<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/NCT03004183</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00015649</org_study_id>
    <nct_id>NCT03004183</nct_id>
  </id_info>
  <brief_title>SBRT and Oncolytic Virus Therapy Before Pembrolizumab for Metastatic TNBC and NSCLC</brief_title>
  <acronym>STOMP</acronym>
  <official_title>Phase II Window of Opportunity Trial of Stereotactic Body Radiation Therapy and In Situ Oncolytic Virus Therapy in Metastatic Triple Negative Breast Cancer and Metastatic Non-Small Cell Lung Cancer Followed by Pembrolizumab</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Methodist Hospital 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>The Methodist Hospital 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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a Phase II trial to determine the efficacy and safety of stereotactic body radiation&#xD;
      therapy (SBRT) and in situ oncolytic virus therapy used as a window of opportunity treatment&#xD;
      before pembrolizumab in patients with metastatic triple negative breast cancer (TNBC) and&#xD;
      metastatic non-small cell lung cancer (NSCLC). In situ oncolytic virus therapy will consist&#xD;
      of adenovirus-mediated expression of herpes simplex virus thymidine kinase (ADV/HSV-tk) plus&#xD;
      valacyclovir therapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a Phase II trial to determine the efficacy and safety of stereotactic body radiation&#xD;
      therapy (SBRT) and in situ oncolytic virus therapy used as a window of opportunity treatment&#xD;
      before pembrolizumab in patients with metastatic triple negative breast cancer (TNBC) and&#xD;
      metastatic non-small cell lung cancer (NSCLC). In situ oncolytic virus therapy will consist&#xD;
      of adenovirus-mediated expression of herpes simplex virus thymidine kinase (ADV/HSV-tk) plus&#xD;
      valacyclovir. Male and female patients aged ≥ 18 years with histologically confirmed locally&#xD;
      advanced or metastatic TNBC that has relapsed on or is refractory to 1 or more lines of&#xD;
      standard of care therapy or histologically or cytologically confirmed metastatic NSCLC that&#xD;
      is immunotherapy and chemotherapy naïve or previously treated with 1 cycle of&#xD;
      platinum-containing chemotherapy are eligible to participate in the study. ADV/HSV-tk (5 x&#xD;
      1011 viral particles) in a 2-mL total volume will be injected intratumorally on Day 0 of the&#xD;
      study. Valacyclovir will be orally administered at a dose of 2 g three times daily for 14&#xD;
      days. Valacyclovir treatment will be administered 24 hours after the gene vector injection&#xD;
      from Day 1 to Day 15 of the study. SBRT of 30 gray (Gy; 6 Gy X 5 fractions) will be&#xD;
      administered over 2 weeks from Day 2 to Day 16 of the study. Pembrolizumab (200 mg) will be&#xD;
      administered intravenously over 30 minutes every 3 weeks starting on Day 17 of the study and&#xD;
      continuing until disease progression, unacceptable toxicity, or up to 24 months in patients&#xD;
      without disease progression. The primary endpoint will be the objective response rate of&#xD;
      ADV/HSV-tk + valacyclovir therapy in combination with SBRT used as a window of opportunity&#xD;
      treatment before pembrolizumab in patients with metastatic TNBC and metastatic NSCLC. RECIST&#xD;
      1.1 will be used to assess treatment response. Secondary endpoints will include a) clinical&#xD;
      benefit rate; b) duration of response; c) overall survival and progression-free survival&#xD;
      rates; d) toxicity (toxicity will be defined as any treatment-related death or any ≥ grade 3&#xD;
      toxicity excluding alopecia and constitutional symptoms as assessed by the NCI CTCAE v4.03);&#xD;
      and e) antitumor activity of ADV/HSV-tk plus valacyclovir therapy in combination with SBRT&#xD;
      used as a window of opportunity treatment before pembrolizumab.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 1, 2017</start_date>
  <completion_date type="Anticipated">November 2023</completion_date>
  <primary_completion_date type="Actual">July 22, 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>Objective Response Rate</measure>
    <time_frame>30 days after the last dose of pembrolizumab until disease progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. Median duration of follow-up was 8.3 months (95% CI 3.0-10.1 months).</time_frame>
    <description>The objective response rate (ORR) of ADV/HSV-tk plus (+) valacyclovir therapy in combination with SBRT used as a window of opportunity treatment before pembrolizumab in patients with metastatic TNBC and metastatic NSCLC. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be used to assess treatment response. Modified immune-related response criteria (irRC; derived from RECIST 1.1) will also be documented.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Duration of Response</measure>
    <time_frame>30 days after the last dose of pembrolizumab until disease progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. Median duration of follow-up was 8.3 months (95% CI 3.0-10.1 months).</time_frame>
    <description>Duration of response to ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival Rate</measure>
    <time_frame>After confirmed disease progression or starts a new therapy, the subject moves into the Survival Follow-up to be contacted every 12 weeks to assess for survival status until death, withdrawal, or end of study. Median duration of follow-up was 8.3 months.</time_frame>
    <description>Overall survival (OS) rate in subjects receiving ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab. OS is the time (measured in months) from intratumoral viral injection to death or last date of contact.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival Rate</measure>
    <time_frame>Subjects in the follow up phase will be assessed every 6 weeks (42 ± 7 days) by radiologic imaging to monitor disease status. After 1 year, the imaging time point will occur every 9 weeks (± 7 days).</time_frame>
    <description>Progression-free survival rate in subjects receiving ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Treatment-related Adverse Events</measure>
    <time_frame>Adverse Events (AEs) and Serious Adverse Events (SAEs) will be captured from the time of informed consent signing up to 30 days after the final dose of pembrolizumab, (up to 24 months of treatment for patients without disease progression).</time_frame>
    <description>To document the toxicities associated with ADV/HSV-tk + valacyclovir therapy in combination with SBRT used as a window of opportunity treatment before pembrolizumab in patients with metastatic TNBC and metastatic NSCLC. Toxicity will be defined as the number of participants with any treatment-related death or any ≥ Grade 3 hematological toxicity excluding alopecia and constitutional symptoms, as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Antitumor Activity</measure>
    <time_frame>30 days after the last dose of pembrolizumab</time_frame>
    <description>Measure the antitumor activity as assessed by RECIST 1.1. Modified immune-related response criteria will also be documented.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Benefit Rate</measure>
    <time_frame>30 days after the last dose of pembrolizumab until disease progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. Median duration of follow-up was 8.3 months (95% CI 3.0-10.1 months).</time_frame>
    <description>Clinical benefit rate of ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Computed Tomography-based Response of a Non-target Lesion</measure>
    <time_frame>baseline and 30 days after the last dose of pembrolizumab</time_frame>
    <description>Measure the computed tomography-based response (RECIST 1.1) of a non-target lesion to ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in Immunohistochemical Expression of Tumor-infiltrating Lymphocytes in Tumor Biopsy Tissues</measure>
    <time_frame>baseline and 30 days after the last dose of pembrolizumab</time_frame>
    <description>Measure the change in immunohistochemical expression of tumor-infiltrating lymphocytes in tumor biopsy tissues in response to ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">57</enrollment>
  <condition>Metastatic Non-small Cell Lung Cancer</condition>
  <condition>Metastatic Triple-negative Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Single arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>ADV/HSV-tk (5 x 1011 virus particles) in a 2-mL total volume will be injected intratumorally on Day 0.&#xD;
Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days from Day 1 to Day 15.&#xD;
SBRT of 30 Gy (6 Gy X 5 fractions) will be administered over 2 weeks from Day 2 to Day 16.&#xD;
Pembrolizumab (200 mg) will be administered intravenously over 30 minutes every 3 weeks starting on Day 17 and continuing until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>ADV/HSV-tk</intervention_name>
    <description>Replication-defective recombinant adenovirus vector</description>
    <arm_group_label>Single arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Valacyclovir</intervention_name>
    <description>Prodrug of the antiviral drug acyclovir</description>
    <arm_group_label>Single arm</arm_group_label>
    <other_name>valacyclovir hydrochloride</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>SBRT</intervention_name>
    <description>Low-dose SBRT</description>
    <arm_group_label>Single arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>Humanized immunoglobulin G4 anti-programmed death-1 (PD-1) monoclonal antibody</description>
    <arm_group_label>Single arm</arm_group_label>
    <other_name>Keytruda</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Willing and able to provide written informed consent/assent for the trial.&#xD;
&#xD;
          2. Male or female aged ≥18 years on the day of informed consent signing.&#xD;
&#xD;
          3. Histologically confirmed locally advanced or metastatic TNBC that has relapsed on or&#xD;
             is refractory to standard of care therapy OR histologically or cytologically confirmed&#xD;
             metastatic NSCLC that is immunotherapy and chemotherapy naïve or previously treated&#xD;
             with 1 cycle of platinum-containing chemotherapy. Epidermal growth factor receptor&#xD;
             (EGFR)/anaplastic lymphoma kinase (ALK) mutation-negative NSCLC patients and NSCLC&#xD;
             patients with EGFR or ALK genomic tumor aberrations that have failed FDA-approved&#xD;
             targeted therapy for these aberrations will be eligible for enrollment in the study.&#xD;
&#xD;
          4. Measurable disease based on RECIST 1.1, a target lesion of suitable diameter (at least&#xD;
             1 cm) for SBRT, and a non-target lesion (visceral metastatic lesion) at least 1 cm in&#xD;
             diameter for abscopal effect evaluation.&#xD;
&#xD;
          5. Willing to provide biopsy tissues as required by the study.&#xD;
&#xD;
          6. Eastern Cooperative Oncology Group performance status of 0 or 1.&#xD;
&#xD;
          7. Adequate organ function as defined by the following laboratory values:&#xD;
&#xD;
               -  Absolute neutrophil count ≥1,500/µL (without granulocyte colony stimulating&#xD;
                  factor support within 14 days of assessment)&#xD;
&#xD;
               -  Platelets ≥100,000/µL&#xD;
&#xD;
               -  Hemoglobin ≥8 g/dL or ≥5.6 mmol/L without transfusion or erythropoietin&#xD;
                  dependency (within 7 days of assessment)&#xD;
&#xD;
               -  White blood cell count &gt;2,500/µL and &lt;15,000/µL&#xD;
&#xD;
               -  Lymphocyte count ≥500/µL&#xD;
&#xD;
               -  Serum creatinine &lt;2 X upper limit of normal (ULN)&#xD;
&#xD;
               -  Serum total bilirubin ≤1.0 X ULN (Subjects with known Gilbert's disease who have&#xD;
                  serum bilirubin level ≤3 X ULN may be enrolled)&#xD;
&#xD;
               -  Asparate transaminase and alanine transaminase ≤2.5 X ULN with normal alkaline&#xD;
                  phosphatase (≤5 X ULN for subjects with liver metastases) OR ≤1.5 X ULN in&#xD;
                  conjunction with alkaline phosphatase &gt;2.5 X ULN&#xD;
&#xD;
               -  Albumin &gt;2.5 mg/dL&#xD;
&#xD;
               -  International normalized ratio or prothrombin time (PT) ≤1.5 X ULN unless subject&#xD;
                  is receiving anticoagulant therapy as long as PT or activated partial&#xD;
                  thromboplastin time (aPTT) is within therapeutic range of intended use of&#xD;
                  anticoagulants&#xD;
&#xD;
               -  aPTT ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT&#xD;
                  or aPTT is within therapeutic range of intended use of anticoagulants&#xD;
&#xD;
          8. Life expectancy ≥ 6 months.&#xD;
&#xD;
          9. ≥ 4 weeks since any major surgery, completion of radiation therapy, or completion of&#xD;
             all prior systemic anticancer therapy (adequately recovered from the acute toxicities&#xD;
             of any prior therapy).&#xD;
&#xD;
         10. Female subjects of childbearing potential should have a negative serum pregnancy&#xD;
             (beta-human chorionic gonadotropin) within 7 days prior to receiving the first dose of&#xD;
             the trial treatment and should not be lactating.&#xD;
&#xD;
         11. Female subjects of childbearing potential must be willing to use an adequate method of&#xD;
             contraception for the course of the study through 120 days after the last dose of&#xD;
             study therapy.&#xD;
&#xD;
         12. Male subjects of childbearing potential must agree to use an adequate method of&#xD;
             contraception for the course of the study through 120 days after the last dose of&#xD;
             study therapy.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Unwilling or unable to comply with the study protocol.&#xD;
&#xD;
          2. Subjects for who bone metastases are the only available non-target lesions for&#xD;
             abscopal effect evaluation.&#xD;
&#xD;
          3. Subjects with tumors for which SBRT is not considered appropriate standard therapy.&#xD;
             This includes subjects with target lesions less than 1 cm in diameter and those with&#xD;
             large central lung lesions.&#xD;
&#xD;
          4. 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 trial treatment.&#xD;
&#xD;
          5. 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;
          6. Known history of active tuberculosis (Bacillus Tuberculosis).&#xD;
&#xD;
          7. Known or suspected hypersensitivity to pembrolizumab or any of its excipients or any&#xD;
             component of the proposed regimen (gene vector/valacyclovir).&#xD;
&#xD;
          8. Known gallbladder or bile duct disease (i.e., infection or cholecystitis) or acute or&#xD;
             chronic pancreatitis.&#xD;
&#xD;
          9. Eastern Cooperative Oncology Group performance status of ≥2 or oxygen dependence&#xD;
             (e.g., advanced chronic obstructive pulmonary disease).&#xD;
&#xD;
         10. Inability to swallow food or any condition of the upper gastrointestinal tract that&#xD;
             precludes administration of oral medications (valacyclovir).&#xD;
&#xD;
         11. Congestive heart failure: New York Association class III or IV heart failure or&#xD;
             unstable angina.&#xD;
&#xD;
         12. Sustained or clinically significant cardiac arrhythmias including sustained&#xD;
             ventricular tachycardia, ventricular fibrillation, clinically significant bradycardia,&#xD;
             advanced heart block (Mobitz II or higher atrioventricular nodal block), prolonged&#xD;
             corrected QT interval (longer than 470 milliseconds), or history of acute myocardial&#xD;
             infarction.&#xD;
&#xD;
         13. Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by&#xD;
             diabetes or Parkinson's disease), human immunodeficiency virus (HIV), cirrhosis,&#xD;
             uncontrolled hypothyroidism, or cardiac failure.&#xD;
&#xD;
         14. History of syncope or family history of idiopathic sudden death.&#xD;
&#xD;
         15. Targeted small molecule therapy or monoclonal antibody or radiation therapy within 3&#xD;
             weeks prior to study Day 0 or has not recovered (i.e., ≤ Grade 1 or at baseline) from&#xD;
             adverse events due to a previously administered agent.&#xD;
&#xD;
             - Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may&#xD;
             qualify for the study.&#xD;
&#xD;
         16. 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;
         17. Known active central nervous system metastases and/or carcinomatous meningitis.&#xD;
             Subjects with previously treated brain metastases may participate provided they are&#xD;
             stable (without evidence of progression by imaging for at least 4 weeks prior to the&#xD;
             first dose of trial treatment and any neurologic symptoms have returned to baseline),&#xD;
             have no evidence of new or enlarging brain metastases, and are not using steroids for&#xD;
             at least 7 days prior to trial treatment. This exception does not include&#xD;
             carcinomatous meningitis, which is excluded regardless of clinical stability.&#xD;
&#xD;
         18. 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). Replacement therapy (e.g., 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;
         19. History of (non-infectious) pneumonitis that required steroids or current pneumonitis.&#xD;
&#xD;
         20. Active infection requiring systemic therapy.&#xD;
&#xD;
         21. 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;
         22. Known psychiatric or substance abuse disorders that would interfere with cooperation&#xD;
             with the requirements of the trial.&#xD;
&#xD;
         23. Pregnant or breastfeeding, expecting to conceive or father children within the&#xD;
             projected duration of the trial, starting with the prescreening or screening visit&#xD;
             through 120 days after the last dose of trial treatment, or is unwilling to practice&#xD;
             an effective method of birth control. Women of childbearing potential must have a&#xD;
             negative serum pregnancy test within 7 days prior to administration of trial&#xD;
             treatment.&#xD;
&#xD;
         24. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent (TNBC cohort only).&#xD;
&#xD;
         25. Prior treatment with immunomodulatory therapy or immunotherapy (TNBC cohort only).&#xD;
&#xD;
         26. Prior treatment with gene vector therapy.&#xD;
&#xD;
         27. Received prior systemic cytotoxic chemotherapy for metastatic disease (NSCLC cohort).&#xD;
&#xD;
         28. Known history of HIV (HIV 1/2 antibodies).&#xD;
&#xD;
         29. History of liver disease such as cirrhosis or known active hepatitis B (e.g.,&#xD;
             hepatitis B surface antigen reactive) or hepatitis C (e.g., hepatitis C virus RNA&#xD;
             [qualitative] is detected).&#xD;
&#xD;
         30. History of or current alcohol misuse/abuse within the past 12 months.&#xD;
&#xD;
         31. Major surgery within 4 weeks prior to study enrollment.&#xD;
&#xD;
         32. Received a live vaccine within 30 days of planned start of trial 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;
      </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>Jenny Chang, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Houston Methodist Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Houston Methodist 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>December 2022</verification_date>
  <study_first_submitted>December 20, 2016</study_first_submitted>
  <study_first_submitted_qc>December 22, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 28, 2016</study_first_posted>
  <results_first_submitted>August 30, 2022</results_first_submitted>
  <results_first_submitted_qc>December 28, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">January 25, 2023</results_first_posted>
  <last_update_submitted>December 28, 2022</last_update_submitted>
  <last_update_submitted_qc>December 28, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">January 25, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The Methodist Hospital Research Institute</investigator_affiliation>
    <investigator_full_name>Jenny C. Chang, MD</investigator_full_name>
    <investigator_title>Director of the Houston Methodist Cancer Center</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Lung Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
    <mesh_term>Triple Negative Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Valacyclovir</mesh_term>
    <mesh_term>Pembrolizumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Data and materials on human subjects will be shared with other eligible investigators through appropriate means in accordance with the NIH policy on Sharing Research Data (NIH Guide, February 26, 2003). Data will be also shared with the funding agency and regulatory agencies as required. Data will be shared with other investigators within the limits of HIPAA and other patient confidentiality requirements. This will generally require removal of all patient identifiers for all source documents and the use of arbitrarily assigned one-way identifiers. In some cases, requestors will be asked to sign a formal data sharing agreement that will provide for a commitment to use data only for research purposes and not to identify individuals, keep the data secure, and destroy or return data after analyses are complete. Prior approval will be obtained from collaborating investigators, research sponsors, and/or other stake-holders before sharing if proprietary information or products are involved.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_time_frame>During and/or after result submission.</ipd_time_frame>
    <ipd_access_criteria>The study protocol will be included on clinicaltrials.gov</ipd_access_criteria>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>September 25, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/83/NCT03004183/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>57 overall participants (28 TNBC and 29 NSCLS)</recruitment_details>
      <pre_assignment_details>The Triple Negative Breast Cancer (TNBC) patients with histologically confirmed locally advanced or metastatic TNBC that has relapsed or is refractory to ≥1 lines of standard of care therapy. The Non-Small Cell Lung Cancer (NSCLC) cohort will include male &amp; female patients with confirmed metastatic NSCLC that is immunotherapy naïve or previously treated with a maximum of 1 immunotherapy regimen &amp; chemotherapy naïve or previously treated with 1 cycle of platinum-containing chemotherapy.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Single Arm</title>
          <description>ADV/HSV-tk (5 x 1011 virus particles) in a 2-mL total volume will be injected intratumorally on Day 0.&#xD;
Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days from Day 1 to Day 15.&#xD;
SBRT of 30 Gy (6 Gy X 5 fractions) will be administered over 2 weeks from Day 2 to Day 16.&#xD;
Pembrolizumab (200 mg) will be administered intravenously over 30 minutes every 3 weeks starting on Day 17 and continuing until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.&#xD;
ADV/HSV-tk: Replication-defective recombinant adenovirus vector&#xD;
Valacyclovir: Prodrug of the antiviral drug acyclovir&#xD;
SBRT: Low-dose SBRT&#xD;
Pembrolizumab: Humanized immunoglobulin G4 anti-programmed death-1 (PD-1) monoclonal antibody</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="57"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>TNBC</title>
              <participants_list>
                <participants group_id="P1" count="28"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NSCLC</title>
              <participants_list>
                <participants group_id="P1" count="29"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7">1 TNBC and 6 NSCLC</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="50"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="40"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>COVID-19</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>There are 57 total patients enrolled in this trial, the results are based on a total of 56 patients (28 TNBC and 28 NSCLC evaluable patients).</population>
      <group_list>
        <group group_id="B1">
          <title>Single Arm</title>
          <description>ADV/HSV-tk (5 x 1011 virus particles) in a 2-mL total volume will be injected intratumorally on Day 0.&#xD;
Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days from Day 1 to Day 15.&#xD;
SBRT of 30 Gy (6 Gy X 5 fractions) will be administered over 2 weeks from Day 2 to Day 16.&#xD;
Pembrolizumab (200 mg) will be administered intravenously over 30 minutes every 3 weeks starting on Day 17 and continuing until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.&#xD;
ADV/HSV-tk: Replication-defective recombinant adenovirus vector&#xD;
Valacyclovir: Prodrug of the antiviral drug acyclovir&#xD;
SBRT: Low-dose SBRT&#xD;
Pembrolizumab: Humanized immunoglobulin G4 anti-programmed death-1 (PD-1) monoclonal antibody</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="56"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <population>The results are distributed based on a total of 56 patients, 28 TNBC and 28 NSCLC evaluable patients.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Overall</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="56"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="32"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TNBC</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="28"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="24"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>NSCLC</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="28"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <population>The results are distributed based on a total of 56 patients, 28 TNBC and 28 NSCLC evaluable patients.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Overall</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="56"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="40"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TNBC</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="28"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="28"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>NSCLC</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="28"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <population>The results are distributed based on a total of 56 patients, 28 TNBC and 28 NSCLC evaluable patients.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Overall</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="56"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="52"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TNBC</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="28"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="25"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>NSCLC</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="28"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="27"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <population>The results are distributed based on a total of 56 patients, 28 TNBC and 28 NSCLC evaluable patients.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Overall</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="56"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="41"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TNBC</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="28"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>NSCLC</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="28"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="23"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>TNBC and NSCLC patient distribution</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="56"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>TNBC</title>
                  <measurement_list>
                    <measurement group_id="B1" value="28"/>
                  </measurement_list>
                </category>
                <category>
                  <title>NSLC</title>
                  <measurement_list>
                    <measurement group_id="B1" value="28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Objective Response Rate</title>
        <description>The objective response rate (ORR) of ADV/HSV-tk plus (+) valacyclovir therapy in combination with SBRT used as a window of opportunity treatment before pembrolizumab in patients with metastatic TNBC and metastatic NSCLC. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be used to assess treatment response. Modified immune-related response criteria (irRC; derived from RECIST 1.1) will also be documented.</description>
        <time_frame>30 days after the last dose of pembrolizumab until disease progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. Median duration of follow-up was 8.3 months (95% CI 3.0-10.1 months).</time_frame>
        <population>A total of 56 patient's data was analyzed, 28 patients with mTNBC and 28 patients with NSCLC.</population>
        <group_list>
          <group group_id="O1">
            <title>Single Arm</title>
            <description>ADV/HSV-tk (5 x 1011 virus particles) in a 2-mL total volume will be injected intratumorally on Day 0.&#xD;
Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days from Day 1 to Day 15.&#xD;
SBRT of 30 Gy (6 Gy X 5 fractions) will be administered over 2 weeks from Day 2 to Day 16.&#xD;
Pembrolizumab (200 mg) will be administered intravenously over 30 minutes every 3 weeks starting on Day 17 and continuing until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.&#xD;
ADV/HSV-tk: Replication-defective recombinant adenovirus vector&#xD;
Valacyclovir: Prodrug of the antiviral drug acyclovir&#xD;
SBRT: Low-dose SBRT&#xD;
Pembrolizumab: Humanized immunoglobulin G4 anti-programmed death-1 (PD-1) monoclonal antibody</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response Rate</title>
          <description>The objective response rate (ORR) of ADV/HSV-tk plus (+) valacyclovir therapy in combination with SBRT used as a window of opportunity treatment before pembrolizumab in patients with metastatic TNBC and metastatic NSCLC. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be used to assess treatment response. Modified immune-related response criteria (irRC; derived from RECIST 1.1) will also be documented.</description>
          <population>A total of 56 patient's data was analyzed, 28 patients with mTNBC and 28 patients with NSCLC.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="56"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Overall</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="56"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Complete Response</title>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Partial Response</title>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Stable Diseases</title>
                  <measurement_list>
                    <measurement group_id="O1" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Progressive Disease</title>
                  <measurement_list>
                    <measurement group_id="O1" value="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TNBC</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="28"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Complete Response</title>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Partial Response</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Stable Diseases</title>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Progressive Disease</title>
                  <measurement_list>
                    <measurement group_id="O1" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>NSCLC</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="28"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Complete Response</title>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Partial Response</title>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Stable Diseases</title>
                  <measurement_list>
                    <measurement group_id="O1" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Progressive Disease</title>
                  <measurement_list>
                    <measurement group_id="O1" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Duration of Response</title>
        <description>Duration of response to ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab</description>
        <time_frame>30 days after the last dose of pembrolizumab until disease progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. Median duration of follow-up was 8.3 months (95% CI 3.0-10.1 months).</time_frame>
        <population>Median duration of response from last line of treatment (range), months</population>
        <group_list>
          <group group_id="O1">
            <title>Single Arm</title>
            <description>ADV/HSV-tk (5 x 1011 virus particles) in a 2-mL total volume will be injected intratumorally on Day 0.&#xD;
Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days from Day 1 to Day 15.&#xD;
SBRT of 30 Gy (6 Gy X 5 fractions) will be administered over 2 weeks from Day 2 to Day 16.&#xD;
Pembrolizumab (200 mg) will be administered intravenously over 30 minutes every 3 weeks starting on Day 17 and continuing until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.&#xD;
ADV/HSV-tk: Replication-defective recombinant adenovirus vector&#xD;
Valacyclovir: Prodrug of the antiviral drug acyclovir&#xD;
SBRT: Low-dose SBRT&#xD;
Pembrolizumab: Humanized immunoglobulin G4 anti-programmed death-1 (PD-1) monoclonal antibody</description>
          </group>
        </group_list>
        <measure>
          <title>Duration of Response</title>
          <description>Duration of response to ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab</description>
          <population>Median duration of response from last line of treatment (range), months</population>
          <units>Months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="56"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>TNBC</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="28"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2" lower_limit="1" upper_limit="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>NSCLC</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="28"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.5" lower_limit="0" upper_limit="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival Rate</title>
        <description>Overall survival (OS) rate in subjects receiving ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab. OS is the time (measured in months) from intratumoral viral injection to death or last date of contact.</description>
        <time_frame>After confirmed disease progression or starts a new therapy, the subject moves into the Survival Follow-up to be contacted every 12 weeks to assess for survival status until death, withdrawal, or end of study. Median duration of follow-up was 8.3 months.</time_frame>
        <population>Median overall survival for all patient and for patients with clinical benefit</population>
        <group_list>
          <group group_id="O1">
            <title>Single Arm</title>
            <description>ADV/HSV-tk (5 x 1011 virus particles) in a 2-mL total volume will be injected intratumorally on Day 0.&#xD;
Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days from Day 1 to Day 15.&#xD;
SBRT of 30 Gy (6 Gy X 5 fractions) will be administered over 2 weeks from Day 2 to Day 16.&#xD;
Pembrolizumab (200 mg) will be administered intravenously over 30 minutes every 3 weeks starting on Day 17 and continuing until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.&#xD;
ADV/HSV-tk: Replication-defective recombinant adenovirus vector&#xD;
Valacyclovir: Prodrug of the antiviral drug acyclovir&#xD;
SBRT: Low-dose SBRT&#xD;
Pembrolizumab: Humanized immunoglobulin G4 anti-programmed death-1 (PD-1) monoclonal antibody</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival Rate</title>
          <description>Overall survival (OS) rate in subjects receiving ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab. OS is the time (measured in months) from intratumoral viral injection to death or last date of contact.</description>
          <population>Median overall survival for all patient and for patients with clinical benefit</population>
          <units>Months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="56"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>TNBC</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="28"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.6" lower_limit="0" upper_limit="50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>NSCLC</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="28"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.9" lower_limit="0" upper_limit="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression-free Survival Rate</title>
        <description>Progression-free survival rate in subjects receiving ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab</description>
        <time_frame>Subjects in the follow up phase will be assessed every 6 weeks (42 ± 7 days) by radiologic imaging to monitor disease status. After 1 year, the imaging time point will occur every 9 weeks (± 7 days).</time_frame>
        <posting_date>12/2023</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Treatment-related Adverse Events</title>
        <description>To document the toxicities associated with ADV/HSV-tk + valacyclovir therapy in combination with SBRT used as a window of opportunity treatment before pembrolizumab in patients with metastatic TNBC and metastatic NSCLC. Toxicity will be defined as the number of participants with any treatment-related death or any ≥ Grade 3 hematological toxicity excluding alopecia and constitutional symptoms, as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03.</description>
        <time_frame>Adverse Events (AEs) and Serious Adverse Events (SAEs) will be captured from the time of informed consent signing up to 30 days after the final dose of pembrolizumab, (up to 24 months of treatment for patients without disease progression).</time_frame>
        <population>The results are distributed based on a total of 56 patients, 28 TNBC and 28 NSCLC evaluable patients.</population>
        <group_list>
          <group group_id="O1">
            <title>Single Arm</title>
            <description>ADV/HSV-tk (5 x 1011 virus particles) in a 2-mL total volume will be injected intratumorally on Day 0.&#xD;
Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days from Day 1 to Day 15.&#xD;
SBRT of 30 Gy (6 Gy X 5 fractions) will be administered over 2 weeks from Day 2 to Day 16.&#xD;
Pembrolizumab (200 mg) will be administered intravenously over 30 minutes every 3 weeks starting on Day 17 and continuing until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.&#xD;
ADV/HSV-tk: Replication-defective recombinant adenovirus vector&#xD;
Valacyclovir: Prodrug of the antiviral drug acyclovir&#xD;
SBRT: Low-dose SBRT&#xD;
Pembrolizumab: Humanized immunoglobulin G4 anti-programmed death-1 (PD-1) monoclonal antibody</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Treatment-related Adverse Events</title>
          <description>To document the toxicities associated with ADV/HSV-tk + valacyclovir therapy in combination with SBRT used as a window of opportunity treatment before pembrolizumab in patients with metastatic TNBC and metastatic NSCLC. Toxicity will be defined as the number of participants with any treatment-related death or any ≥ Grade 3 hematological toxicity excluding alopecia and constitutional symptoms, as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03.</description>
          <population>The results are distributed based on a total of 56 patients, 28 TNBC and 28 NSCLC evaluable patients.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="56"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Total with Related SAE</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="56"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TNBC</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="28"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>NSCLC</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="28"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Antitumor Activity</title>
        <description>Measure the antitumor activity as assessed by RECIST 1.1. Modified immune-related response criteria will also be documented.</description>
        <time_frame>30 days after the last dose of pembrolizumab</time_frame>
        <population>At this point in the data analysis has not been completed, information will be updated as it becomes available.</population>
        <group_list>
          <group group_id="O1">
            <title>Single Arm</title>
            <description>ADV/HSV-tk (5 x 1011 virus particles) in a 2-mL total volume will be injected intratumorally on Day 0.&#xD;
Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days from Day 1 to Day 15.&#xD;
SBRT of 30 Gy (6 Gy X 5 fractions) will be administered over 2 weeks from Day 2 to Day 16.&#xD;
Pembrolizumab (200 mg) will be administered intravenously over 30 minutes every 3 weeks starting on Day 17 and continuing until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.&#xD;
ADV/HSV-tk: Replication-defective recombinant adenovirus vector&#xD;
Valacyclovir: Prodrug of the antiviral drug acyclovir&#xD;
SBRT: Low-dose SBRT&#xD;
Pembrolizumab: Humanized immunoglobulin G4 anti-programmed death-1 (PD-1) monoclonal antibody</description>
          </group>
        </group_list>
        <measure>
          <title>Antitumor Activity</title>
          <description>Measure the antitumor activity as assessed by RECIST 1.1. Modified immune-related response criteria will also be documented.</description>
          <population>At this point in the data analysis has not been completed, information will be updated as it becomes available.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="56"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Overall</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="56"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Complete Response</title>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Partial Response</title>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Stable Diseases</title>
                  <measurement_list>
                    <measurement group_id="O1" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Progressive Disease</title>
                  <measurement_list>
                    <measurement group_id="O1" value="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TNBC</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="28"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Complete Response</title>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Partial Response</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Stable Diseases</title>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Progressive Disease</title>
                  <measurement_list>
                    <measurement group_id="O1" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>NSCLS</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="28"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Complete Response</title>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Partial Response</title>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Stable Diseases</title>
                  <measurement_list>
                    <measurement group_id="O1" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Progressive Disease</title>
                  <measurement_list>
                    <measurement group_id="O1" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clinical Benefit Rate</title>
        <description>Clinical benefit rate of ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab</description>
        <time_frame>30 days after the last dose of pembrolizumab until disease progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. Median duration of follow-up was 8.3 months (95% CI 3.0-10.1 months).</time_frame>
        <population>The Clinical Benefit Rate measured as Complete Response plus Partial Response plus Stable Disease</population>
        <group_list>
          <group group_id="O1">
            <title>Single Arm</title>
            <description>ADV/HSV-tk (5 x 1011 virus particles) in a 2-mL total volume will be injected intratumorally on Day 0.&#xD;
Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days from Day 1 to Day 15.&#xD;
SBRT of 30 Gy (6 Gy X 5 fractions) will be administered over 2 weeks from Day 2 to Day 16.&#xD;
Pembrolizumab (200 mg) will be administered intravenously over 30 minutes every 3 weeks starting on Day 17 and continuing until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.&#xD;
ADV/HSV-tk: Replication-defective recombinant adenovirus vector&#xD;
Valacyclovir: Prodrug of the antiviral drug acyclovir&#xD;
SBRT: Low-dose SBRT&#xD;
Pembrolizumab: Humanized immunoglobulin G4 anti-programmed death-1 (PD-1) monoclonal antibody</description>
          </group>
        </group_list>
        <measure>
          <title>Clinical Benefit Rate</title>
          <description>Clinical benefit rate of ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab</description>
          <population>The Clinical Benefit Rate measured as Complete Response plus Partial Response plus Stable Disease</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="56"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Overall</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="56"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TNBC</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="28"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>NSCLC</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="28"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Computed Tomography-based Response of a Non-target Lesion</title>
        <description>Measure the computed tomography-based response (RECIST 1.1) of a non-target lesion to ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab</description>
        <time_frame>baseline and 30 days after the last dose of pembrolizumab</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Change in Immunohistochemical Expression of Tumor-infiltrating Lymphocytes in Tumor Biopsy Tissues</title>
        <description>Measure the change in immunohistochemical expression of tumor-infiltrating lymphocytes in tumor biopsy tissues in response to ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab</description>
        <time_frame>baseline and 30 days after the last dose of pembrolizumab</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>AEs and SAEs will be captured from the time of informed consent signing up to 30 days after the final dose of pembrolizumab. Study treatment-related SAEs and any study patient death occurring beyond 30 days after the last dose of pembrolizumab should also be reported. Patients will be treated until disease progression, unacceptable toxicity, or up to 24 months in subjects without disease progression.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Single Arm</title>
          <description>ADV/HSV-tk (5 x 1011 virus particles) in a 2-mL total volume will be injected intratumorally on Day 0.&#xD;
Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days from Day 1 to Day 15.&#xD;
SBRT of 30 Gy (6 Gy X 5 fractions) will be administered over 2 weeks from Day 2 to Day 16.&#xD;
Pembrolizumab (200 mg) will be administered intravenously over 30 minutes every 3 weeks starting on Day 17 and continuing until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.&#xD;
ADV/HSV-tk: Replication-defective recombinant adenovirus vector&#xD;
Valacyclovir: Prodrug of the antiviral drug acyclovir&#xD;
SBRT: Low-dose SBRT&#xD;
Pembrolizumab: Humanized immunoglobulin G4 anti-programmed death-1 (PD-1) monoclonal antibody</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="29" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation with rapid ventricular response</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>colitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Malnutrition, Hypercalcemia and Weakness</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Intractable pain, back pain, hip pain</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Kidney Injury and/or Infection</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pneumothorax</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Shortness of Breath</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Skin rash</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="28" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="12" subjects_affected="12" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Activated partial thromboplastin time prolonged</sub_title>
                <counts group_id="E1" events="10" subjects_affected="3" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Weight Loss</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Jenny C Chang, MD</name_or_title>
      <organization>Houston Methodist Cancer Center</organization>
      <phone>713-441-0629</phone>
      <email>ccresearch@houstonmethodist.org</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03004183
org study id: Pro00015649
nct id: NCT03004183
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This is a Phase II trial to determine the efficacy and safety of stereotactic body radiation
      therapy (SBRT) and in situ oncolytic virus therapy used as a window of opportunity treatment
      before pembrolizumab in patients with metastatic triple negative breast cancer (TNBC) and
      metastatic non-small cell lung cancer (NSCLC). In situ oncolytic virus therapy will consist
      of adenovirus-mediated expression of herpes simplex virus thymidine kinase (ADV/HSV-tk) plus
      valacyclovir therapy.
This is a Phase II trial to determine the efficacy and safety of stereotactic body radiation
      therapy (SBRT) and in situ oncolytic virus therapy used as a window of opportunity treatment
      before pembrolizumab in patients with metastatic triple negative breast cancer (TNBC) and
      metastatic non-small cell lung cancer (NSCLC). In situ oncolytic virus therapy will consist
      of adenovirus-mediated expression of herpes simplex virus thymidine kinase (ADV/HSV-tk) plus
      valacyclovir. Male and female patients aged ≥ 18 years with histologically confirmed locally
      advanced or metastatic TNBC that has relapsed on or is refractory to 1 or more lines of
      standard of care therapy or histologically or cytologically confirmed metastatic NSCLC that
      is immunotherapy and chemotherapy naïve or previously treated with 1 cycle of
      platinum-containing chemotherapy are eligible to participate in the study. ADV/HSV-tk (5 x
      1011 viral particles) in a 2-mL total volume will be injected intratumorally on Day 0 of the
      study. Valacyclovir will be orally administered at a dose of 2 g three times daily for 14
      days. Valacyclovir treatment will be administered 24 hours after the gene vector injection
      from Day 1 to Day 15 of the study. SBRT of 30 gray (Gy; 6 Gy X 5 fractions) will be
      administered over 2 weeks from Day 2 to Day 16 of the study. Pembrolizumab (200 mg) will be
      administered intravenously over 30 minutes every 3 weeks starting on Day 17 of the study and
      continuing until disease progression, unacceptable toxicity, or up to 24 months in patients
      without disease progression. The primary endpoint will be the objective response rate of
      ADV/HSV-tk + valacyclovir therapy in combination with SBRT used as a window of opportunity
      treatment before pembrolizumab in patients with metastatic TNBC and metastatic NSCLC. RECIST
      1.1 will be used to assess treatment response. Secondary endpoints will include a) clinical
      benefit rate; b) duration of response; c) overall survival and progression-free survival
      rates; d) toxicity (toxicity will be defined as any treatment-related death or any ≥ grade 3
      toxicity excluding alopecia and constitutional symptoms as assessed by the NCI CTCAE v4.03);
      and e) antitumor activity of ADV/HSV-tk plus valacyclovir therapy in combination with SBRT
      used as a window of opportunity treatment before pembrolizumab.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Objective Response Rate
time frame: 30 days after the last dose of pembrolizumab until disease progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. Median duration of follow-up was 8.3 months (95% CI 3.0-10.1 months).
description: The objective response rate (ORR) of ADV/HSV-tk plus (+) valacyclovir therapy in combination with SBRT used as a window of opportunity treatment before pembrolizumab in patients with metastatic TNBC and metastatic NSCLC. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be used to assess treatment response. Modified immune-related response criteria (irRC; derived from RECIST 1.1) will also be documented.
measure: Duration of Response
time frame: 30 days after the last dose of pembrolizumab until disease progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. Median duration of follow-up was 8.3 months (95% CI 3.0-10.1 months).
description: Duration of response to ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab
measure: Overall Survival Rate
time frame: After confirmed disease progression or starts a new therapy, the subject moves into the Survival Follow-up to be contacted every 12 weeks to assess for survival status until death, withdrawal, or end of study. Median duration of follow-up was 8.3 months.
description: Overall survival (OS) rate in subjects receiving ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab. OS is the time (measured in months) from intratumoral viral injection to death or last date of contact.
measure: Progression-free Survival Rate
time frame: Subjects in the follow up phase will be assessed every 6 weeks (42 ± 7 days) by radiologic imaging to monitor disease status. After 1 year, the imaging time point will occur every 9 weeks (± 7 days).
description: Progression-free survival rate in subjects receiving ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab
measure: Number of Participants With Treatment-related Adverse Events
time frame: Adverse Events (AEs) and Serious Adverse Events (SAEs) will be captured from the time of informed consent signing up to 30 days after the final dose of pembrolizumab, (up to 24 months of treatment for patients without disease progression).
description: To document the toxicities associated with ADV/HSV-tk + valacyclovir therapy in combination with SBRT used as a window of opportunity treatment before pembrolizumab in patients with metastatic TNBC and metastatic NSCLC. Toxicity will be defined as the number of participants with any treatment-related death or any ≥ Grade 3 hematological toxicity excluding alopecia and constitutional symptoms, as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03.
measure: Antitumor Activity
time frame: 30 days after the last dose of pembrolizumab
description: Measure the antitumor activity as assessed by RECIST 1.1. Modified immune-related response criteria will also be documented.
measure: Clinical Benefit Rate
time frame: 30 days after the last dose of pembrolizumab until disease progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. Median duration of follow-up was 8.3 months (95% CI 3.0-10.1 months).
description: Clinical benefit rate of ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab
measure: Computed Tomography-based Response of a Non-target Lesion
time frame: baseline and 30 days after the last dose of pembrolizumab
description: Measure the computed tomography-based response (RECIST 1.1) of a non-target lesion to ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab
measure: Change in Immunohistochemical Expression of Tumor-infiltrating Lymphocytes in Tumor Biopsy Tissues
time frame: baseline and 30 days after the last dose of pembrolizumab
description: Measure the change in immunohistochemical expression of tumor-infiltrating lymphocytes in tumor biopsy tissues in response to ADV/HSV-tk plus valacyclovir therapy in combination with SBRT followed by pembrolizumab
arm group label: Single arm
arm group type: Experimental
description: ADV/HSV-tk (5 x 1011 virus particles) in a 2-mL total volume will be injected intratumorally on Day 0.
Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days from Day 1 to Day 15.
SBRT of 30 Gy (6 Gy X 5 fractions) will be administered over 2 weeks from Day 2 to Day 16.
Pembrolizumab (200 mg) will be administered intravenously over 30 minutes every 3 weeks starting on Day 17 and continuing until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
intervention type: Biological
intervention name: ADV/HSV-tk
description: Replication-defective recombinant adenovirus vector
arm group label: Single arm
intervention type: Drug
intervention name: Valacyclovir
description: Prodrug of the antiviral drug acyclovir
arm group label: Single arm
other name: valacyclovir hydrochloride
intervention type: Radiation
intervention name: SBRT
description: Low-dose SBRT
arm group label: Single arm
intervention type: Drug
intervention name: Pembrolizumab
description: Humanized immunoglobulin G4 anti-programmed death-1 (PD-1) monoclonal antibody
arm group label: Single arm
other name: Keytruda
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jenny Chang, MD
role: Principal Investigator
affiliation: Houston Methodist Cancer Center
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: The Methodist Hospital Research Institute
investigator full name: Jenny C. Chang, MD
investigator title: Director of the Houston Methodist Cancer Center
mesh term: Breast Neoplasms
mesh term: Lung Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Triple Negative Breast Neoplasms
mesh term: Valacyclovir
mesh term: Pembrolizumab
sharing ipd: Yes
ipd description: Data and materials on human subjects will be shared with other eligible investigators through appropriate means in accordance with the NIH policy on Sharing Research Data (NIH Guide, February 26, 2003). Data will be also shared with the funding agency and regulatory agencies as required. Data will be shared with other investigators within the limits of HIPAA and other patient confidentiality requirements. This will generally require removal of all patient identifiers for all source documents and the use of arbitrarily assigned one-way identifiers. In some cases, requestors will be asked to sign a formal data sharing agreement that will provide for a commitment to use data only for research purposes and not to identify individuals, keep the data secure, and destroy or return data after analyses are complete. Prior approval will be obtained from collaborating investigators, research sponsors, and/or other stake-holders before sharing if proprietary information or products are involved.
ipd info type: Study Protocol
ipd time frame: During and/or after result submission.
ipd access criteria: The study protocol will be included on clinicaltrials.gov
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 