xml: <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/NCT05980000</url>
    </required_header>
    <id_info>
      <org_study_id>23-X273</org_study_id>
      <nct_id>NCT05980000</nct_id>
    </id_info>
    <brief_title>Ramucirumab and Pembrolizumab vs Pembrolizumab Monotherapy in PD-L1 Positive Head and Neck Squamous-Cell Carcinoma</brief_title>
    <acronym>Rambro2</acronym>
    <official_title>Open-Label, Randomized Phase 2 Trial of Ramucirumab in Combination With Pembrolizumab Versus Pembrolizumab Alone as First-Line Treatment of PD-L1 Positive, Recurrent or Metastatic Head and Neck Squamous-Cell Carcinoma (RM-HNSCC)</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Washington University School of Medicine</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Eli Lilly and Company</agency>
        <agency_class>Industry</agency_class>
      </collaborator>
    </sponsors>
    <source>Washington University School of Medicine</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>
        This is a phase 2 study investigating the efficacy of ramucirumab in combination with&#xD;
        pembrolizumab compared to pembrolizumab monotherapy. Ramucirumab is a VEGFR-2 inhibitor&#xD;
        believed to potentially enhance the efficacy of PD-1 inhibitors such as pembrolizumab.&#xD;
      </textblock>
    </brief_summary>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">October 31, 2023</start_date>
    <completion_date type="Anticipated">April 30, 2031</completion_date>
    <primary_completion_date type="Anticipated">April 30, 2028</primary_completion_date>
    <phase>Phase 2</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <intervention_model_description>Patients will be randomized on a 2:1 basis to Arm 1 or Arm 2.</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Overall Response Rate (ORR)</measure>
      <time_frame>From start of study treatment through completion of treatment (estimated to be 24 months)</time_frame>
      <description>ORR is defined as the number of patients with a complete response (CR) and a partial response (PR) by RECIST 1.1 criteria. A CR is defined as the disappearance of all target lesions, reduction in pathological lymph nodes to &lt;10 mm in short axis, and disappearance of all non-target lesions with normalization of tumor marker level. A PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Duration of Overall Response</measure>
      <time_frame>From time criteria is met for CR or PR through completion of treatment (estimated to be 1 year and 40 weeks)</time_frame>
      <description>Duration of overall response is measured from the time criteria are met for a CR or PR per RECIST 1.1 (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented. Duration of overall CR is measured from the time criteria are met for a CR per RECIST 1.1 until the first date that progressive disease is objectively documented.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Progression-Free Survival (PFS)</measure>
      <time_frame>From start of study treatment through 5 years</time_frame>
      <description>PFS is defined as the duration of time from the start of treatment to time of progression or death, whichever occurs first.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overall Survival (OS)</measure>
      <time_frame>From start of study treatment through 5 years</time_frame>
      <description>OS is defined as the time from start of treatment to the date of death, censored at the last follow-up otherwise.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence rate, frequency, and severity of AEs</measure>
      <time_frame>From start of study treatment through 30 days after last dose (expected to be 2 years and 1 month)</time_frame>
      <description>AEs will be assessed using CTCAE v4.0 and summarized by arm.</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">72</enrollment>
    <condition>Recurrent Head and Neck Cancer</condition>
    <condition>Recurrent Head and Neck Squamous Cell Carcinoma</condition>
    <condition>Recurrent Head and Neck Carcinoma</condition>
    <condition>Metastatic Head-and-neck Squamous-cell Carcinoma</condition>
    <condition>Metastatic Head and Neck Cancer</condition>
    <condition>HNSCC</condition>
    <arm_group>
      <arm_group_label>Arm 1: Ramucirumab and Pembrolizumab</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Patients receive ramucirumab IV and pembrolizumab IV every 3 weeks. Cycles are 21 days in length. Treatment will continue until progression or unacceptable toxicity for up to 35 cycles of treatment.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Arm 2: Pembrolizumab monotherapy</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Patients receive pembrolizumab IV every 3 weeks. Cycles are 21 days in length. Treatment will continue until progression or unacceptable toxicity for up to 35 cycles of treatment.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Ramucirumab</intervention_name>
      <description>Ramucirumab is administered at a dose of 10 mg/kg over 60 minutes.</description>
      <arm_group_label>Arm 1: Ramucirumab and Pembrolizumab</arm_group_label>
      <other_name>Cyramza</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Pembrolizumab</intervention_name>
      <description>Pembrolizumab is administered at a flat dose of 200 mg over 30 minutes.</description>
      <arm_group_label>Arm 1: Ramucirumab and Pembrolizumab</arm_group_label>
      <arm_group_label>Arm 2: Pembrolizumab monotherapy</arm_group_label>
      <other_name>MK-3475</other_name>
      <other_name>Keytruda</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Incurable RM-HNSCC, defined as RM disease or second or subsequent primary HNSCC not&#xD;
               amenable to cure by surgery and/or radiation therapy or patient declines or is&#xD;
               ineligible for curative therapy. Eligible primary tumor sub-sites include oral cavity,&#xD;
               oropharynx, larynx and hypopharynx only.&#xD;
  &#xD;
            -  PD-L1 positive (CPS ≥1) disease, based on local IHC assay using 22C3 antibody.&#xD;
  &#xD;
            -  Measurable disease per RECIST 1.1 (defined as lesions that can be accurately measured&#xD;
               in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan,&#xD;
               as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam).&#xD;
  &#xD;
            -  No prior systemic therapy for RM-HNSCC. RM disease developing within 6 months of&#xD;
               completion of either a) systemic platinum or cetuximab therapy given as a component of&#xD;
               a curative-intent multi-modality regimen or b) radiation therapy and/or surgery is&#xD;
               eligible.&#xD;
  &#xD;
            -  At least 18 years of age.&#xD;
  &#xD;
            -  ECOG performance status 0-1.&#xD;
  &#xD;
            -  Normal bone marrow and organ function as defined below:&#xD;
  &#xD;
                 -  Absolute neutrophil count ≥ 1.5 K/cumm&#xD;
  &#xD;
                 -  Platelets ≥ 100 K/cumm&#xD;
  &#xD;
                 -  Hemoglobin ≥ 9.0 g/dL&#xD;
  &#xD;
                 -  Total bilirubin ≤ 1.5 x IULN&#xD;
  &#xD;
                 -  AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN. In the setting of liver metastases,&#xD;
                    AST(SGOT)/ALT(SGPT) ≤ 5.0 x IULN&#xD;
  &#xD;
                 -  Creatinine ≤ 1.5 x ULN. If patient has creatinine &gt; 1.5 x ULN, then 24 hour urine&#xD;
                    collection must be performed and creatinine clearance must be ≥ 40 mL/min by&#xD;
                    Cockcroft-Gault&#xD;
  &#xD;
                 -  Urine protein to creatinine ratio (UPC) ≤ 1; if UPC &gt; 1, then a 24-hour urine&#xD;
                    protein must be assessed and patient must have a 24-hour urine protein value &lt; 1&#xD;
                    g to be eligible&#xD;
  &#xD;
                 -  INR ≤ 1.5 (≤ 3.0 if on warfarin) and PTT ≤ 1.5 x ULN (Patients are allowed to be&#xD;
                    on anticoagulation)&#xD;
  &#xD;
            -  The effects of Ramucirumab on the developing human fetus are unknown. For this reason&#xD;
               and because VEGFR2 inhibiting agents are known to be teratogenic, women of&#xD;
               childbearing potential and men must agree to use adequate contraception (hormonal or&#xD;
               barrier method of birth control, abstinence) prior to study entry and for the duration&#xD;
               of study participation. Should a woman become pregnant or suspect she is pregnant&#xD;
               while participating in this study, she must inform her treating physician immediately.&#xD;
               Men treated or enrolled on this protocol must also agree to use adequate contraception&#xD;
               prior to the study, for the duration of the study, and 28 days after completion of the&#xD;
               study.&#xD;
  &#xD;
            -  Ability to understand and willingness to sign an IRB approved written informed consent&#xD;
               document (or that of legally authorized representative, if applicable).&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  PD-L1 negative (CPS 0) disease, based on local IHC assay using 22C3 antibody.&#xD;
  &#xD;
            -  Cutaneous or nasopharynx SCC.&#xD;
  &#xD;
            -  Major surgery within 28 days prior to C1D1, minor surgery or subcutaneous venous&#xD;
               access device placement within 7 days prior to C1D1, history of significant tumor site&#xD;
               bleeding within 14 days prior to C1D1, or elective or planned major surgery to be&#xD;
               performed during the course of the clinical trial.&#xD;
  &#xD;
            -  Palliative radiation therapy within 2 weeks of C1D1.&#xD;
  &#xD;
            -  Serious or non-healing would, ulcer, or bone fracture within 28 days prior to C1D1.&#xD;
  &#xD;
            -  A history of other malignancy ≤ 1 year previous with the exception of completely&#xD;
               resected skin carcinoma or other cancers with a low risk (&lt;10%) of recurrence over the&#xD;
               next 2 years.&#xD;
  &#xD;
            -  Cirrhosis at a level of Child-Pugh B (or worse). Cirrhosis of any degree with a&#xD;
               history of hepatic encephalopathy or clinically meaningful ascites (from cirrhosis&#xD;
               requiring diuretics or paracentesis).&#xD;
  &#xD;
            -  Currently receiving any other investigational agents.&#xD;
  &#xD;
            -  Ongoing toxicity attributed to prior anti-cancer therapy that is &gt; grade 1, except&#xD;
               alopecia, anemia, lymphopenia, xerostomia, fatigue or rash.&#xD;
  &#xD;
            -  Active central nervous system metastases: defined as currently receiving radiation&#xD;
               therapy to metastatic CNS disease. Once radiation therapy is completed and patient has&#xD;
               completed a 2 week washout, patients with CNS disease are eligible if they meet all&#xD;
               other criteria for enrollment.&#xD;
  &#xD;
            -  A history of severe allergic reactions attributed to compounds of similar chemical or&#xD;
               biologic composition to Ramucirumab or other agents used in the study.&#xD;
  &#xD;
            -  Serious uncontrolled intercurrent illness within the 3 months prior to study entry&#xD;
               including, but not limited to, ongoing or active infection, symptomatic congestive&#xD;
               heart failure, or cardiac arrhythmia or psychiatric illness/social situations that&#xD;
               would limit compliance with study requirements.&#xD;
  &#xD;
            -  Receiving systemic corticosteroid therapy (in doses exceeding 10 mg daily of&#xD;
               prednisone equivalent) or any other form of intense immunosuppressive therapy within 7&#xD;
               days prior to C1D1.&#xD;
  &#xD;
            -  Active autoimmune disease (i.e. rheumatoid arthritis, lupus) that has required IV or&#xD;
               subcutaneous systemic treatment in the past 6 months prior to C1D1 (excluding&#xD;
               Rituxan). Replacement therapy (i.e. thyroxine, insulin, or physiologic corticosteroid&#xD;
               replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a&#xD;
               form of systemic treatment.&#xD;
  &#xD;
            -  GI perforation or fistula within 6 months of C1D1.&#xD;
  &#xD;
            -  History of inflammatory bowel disease, ulcerative colitis, or Crohn's disease.&#xD;
  &#xD;
            -  Poorly controlled hypertension (defined as serial high blood pressure measurements&#xD;
               [systolic blood pressures of &gt; 160 mmHg or diastolic blood pressures of &gt; 100 mmHg]&#xD;
               documented during the four-week interval prior to C1D1) despite standard medical&#xD;
               management. Initiation or adjustment of antihypertensive medications to control blood&#xD;
               pressure is permitted prior to study entry.&#xD;
  &#xD;
            -  Arterial thromboembolic events (including but not limited to myocardial infarction,&#xD;
               transient ischemic attack, cerebrovascular accident, or unstable angina) within 6&#xD;
               months, or deep vein thrombosis (DVT), pulmonary embolism (PE), or any other&#xD;
               significant thromboembolism (venous port or catheter thrombosis or superficial venous&#xD;
               thrombosis are not considered &quot;significant&quot;) within 3 months prior to C1D1.&#xD;
  &#xD;
            -  Any bleeding (grade 3 or 4) within 3 months prior to C1D1.&#xD;
  &#xD;
            -  Receiving chronic antiplatelet therapy, including nonsteroidal anti-inflammatory drugs&#xD;
               (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or&#xD;
               similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is permitted.&#xD;
  &#xD;
            -  Current, active bleeding (within 14 days prior to C1D1) or pathological condition&#xD;
               present that carries a high risk of bleeding (for example, tumor involving major&#xD;
               vessels or known varices), if patients are taking an oral anticoagulant or low&#xD;
               molecular weight heparin. Patients on full-dose anticoagulation must be on a stable&#xD;
               dose (minimum duration 14 days) of oral anticoagulant or LMWH prior to C1D1.&#xD;
  &#xD;
            -  Pregnant and/or breastfeeding. Women of childbearing potential must have a negative&#xD;
               serum pregnancy test within 7 days prior to C1D1.&#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>Douglas R Adkins, M.D.</last_name>
      <role>Principal Investigator</role>
      <affiliation>Washington University School of Medicine</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Douglas R Adkins, M.D.</last_name>
      <phone>314-747-8475</phone>
      <email>dadkins@wustl.edu</email>
    </overall_contact>
    <location>
      <facility>
        <name>Washington University School of Medicine</name>
        <address>
          <city>Saint Louis</city>
          <state>Missouri</state>
          <zip>63110</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Douglas R Adkins, M.D.</last_name>
        <phone>314-747-8475</phone>
        <email>dadkins@wustl.edu</email>
      </contact>
      <investigator>
        <last_name>Douglas R Adkins, M.D.</last_name>
        <role>Principal Investigator</role>
      </investigator>
      <investigator>
        <last_name>Peter Oppelt, M.D.</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Esther Lu, Ph.D.</last_name>
        <role>Sub-Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <link>
      <url>http://www.siteman.wustl.edu</url>
      <description>Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine</description>
    </link>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>July 30, 2023</study_first_submitted>
    <study_first_submitted_qc>July 30, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 7, 2023</study_first_posted>
    <last_update_submitted>July 30, 2023</last_update_submitted>
    <last_update_submitted_qc>July 30, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 7, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>PD-L1 positive RM-HNSCC</keyword>
    <keyword>RM-HNSCC</keyword>
    <keyword>oral cavity HNSCC</keyword>
    <keyword>oropharynx HNSCC</keyword>
    <keyword>larynx HNSCC</keyword>
    <keyword>hypopharynx HNSCC</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Carcinoma</mesh_term>
      <mesh_term>Carcinoma, Squamous Cell</mesh_term>
      <mesh_term>Head and Neck Neoplasms</mesh_term>
      <mesh_term>Squamous Cell Carcinoma of Head and Neck</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>Ramucirumab</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05980000
  org study id: 23-X273
  nct id: NCT05980000
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: Yes
  is fda regulated device: No
  is us export: Yes
  This is a phase 2 study investigating the efficacy of ramucirumab in combination with
        pembrolizumab compared to pembrolizumab monotherapy. Ramucirumab is a VEGFR-2 inhibitor
        believed to potentially enhance the efficacy of PD-1 inhibitors such as pembrolizumab.
  allocation: Randomized
  intervention model: Parallel Assignment
  intervention model description: Patients will be randomized on a 2:1 basis to Arm 1 or Arm 2.
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Overall Response Rate (ORR)
  time frame: From start of study treatment through completion of treatment (estimated to be 24 months)
  description: ORR is defined as the number of patients with a complete response (CR) and a partial response (PR) by RECIST 1.1 criteria. A CR is defined as the disappearance of all target lesions, reduction in pathological lymph nodes to <10 mm in short axis, and disappearance of all non-target lesions with normalization of tumor marker level. A PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
  measure: Duration of Overall Response
  time frame: From time criteria is met for CR or PR through completion of treatment (estimated to be 1 year and 40 weeks)
  description: Duration of overall response is measured from the time criteria are met for a CR or PR per RECIST 1.1 (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented. Duration of overall CR is measured from the time criteria are met for a CR per RECIST 1.1 until the first date that progressive disease is objectively documented.
  measure: Progression-Free Survival (PFS)
  time frame: From start of study treatment through 5 years
  description: PFS is defined as the duration of time from the start of treatment to time of progression or death, whichever occurs first.
  measure: Overall Survival (OS)
  time frame: From start of study treatment through 5 years
  description: OS is defined as the time from start of treatment to the date of death, censored at the last follow-up otherwise.
  measure: Incidence rate, frequency, and severity of AEs
  time frame: From start of study treatment through 30 days after last dose (expected to be 2 years and 1 month)
  description: AEs will be assessed using CTCAE v4.0 and summarized by arm.
  arm group label: Arm 1: Ramucirumab and Pembrolizumab
  arm group type: Experimental
  description: Patients receive ramucirumab IV and pembrolizumab IV every 3 weeks. Cycles are 21 days in length. Treatment will continue until progression or unacceptable toxicity for up to 35 cycles of treatment.
  arm group label: Arm 2: Pembrolizumab monotherapy
  arm group type: Active Comparator
  description: Patients receive pembrolizumab IV every 3 weeks. Cycles are 21 days in length. Treatment will continue until progression or unacceptable toxicity for up to 35 cycles of treatment.
  intervention type: Drug
  intervention name: Ramucirumab
  description: Ramucirumab is administered at a dose of 10 mg/kg over 60 minutes.
  arm group label: Arm 1: Ramucirumab and Pembrolizumab
  other name: Cyramza
  intervention type: Drug
  intervention name: Pembrolizumab
  description: Pembrolizumab is administered at a flat dose of 200 mg over 30 minutes.
  arm group label: Arm 1: Ramucirumab and Pembrolizumab
  arm group label: Arm 2: Pembrolizumab monotherapy
  other name: MK-3475
  other name: Keytruda
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Douglas R Adkins, M.D.
  role: Principal Investigator
  affiliation: Washington University School of Medicine
  last name: Douglas R Adkins, M.D.
  phone: 314-747-8475
  email: dadkins@wustl.edu
  facility: 
  contact: 
  investigator: 
  investigator: 
  investigator: 
  country: United States
  url: http://www.siteman.wustl.edu
  description: Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
  responsible party type: Sponsor
  mesh term: Carcinoma
  mesh term: Carcinoma, Squamous Cell
  mesh term: Head and Neck Neoplasms
  mesh term: Squamous Cell Carcinoma of Head and Neck
  mesh term: Recurrence
  mesh term: Pembrolizumab
  mesh term: Ramucirumab
  sharing ipd: No