<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/NCT02987166</url>
  </required_header>
  <id_info>
    <org_study_id>18488</org_study_id>
    <nct_id>NCT02987166</nct_id>
  </id_info>
  <brief_title>HDCRT Plus Pembrolizumab in Advanced Malignancies</brief_title>
  <acronym>UVA-AM-001</acronym>
  <official_title>A Pilot Study to Assess the Combination of High-Dose Conformal Radiation Therapy (HDCRT) and Pembrolizumab in Modulating Local and Systemic T-cell Responses in Advanced Malignancies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>James Larner, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Virginia</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is a pilot study to evaluate high-dose conformal radiation therapy (HDCRT)&#xD;
      administered in combination with pembrolizumab in patients with solid tumors.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 21, 2017</start_date>
  <completion_date type="Actual">February 10, 2020</completion_date>
  <primary_completion_date type="Actual">January 13, 2020</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety: adverse event profile</measure>
    <time_frame>30 days post-treatment for adverse events; 90 days post-treatment for serious adverse events</time_frame>
    <description>Obtain preliminary data on the safety of HDCRT with immunotherapy, delivered concurrently (Arm A) or sequentially (Arms B and C)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Immunologic: effect on T cell tumor infiltration</measure>
    <time_frame>through day 43</time_frame>
    <description>Estimate the effect of HDCRT, pembrolizumab, and the combination of HDCRT and pembrolizumab on CD8+ T cell and CD4+ T regulatory cell infiltration in tumors.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Immunologic: effect on lymphocyte composition of blood</measure>
    <time_frame>up to year 2</time_frame>
    <description>Estimate the effect of HDCRT, pembrolizumab, and the combination of HDCRT and pembrolizumab on the lymphocyte composition of blood over time.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">21</enrollment>
  <condition>Solid Tumor</condition>
  <arm_group>
    <arm_group_label>Arm A: HDCRT administered with first dose of pembrolizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pembrolizumab (200 mg) plus HDCRT (24 Gy in 3 fractions of 8 Gy each for bone and/or soft tissue lesions; 30 Gy in 5 fractions of 6 Gy each for the prostate gland) are both administered beginning on day 1.&#xD;
Pembrolizumab (200 mg) will be administered on days 1, 43, 64, 85. Subjects who have measurable disease outside of the radiation field and who have derived benefit from the 4 doses of pembrolizumab may continue to receive pembrolizumab every 3 weeks for up to 2 years.&#xD;
HDCRT will be administered to the primary tumor and/or sites of metastatic disease (1 or more sites permitted) over a period of 3-5 days. The length of time for administration of the HDCRT will depend on the site of disease that is to be radiated. HDCRT will begin on day 1.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B: HDCRT administered between doses 1&amp; 2 of pembrolizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pembrolizumab (200 mg) begins on day 1. HDCRT (24 Gy in 3 fractions of 8 Gy each for bone and/or soft tissue lesions; 30 Gy in 5 fractions of 6 Gy each for the prostate gland) begins on day 22.&#xD;
Pembrolizumab (200 mg) will be administered on days 1, 43, 64, 85. Subjects who have measurable disease outside of the radiation field and who have derived benefit from the 4 doses of pembrolizumab may continue to receive pembrolizumab every 3 weeks for up to 2 years.&#xD;
HDCRT will be administered to the primary tumor and/or sites of metastatic disease (1 or more sites permitted) over a period of 3-5 days. The length of time for administration of the HDCRT will depend on the site of disease that is to be radiated. HDCRT will begin on day 22.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm C: HDCRT administered prior to first dose of pembrolizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pembrolizumab (200 mg) begins on day 1. HDCRT (24 Gy in 3 fractions of 8 Gy each for bone and/or soft tissue lesions; 30 Gy in 5 fractions of 6 Gy each for the prostate gland) begins on day 1.&#xD;
Pembrolizumab will be administered on days 22, 43, 64, and 85. Subjects who have measurable disease outside of the radiation field and who have derived benefit from the four doses of pembrolizumab may continue to receive pembrolizumab every 3 weeks for up to 2 years.&#xD;
HDCRT will be administered to the primary tumor and/or sites of metastatic disease (1 or more sites permitted) over a period of 3-5 days. The length of time for administration of the HDCRT will depend on the site of disease that is to be radiated. HDCRT will begin on day 1.</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>High-Dose Conformal Radiation Therapy</intervention_name>
    <description>24 Gy in 3 fractions of 8Gy each for bone and/or soft tissue lesions&#xD;
30 Gy in 5 fractions of 6 Gy each for prostate gland</description>
    <arm_group_label>Arm A: HDCRT administered with first dose of pembrolizumab</arm_group_label>
    <arm_group_label>Arm B: HDCRT administered between doses 1&amp; 2 of pembrolizumab</arm_group_label>
    <arm_group_label>Arm C: HDCRT administered prior to first dose of pembrolizumab</arm_group_label>
    <other_name>HDCRT</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>200 mg</description>
    <arm_group_label>Arm A: HDCRT administered with first dose of pembrolizumab</arm_group_label>
    <arm_group_label>Arm B: HDCRT administered between doses 1&amp; 2 of pembrolizumab</arm_group_label>
    <arm_group_label>Arm C: HDCRT administered prior to first dose of pembrolizumab</arm_group_label>
    <other_name>Keytruda</other_name>
    <other_name>MK-3475</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects must have a histologically or cytologically proven advanced solid tumor&#xD;
             malignancy for which palliative radiation is recommended. In solid tumors where&#xD;
             pembrolizumab has been approved for use, patients may receive pembrolizumab as&#xD;
             indicated, in the context of this protocol. In solid tumors where pembrolizumab has&#xD;
             not been approved for use, the following criteria apply:&#xD;
&#xD;
               -  Patients must be resistant to at least 1 prior conventional chemotherapy regimen&#xD;
                  or other standard of care regimen,&#xD;
&#xD;
               -  Patient must have no remaining conventional treatment options proven to provide&#xD;
                  long-term disease control, and&#xD;
&#xD;
               -  Patient has declined other conventional treatment options&#xD;
&#xD;
          -  Palliative radiation therapy may be recommended for primary tumor and/or any&#xD;
             metastatic site that is accessible to biopsy.&#xD;
&#xD;
          -  At least one site of disease that is accessible to radiation and multiple biopsies.&#xD;
             Subjects may have disease that is encompassed within the radiation field or may have&#xD;
             known disease both inside and outside of the radiation field.&#xD;
&#xD;
          -  Must be able to provide tissue from 2-3 separate biopsy procedures that will be&#xD;
             completed throughout the course of the study.&#xD;
&#xD;
          -  A performance status of 0, 1 or 2 on the ECOG Performance Scale.&#xD;
&#xD;
          -  Subjects must demonstrate adequate organ function.&#xD;
&#xD;
          -  A life expectancy ≥ 6 months.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Requires urgent treatment with cytotoxic chemotherapy or other therapy is indicated.&#xD;
&#xD;
          -  A diagnosis of immunodeficiency.&#xD;
&#xD;
          -  A known history of active TB (Bacillus Tuberculosis).&#xD;
&#xD;
          -  Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.&#xD;
             Subjects with untreated brain metastases and patients who have had brain metastases&#xD;
             re-treated with radiation will be excluded. Patients whom have either midline shift,&#xD;
             or any signs of herniation (even if disease has been treated with GK) will be&#xD;
             excluded. Subjects with previously treated brain metastases may participate provided&#xD;
             they are 1) stable (without clinical evidence of progression) 2) are out at least 10&#xD;
             days from CNS radiation and 3) and are not using steroids as part of treatment for&#xD;
             their brain lesions for at least 7 days prior to trial treatment. This exception does&#xD;
             not include carcinomatous meningitis which is excluded regardless of clinical&#xD;
             stability.&#xD;
&#xD;
          -  Active autoimmune disease that has required systemic treatment in the past 2 years.&#xD;
&#xD;
          -  A history of (non-infectious) pneumonitis that required steroids or current&#xD;
             pneumonitis.&#xD;
&#xD;
          -  An infection requiring systemic therapy.&#xD;
&#xD;
          -  Pregnancy.&#xD;
&#xD;
          -  HIV positivity.&#xD;
&#xD;
          -  Evidence of active Hepatitis B virus or Hepatitis C virus.&#xD;
&#xD;
          -  Significant cardiovascular disease including unstable angina pectoris, uncontrolled&#xD;
             hypertension, uncontrolled arrhythmias, or severe valvular heart disease, or a&#xD;
             myocardial infarction within 6 months prior to the first dose of study treatment.&#xD;
&#xD;
          -  Active bleeding disorders or evidence of chronic or acute disseminated intravascular&#xD;
             coagulation (DIC).&#xD;
&#xD;
          -  Class III or IV heart disease (New York Heart Association classification).&#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>James Larner, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Virginia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Virginia</name>
      <address>
        <city>Charlottesville</city>
        <state>Virginia</state>
        <zip>22908</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2020</verification_date>
  <study_first_submitted>November 30, 2016</study_first_submitted>
  <study_first_submitted_qc>December 5, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 8, 2016</study_first_posted>
  <last_update_submitted>December 11, 2020</last_update_submitted>
  <last_update_submitted_qc>December 11, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">December 16, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Virginia</investigator_affiliation>
    <investigator_full_name>James Larner, MD</investigator_full_name>
    <investigator_title>James Larner, MD</investigator_title>
  </responsible_party>
  <keyword>immunotherapy</keyword>
  <keyword>pembrolizumab</keyword>
  <keyword>MK-3475</keyword>
  <keyword>High-dose conformal radiation therapy</keyword>
  <keyword>HDCRT</keyword>
  <keyword>advanced solid tumor</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02987166
org study id: 18488
nct id: NCT02987166
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This study is a pilot study to evaluate high-dose conformal radiation therapy (HDCRT)
      administered in combination with pembrolizumab in patients with solid tumors.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Safety: adverse event profile
time frame: 30 days post-treatment for adverse events; 90 days post-treatment for serious adverse events
description: Obtain preliminary data on the safety of HDCRT with immunotherapy, delivered concurrently (Arm A) or sequentially (Arms B and C)
measure: Immunologic: effect on T cell tumor infiltration
time frame: through day 43
description: Estimate the effect of HDCRT, pembrolizumab, and the combination of HDCRT and pembrolizumab on CD8+ T cell and CD4+ T regulatory cell infiltration in tumors.
measure: Immunologic: effect on lymphocyte composition of blood
time frame: up to year 2
description: Estimate the effect of HDCRT, pembrolizumab, and the combination of HDCRT and pembrolizumab on the lymphocyte composition of blood over time.
arm group label: Arm A: HDCRT administered with first dose of pembrolizumab
arm group type: Experimental
description: Pembrolizumab (200 mg) plus HDCRT (24 Gy in 3 fractions of 8 Gy each for bone and/or soft tissue lesions; 30 Gy in 5 fractions of 6 Gy each for the prostate gland) are both administered beginning on day 1.
Pembrolizumab (200 mg) will be administered on days 1, 43, 64, 85. Subjects who have measurable disease outside of the radiation field and who have derived benefit from the 4 doses of pembrolizumab may continue to receive pembrolizumab every 3 weeks for up to 2 years.
HDCRT will be administered to the primary tumor and/or sites of metastatic disease (1 or more sites permitted) over a period of 3-5 days. The length of time for administration of the HDCRT will depend on the site of disease that is to be radiated. HDCRT will begin on day 1.
arm group label: Arm B: HDCRT administered between doses 1& 2 of pembrolizumab
arm group type: Experimental
description: Pembrolizumab (200 mg) begins on day 1. HDCRT (24 Gy in 3 fractions of 8 Gy each for bone and/or soft tissue lesions; 30 Gy in 5 fractions of 6 Gy each for the prostate gland) begins on day 22.
Pembrolizumab (200 mg) will be administered on days 1, 43, 64, 85. Subjects who have measurable disease outside of the radiation field and who have derived benefit from the 4 doses of pembrolizumab may continue to receive pembrolizumab every 3 weeks for up to 2 years.
HDCRT will be administered to the primary tumor and/or sites of metastatic disease (1 or more sites permitted) over a period of 3-5 days. The length of time for administration of the HDCRT will depend on the site of disease that is to be radiated. HDCRT will begin on day 22.
arm group label: Arm C: HDCRT administered prior to first dose of pembrolizumab
arm group type: Experimental
description: Pembrolizumab (200 mg) begins on day 1. HDCRT (24 Gy in 3 fractions of 8 Gy each for bone and/or soft tissue lesions; 30 Gy in 5 fractions of 6 Gy each for the prostate gland) begins on day 1.
Pembrolizumab will be administered on days 22, 43, 64, and 85. Subjects who have measurable disease outside of the radiation field and who have derived benefit from the four doses of pembrolizumab may continue to receive pembrolizumab every 3 weeks for up to 2 years.
HDCRT will be administered to the primary tumor and/or sites of metastatic disease (1 or more sites permitted) over a period of 3-5 days. The length of time for administration of the HDCRT will depend on the site of disease that is to be radiated. HDCRT will begin on day 1.
intervention type: Radiation
intervention name: High-Dose Conformal Radiation Therapy
description: 24 Gy in 3 fractions of 8Gy each for bone and/or soft tissue lesions
30 Gy in 5 fractions of 6 Gy each for prostate gland
arm group label: Arm A: HDCRT administered with first dose of pembrolizumab
arm group label: Arm B: HDCRT administered between doses 1& 2 of pembrolizumab
arm group label: Arm C: HDCRT administered prior to first dose of pembrolizumab
other name: HDCRT
intervention type: Drug
intervention name: Pembrolizumab
description: 200 mg
arm group label: Arm A: HDCRT administered with first dose of pembrolizumab
arm group label: Arm B: HDCRT administered between doses 1& 2 of pembrolizumab
arm group label: Arm C: HDCRT administered prior to first dose of pembrolizumab
other name: Keytruda
other name: MK-3475
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: James Larner, MD
role: Principal Investigator
affiliation: University of Virginia
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Virginia
investigator full name: James Larner, MD
investigator title: James Larner, MD
mesh term: Neoplasms
mesh term: Pembrolizumab
sharing ipd: No