lesions that are fludeoxyglucose F-18 (FDG)-avid (&gt; 5&#xD;
                  standardized uptake value [SUV]), if positron emission tomography (PET)/CT scan&#xD;
                  performed; these lesions may also be RAI-avid&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1,500 /mcL (obtained =&lt; 30 days prior to&#xD;
             registration)&#xD;
&#xD;
          -  Platelets &gt;= 100,000 / mcL (obtained =&lt; 30 days prior to registration)&#xD;
&#xD;
          -  Hemoglobin &gt;= 9 g/dL or &gt;= 5.6 mmol/L without transfusion or erythropoietin dependency&#xD;
             (=&lt; 7 days prior to registration) (obtained =&lt; 30 days prior to registration)&#xD;
&#xD;
          -  Serum creatinine =&lt; 1.5 X upper limit of normal (ULN) OR measured or calculated&#xD;
             creatinine clearance (glomerular filtration rate [GFR] can also be used in place of&#xD;
             creatinine or creatinine clearance [CrCl]) &gt;= 60 mL/min for subject with creatinine&#xD;
             levels &gt; 1.5 X institutional ULN (obtained =&lt; 30 days prior to registration)&#xD;
&#xD;
          -  Serum total bilirubin =&lt; 1.5 X ULN OR direct bilirubin =&lt; ULN for subjects with total&#xD;
             bilirubin levels &gt; 1.5 ULN (obtained =&lt; 30 days prior to registration)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and&#xD;
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =&lt; 2.5 X&#xD;
             ULN OR =&lt; 5 X ULN for subjects with liver metastases (obtained =&lt; 30 days prior to&#xD;
             registration)&#xD;
&#xD;
          -  Albumin &gt;= 2.5 mg/dL (obtained =&lt; 30 days prior to registration)&#xD;
&#xD;
          -  International normalized ratio (INR) or prothrombin time (PT) =&lt; 1.5 X ULN unless&#xD;
             subject is receiving anticoagulant therapy as long as PT or partial thromboplastin&#xD;
             time (PTT) is within therapeutic range of intended use of anticoagulants (obtained =&lt;&#xD;
             30 days prior to registration)&#xD;
&#xD;
          -  Activated partial thromboplastin time (aPTT) =&lt; 1.5 X ULN unless subject is receiving&#xD;
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use&#xD;
             of anticoagulants (obtained =&lt; 30 days prior to registration)&#xD;
&#xD;
          -  Adequately controlled blood pressure with or without antihypertensive medications&#xD;
             defined as blood pressure (BP) &lt; 150/90 mmHg at screening&#xD;
&#xD;
          -  Negative pregnancy test done =&lt; 7 days prior to registration, for women of&#xD;
             childbearing potential only&#xD;
&#xD;
          -  Ability to complete patient medication and blood pressure diaries by themselves or&#xD;
             with assistance&#xD;
&#xD;
          -  Willing and able to provide informed written consent&#xD;
&#xD;
          -  Willing to return to enrolling institution for follow-up (during the active monitoring&#xD;
             phase of the study)&#xD;
&#xD;
               -  Note: during the active monitoring phase of a study (i.e., active treatment and&#xD;
                  observation), participants must be willing to return to the consenting&#xD;
                  institution for follow-up&#xD;
&#xD;
          -  Willing to provide tissue and blood samples for correlative research purposes&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Cohort 1 only: prior treatment with previous VEGFR active multikinase inhibitor&#xD;
&#xD;
          -  Cohort 2 only: discontinued lenvatinib due to toxicity&#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;
          -  Female subjects of childbearing potential: unwilling or unable to use 2 methods of&#xD;
             birth control or be surgically sterile, or abstain from heterosexual activity for the&#xD;
             course of the study through 120 days after the last dose of study medication; NOTE:&#xD;
             subjects of childbearing potential are those who have not been surgically sterilized&#xD;
             or have not been free from menses for &gt; 1 year&#xD;
&#xD;
          -  Male subjects: unwilling or unable to use an adequate method of contraception starting&#xD;
             with the first dose of study therapy through 120 days after the last dose of study&#xD;
             therapy&#xD;
&#xD;
          -  Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment&#xD;
             of the investigator, would make the patient inappropriate for entry into this study or&#xD;
             interfere significantly with the proper assessment of safety and toxicity of the&#xD;
             prescribed regimens&#xD;
&#xD;
          -  Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)&#xD;
             positive (HIV 1/2 antibodies) and currently receiving antiretroviral therapy&#xD;
&#xD;
          -  Currently participating and receiving study therapy (except lenvatinib for patients in&#xD;
             cohort 2) or has participated in a study of an investigational agent and received&#xD;
             study therapy within 4 weeks prior to registration&#xD;
&#xD;
          -  Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other&#xD;
             form of immunosuppressive therapy =&lt; 7 days prior to the first dose of trial treatment&#xD;
&#xD;
          -  Known history of active TB (Bacillus tuberculosis)&#xD;
&#xD;
          -  Hypersensitivity to pembrolizumab or any of its excipients&#xD;
&#xD;
          -  Prior anti-cancer monoclonal antibody (mAb) =&lt; 4 weeks prior to registration or who&#xD;
             has not recovered (i.e., =&lt; grade 1 or at baseline) from adverse events due to agents&#xD;
             administered &gt;= 4 weeks prior to registration&#xD;
&#xD;
          -  Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2&#xD;
             weeks prior to study day 1 (except lenvatinib for patients in cohort 2) or who has not&#xD;
             recovered (i.e., =&lt; grade 1 or at baseline) from adverse events due to a previously&#xD;
             administered agent&#xD;
&#xD;
               -  NOTE:&#xD;
&#xD;
                    -  Subjects with =&lt; grade 2 neuropathy are an exception to this criterion and&#xD;
                       may qualify for the study&#xD;
&#xD;
                    -  If subject received major surgery, they must have recovered adequately from&#xD;
                       the toxicity and/or complications from the intervention prior to&#xD;
                       registration, as deemed by treating investigator or site PI&#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;
             NOTE: subjects with previously treated brain metastases may participate provided they&#xD;
             are stable (without evidence of progression by imaging for at least four weeks prior&#xD;
             to the first dose of trial treatment and any neurologic symptoms have returned to&#xD;
             baseline), have no evidence of new or enlarging brain metastases, and are not using&#xD;
             steroids for &gt;= 7 days prior to trial treatment; this exception does not include&#xD;
             carcinomatous meningitis which is excluded regardless of clinical stability&#xD;
&#xD;
          -  Active autoimmune disease that has required systemic treatment in the past 2 years&#xD;
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive&#xD;
             drugs); NOTE: replacement therapy (e.g., thyroxine, insulin, or physiologic&#xD;
             corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is&#xD;
             not considered a form of systemic treatment&#xD;
&#xD;
          -  Known history of, or any evidence of active, non-infectious pneumonitis that required&#xD;
             steroids&#xD;
&#xD;
          -  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;
          -  Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent&#xD;
&#xD;
          -  Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or&#xD;
             hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is&#xD;
             detected)&#xD;
&#xD;
          -  Received a live vaccine =&lt; 30 days of planned start of study therapy; NOTE: seasonal&#xD;
             influenza vaccines for injection are generally inactivated flu vaccines and are&#xD;
             allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated&#xD;
             vaccines, and are not allowed&#xD;
&#xD;
          -  Proteinuria &gt; 1+ on dipstick urinalysis; patients with &gt; 1+ proteinuria on dipstick&#xD;
             urinalysis will undergo 24-hour urine collection for quantitative assessment; NOTE:&#xD;
             patients with &gt; 1 g/24 hours will be ineligible&#xD;
&#xD;
          -  Clinically significant gastrointestinal malabsorption syndrome&#xD;
&#xD;
          -  New York Heart Association congestive heart failure of grade II or above, unstable&#xD;
             angina, myocardial infarction within the past 6 months, or serious cardiac arrhythmia&#xD;
             associated with significant cardiovascular impairment within the past 6 months;&#xD;
             ejection fraction (EF) by multi-gated acquisition (MUGA) or echo should not be less&#xD;
             than the institutional lower limit of normal&#xD;
&#xD;
          -  Corrected QT (QTc) prolongation &gt; 480 msec, as calculated by either the Bazett or&#xD;
             Fridericia formula, as per institutional standard&#xD;
&#xD;
          -  Active hemoptysis (bright red blood &gt; 1 teaspoon on more than one occasion) =&lt; 3 weeks&#xD;
             prior to registration&#xD;
&#xD;
          -  Cohort 2 only: more than one prior treatment with VEGFR active multikinase inhibitor&#xD;
             prior to original start 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>Bryan R Haugen</last_name>
    <role>Principal Investigator</role>
    <affiliation>Academic and Community Cancer Research United</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center</name>
      <address>
        <city>Torrance</city>
        <state>California</state>
        <zip>90502</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Colorado Hospital</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Massachusetts General Hospital Cancer Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Michigan Comprehensive Cancer Center</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ohio State University Comprehensive Cancer Center</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>M D Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>November 23, 2016</study_first_submitted>
  <study_first_submitted_qc>November 23, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 28, 2016</study_first_posted>
  <last_update_submitted>February 13, 2023</last_update_submitted>
  <last_update_submitted_qc>February 13, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 14, 2023</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>Thyroid Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Papillary</mesh_term>
    <mesh_term>Thyroid Cancer, Papillary</mesh_term>
    <mesh_term>Adenocarcinoma, Follicular</mesh_term>
    <mesh_term>Thyroid Diseases</mesh_term>
    <mesh_term>Recurrence</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>
  <pending_results>
    <submitted>July 5, 2023</submitted>
    <returned>July 25, 2023</returned>
    <submitted>August 15, 2023</submitted>
    <returned>September 1, 2023</returned>
  </pending_results>
  <!-- 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/NCT02973997
org study id: ACCRU-ITOG-1504
secondary id: NCI-2016-01752
secondary id: ACCRU-ITOG-1504
secondary id: P30CA015083
nct id: NCT02973997
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase II trial studies how well pembrolizumab and lenvatinib work in treating patients
      with differentiated thyroid cancer that has spread to other places in the body or has come
      back and cannot be removed by surgery. Immunotherapy with monoclonal antibodies, such as
      pembrolizumab, may help the body's immune system attack the cancer, and may interfere with
      the ability of tumor cells to grow and spread.
PRIMARY OBJECTIVES:

      I. To investigate the clinical efficacy, as indicated by the rate of complete response (CR)
      per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, of combination therapy with
      pembrolizumab and lenvatinib in lenvatinib-naive patients with progressive
      radioiodine-refractory differentiated thyroid cancers (DTC). (Cohort 1) II. To determine the
      overall response rate (ORR) by the addition of pembrolizumab to patients with
      radioiodine-refractory DTC who have progressive disease on lenvatinib alone. (Cohort 2)

      SECONDARY OBJECTIVES:

      I. To determine the safety profile and toxicity of combination therapy with pembrolizumab and
      lenvatinib in patients with progressive DTC. (Cohort 1 and cohort 2) II. To determine
      progression-free survival (PFS) and overall survival (OS). (Cohort 1 and cohort 2)

      CORRELATIVE RESEARCH OBJECTIVES:

      I. To correlate tumor response (RECIST 1.1) with pretreatment frequency of CD8+ T cells in
      the primary and/or metastatic tumor. (Cohort 1 and cohort 2) II. To correlate tumor response
      (RECIST 1.1) with pretreatment PD-L1 and PD-L2 levels in the primary and/or metastatic tumor.
      (Cohort 1 and cohort 2) III. To correlate tumor response (RECIST 1.1) with pretreatment
      frequency of lymphocytes expressing CD3, CD4, PD-1, FoxP3, or CD20, and of CD163+
      macrophages. (Cohort 1 and cohort 2) IV. To correlate tumor response (RECIST 1.1) with the
      phenotype and frequency of key leukocyte subsets (i.e., PD-1+ T cells, regulatory T cells
      [Tregs], myeloid subsets) in the peripheral blood before, at 6 and 18 weeks on therapy, and
      at 54 weeks (study completion), progressive disease (PD), or study withdrawal. (Cohort 1) V.
      To correlate tumor response (RECIST 1.1) with PD-1+ T cell functional capacity. (Cohort 1)
      VI. To correlate tumor response (RECIST 1.1) with serum anti-thyroglobulin antibody levels
      assessed before, and at 18 weeks on therapy. (Cohort 1 and 2) VII. To correlate tumor
      response (RECIST 1.1) with tumor mutation status. (Cohort 1) VIII. To broadly investigate
      mechanisms of response and resistance to combination therapy, gene expression profiles will
      be generated from frozen biopsies for analysis by ribonucleic acid-sequencing (RNA-Seq).
      (Cohort 1)

      OUTLINE:

      Patients receive lenvatinib orally (PO) once daily (QD) on days 1-21 and pembrolizumab
      intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 19
      cycles in the absence of disease progression or unacceptable toxicity. Patients may continue
      treatment for up to 35 cycles.

      After completion of study treatment, patients are followed up every 3 months for up to 3
      years.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Complete response rate (Cohort 1)
time frame: Up to 3 years
description: Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Will use a one-stage binomial design.
measure: Confirmed response rate (Cohort 2)
time frame: Up to 3 years
description: Assessed by RECIST 1.1. Will use a 2-stage Simon Optimal MinMax design.
measure: Incidence of adverse events
time frame: Up to 3 years
description: Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. All patients that have initiated treatment will be considered evaluable for assessing adverse events. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine adverse event patterns. Only the grade 2+ adverse events will be assessed, regardless of relationship to the study treatment.
measure: Progression free survival (PFS)
time frame: From registration to the first of either death due to any cause or progression, assessed up to 3 years
description: The distribution of PFS will be estimated using the method of Kaplan-Meier.
measure: Overall survival (OS)
time frame: From registration to death due to any cause, assessed up to 3 years
description: The distribution of survival time will be estimated using the method of Kaplan-Meier.
measure: Biomarker levels analysis following pembrolizumab and lenvatinib combination therapy
time frame: Up to 3 years
description: All analyses with respect to the translational component of this study are intended to be hypothesis-generating and descriptive in manner. Clinical data (i.e. CR rates confirmed response rates, PFS, OS, etc.) will be correlated with tumor marker data of interest (CD8+, PD-L1, PD-L2, T cell functional capacity markers, anti-thyroglobulin antibody levels, tumor mutation status, and other markers). The Chi-Square (or Fisher's Exact test) will be used to assess the association of categorical clinical data with categorical biomarker data. Time-to-event clinical data (PFS, OS) will be correlated with biomarker data using Kaplan-Meier methodology and Cox regression models. Logistic regression models will also be used to predict binary clinical data with baseline biomarker data. Finally, graphical methods and descriptive statistics will be used to summarize the data as well. Two-sided p-values < 0.05 will be considered statistically significant.
arm group label: Treatment (lenvatinib, pembrolizumab)
arm group type: Experimental
description: Patients receive lenvatinib PO QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 19 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment for up to 35 cycles.
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Treatment (lenvatinib, pembrolizumab)
intervention type: Drug
intervention name: Lenvatinib
description: Given PO
arm group label: Treatment (lenvatinib, pembrolizumab)
other name: E7080
other name: ER-203492-00
other name: Multi-Kinase Inhibitor E7080
intervention type: Drug
intervention name: Lenvatinib Mesylate
description: Given PO
arm group label: Treatment (lenvatinib, pembrolizumab)
other name: 4-[3-Chloro-4-(N''-cyclopropylureido)phenoxy]7-methoxyquinoline-6-carboxamide Mesylate
other name: E7080
other name: Lenvima
other name: Multi-Kinase Inhibitor E7080
intervention type: Biological
intervention name: Pembrolizumab
description: Given IV
arm group label: Treatment (lenvatinib, pembrolizumab)
other name: Keytruda
other name: Lambrolizumab
other name: MK-3475
other name: SCH 900475
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Bryan R Haugen
role: Principal Investigator
affiliation: Academic and Community Cancer Research United
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Thyroid Neoplasms
mesh term: Carcinoma, Papillary
mesh term: Thyroid Cancer, Papillary
mesh term: Adenocarcinoma, Follicular
mesh term: Thyroid Diseases
mesh term: Recurrence
mesh term: Pembrolizumab
mesh term: Lenvatinib
submitted: July 5, 2023
returned: July 25, 2023
submitted: August 15, 2023
returned: September 1, 2023