<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/NCT03032107</url>
  </required_header>
  <id_info>
    <org_study_id>16-492</org_study_id>
    <nct_id>NCT03032107</nct_id>
  </id_info>
  <brief_title>A Study Of Pembrolizumab In Combination With Trastuzumab-DM1</brief_title>
  <official_title>A Phase 1b Study Of Pembrolizumab In Combination With Trastuzumab-DM1 In Metastatic HER2-Positive Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dana-Farber Cancer 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>Dana-Farber Cancer Institute</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 research study is studying a combination of drugs as a possible treatment for metastatic&#xD;
      breast cancer.&#xD;
&#xD;
      The interventions involved in this study are:&#xD;
&#xD;
        -  Pembrolizumab&#xD;
&#xD;
        -  Trastuzumab emtansine (also called T-DM1)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This research study is a Phase I clinical trial, which tests the safety of an investigational&#xD;
      intervention and also tries to define the appropriate dose of the investigational&#xD;
      intervention to use for further studies. &quot;Investigational&quot; means that the intervention is&#xD;
      being studied. It also means that the FDA (U.S. Food and Drug Administration) has not&#xD;
      approved the combination of Pembrolizumab and T-DM1 for use in patients, including people&#xD;
      with your type of cancer.&#xD;
&#xD;
      This study will determine what amount (or dose) of Pembrolizumab and of T-DM1 is safe for&#xD;
      people to take and what effects, good or bad, this combination may have on participants and&#xD;
      their disease.&#xD;
&#xD;
      The FDA has not approved Pembrolizumab for this specific disease but it has been approved in&#xD;
      the United Sates for the treatment of other types of cancer.&#xD;
&#xD;
      The FDA has approved Trastuzumab emtansine (T-DM1) as a treatment option for this type of&#xD;
      breast cancer&#xD;
&#xD;
      The combination of Pembrolizumab and T-DM1 is investigational. It is thought that together&#xD;
      these drugs to help get the immune system to attack tumor cells and kill cancer cells that&#xD;
      have the HER2 protein. However, it is not known if giving the two study drugs at the same&#xD;
      time will have a better anti-cancer effect than giving each treatment on its own.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">February 17, 2017</start_date>
  <completion_date type="Anticipated">January 1, 2025</completion_date>
  <primary_completion_date type="Actual">October 29, 2020</primary_completion_date>
  <phase>Phase 1</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>Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]</measure>
    <time_frame>21 days</time_frame>
    <description>The number and type of DLTs as defined in the protocol that occur during the first 21 days of treatment and all maximum grade of all treatment-related adverse events using CTCAE v4.0 will be used to identify a safe and tolerable dose</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration Of Response</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease Control Rate</measure>
    <time_frame>18 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival Rate</measure>
    <time_frame>5 years</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">27</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Pembrolizumab Combine With Trastuzumab Emtansine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pembrolizumab will be administered intravenousely in clinic on day 1 of each 3-week cycle&#xD;
Pembrolizumab will be administered prior to T-DM1 administration&#xD;
Pembrolizumab will be given at a predetermine dose&#xD;
T-DM1 will be administered intravenousely in clinic on day 1 of each 3-week cycle&#xD;
T-DM1 will be given at a predetermine dose</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>T-DM1</intervention_name>
    <description>-T-DM1 will be administered intravenousely in clinic on day 1 of each 3-week cycle</description>
    <arm_group_label>Pembrolizumab Combine With Trastuzumab Emtansine</arm_group_label>
    <other_name>Trastuzumab emtansine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>-Pembrolizumab will be administered intravenousely in clinic on day 1 of each 3-week cycle</description>
    <arm_group_label>Pembrolizumab Combine With Trastuzumab Emtansine</arm_group_label>
    <other_name>Keytruda</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have histologically or cytologically confirmed invasive breast cancer,&#xD;
             with stage IV disease. Patients without pathologic or cytologic confirmation of&#xD;
             metastatic disease should have unequivocal evidence of metastasis from physical&#xD;
             examination or radiologic evaluation.&#xD;
&#xD;
          -  Either the primary tumor and/or the metastasis must have been tested for ER, PR and&#xD;
             HER2. Patient must have HER2+ breast cancer per ASCO CAP guidelines 2013.&#xD;
&#xD;
          -  Prior chemotherapy:&#xD;
&#xD;
               -  History of prior therapy with trastuzumab and a taxane, separately or in&#xD;
                  combination, is required.&#xD;
&#xD;
               -  Patients must have either received one line of prior therapy for metastatic&#xD;
                  breast cancer, or have developed a disease recurrence during or within 6 months&#xD;
                  after completing adjuvant therapy.&#xD;
&#xD;
               -  No prior treatment with T-DM1 is allowed.&#xD;
&#xD;
               -  Last dose of chemotherapy must be at least 21 days prior to registration.&#xD;
&#xD;
          -  Prior biologic therapy:&#xD;
&#xD;
             --Patients must have discontinued all biologic or investigational therapy at least 21&#xD;
             days before registration.&#xD;
&#xD;
          -  Prior radiation therapy:&#xD;
&#xD;
               -  Patients may have received prior radiation therapy in either the metastatic or&#xD;
                  early-stage setting.&#xD;
&#xD;
               -  Radiation therapy must be completed at least 14 days prior to registration.&#xD;
&#xD;
          -  In the dose de-escalation cohort: Subjects must have evaluable disease. In the&#xD;
             expansion cohort: Subjects must have at least one lesion that is not within a&#xD;
             previously radiated field that is measurable on computerized tomography (CT) or&#xD;
             magnetic resonance imaging (MRI) scan per RECIST version 1.1. Bone lesions are not&#xD;
             considered measurable by definition.&#xD;
&#xD;
          -  Age is ≥18 years.&#xD;
&#xD;
          -  ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)&#xD;
&#xD;
          -  Participants must have normal organ and marrow function as defined below:&#xD;
&#xD;
               -  absolute neutrophil count ≥1,500/μl&#xD;
&#xD;
               -  platelets ≥100,000/μl&#xD;
&#xD;
               -  hemoglobin ≥9 g/dL&#xD;
&#xD;
               -  total bilirubin ≤1.5mg/dL (≤2.0 in patients with known Gilberts syndrome)&#xD;
&#xD;
               -  AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN. ≤5.0 × institutional ULN for&#xD;
                  patients with documented liver metastases.&#xD;
&#xD;
               -  albumin &gt;2.5mg/dL&#xD;
&#xD;
               -  serum creatinine ≤1.5mg/dL or calculated GFR ≥60 mL/min&#xD;
&#xD;
               -  INR/PT ≤1.5 times ULN unless participant is receiving anticoagulant therapy, as&#xD;
                  long as PT or PTT is within therapeutic range of intended use of anticoagulants&#xD;
&#xD;
               -  aPTT/PTT ≤1.5 times ULN unless participant is receiving anticoagulant therapy, as&#xD;
                  long as PT or PTT is within therapeutic range of intended use of anticoagulants&#xD;
&#xD;
          -  Participants enrolling in the dose expansion must have tissue that is amenable to&#xD;
             biopsy and be willing to undergo a fresh tissue biopsy at baseline. Participants who&#xD;
             undergo an attempted research biopsy procedure for the purpose of this protocol, and&#xD;
             in whom inadequate tissue is obtained, are not required to undergo a repeat biopsy in&#xD;
             order to continue on protocol.&#xD;
&#xD;
          -  The effects of pembrolizumab on the developing human fetus are unknown. For this&#xD;
             reason and because tratuzumab, a component of T-DM1, is known to be teratogenic, women&#xD;
             of child-bearing potential and men of childbearing potential must agree to use&#xD;
             adequate contraception starting with the first dose of study therapy, for the duration&#xD;
             of study participation, and for an additional 120 days after the last dose of study&#xD;
             medication. Note: abstinence is acceptable if this is the usual lifestyle and&#xD;
             preferred contraception for the subject.&#xD;
&#xD;
               -  Should a woman become pregnant or suspect she is pregnant while she or her&#xD;
                  partner is participating in this study, the treating physician and principal&#xD;
                  investigator should be informed immediately.&#xD;
&#xD;
               -  While on the study, women should not breast-feed.&#xD;
&#xD;
               -  Subjects of childbearing potential are defined as those who have not been&#xD;
                  surgically sterilized and/or have had a menstrual period in the past year&#xD;
&#xD;
          -  Female subject of child-bearing potential must have a negative urine or serum&#xD;
             pregnancy within 72 hours prior to receiving the first dose of study medication. If a&#xD;
             urine test is positive or cannot be confirmed as negative, a serum pregnancy test will&#xD;
             be required.&#xD;
&#xD;
          -  Patients on bisphosphonates may continue receiving bisphosphonate therapy during study&#xD;
             treatment.&#xD;
&#xD;
          -  Left ventricular ejection fraction (LVEF) must be within institutional limits of&#xD;
             normal as assessed by echocardiogram or MUGA documented within 28 days prior to first&#xD;
             dose of study drug.&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  The subject has received another investigational agent within 21 days of the first&#xD;
             dose of study drug.&#xD;
&#xD;
          -  The subject has received prior pembrolizumab or any other anti-PD-1 , anti-PD-L1, or&#xD;
             anti-PD-L2 therapy, or has participated in any prior studies involving pembrolizumab.&#xD;
&#xD;
          -  Pre-existing neuropathy greater than or equal to grade 2.&#xD;
&#xD;
          -  Hypersensitivity to pembrolizumab or T-DM1 or any of their excipients.&#xD;
&#xD;
          -  The subject has any history or evidence of active, non-infectious pneumonitis or&#xD;
             interstitial lung disease.&#xD;
&#xD;
          -  Known brain metastases that are untreated, symptomatic, or require therapy to control&#xD;
             symptoms. Participants with previously diagnosed brain metastases are eligible if they&#xD;
             have completed treatment at least one month prior to trial therapy initiation, are&#xD;
             neurologically stable with an absence of new neurological symptoms for at least 4&#xD;
             weeks prior to study entry, and have recovered from effects of radiotherapy or&#xD;
             surgery. Any corticosteroid use for brain metastases must have been discontinued&#xD;
             without the subsequent appearance of symptoms for ≥2 weeks before the first study&#xD;
             drug. Treatment for brain metastases may include whole brain radiotherapy,&#xD;
             radiosurgery, or a combination as deemed appropriate by the treating physician.&#xD;
&#xD;
          -  Known carcinomatous meningitis.&#xD;
&#xD;
          -  The subject has an uncontrolled intercurrent illness including, but not limited to,&#xD;
             uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia,&#xD;
             congestive heart failure (New York Heart Association Class III or IV; see Appendix B),&#xD;
             active ischemic heart disease, myocardial infarction within the previous six months,&#xD;
             uncontrolled diabetes mellitus, chronic liver or renal disease, or severe&#xD;
             malnutrition.&#xD;
&#xD;
          -  Concurrent use of potent CYP3A4 inhibitors (see Appendix C), such as ketoconazole and&#xD;
             erythromycin, should be avoided during the study treatment with T-DM1.&#xD;
&#xD;
          -  Active infection requiring intravenous antibiotics at cycle 1 day 1.&#xD;
&#xD;
          -  Individuals with a history of a second malignancy are ineligible except for the&#xD;
             following circumstances. Individuals with a history of other malignancies are eligible&#xD;
             if they have been disease-free for at least 5 years and are deemed by the investigator&#xD;
             to be at low risk for recurrence of that malignancy. Individuals with the following&#xD;
             cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer&#xD;
             in situ, and non-melanoma cancer of the skin. Patients with other cancers diagnosed&#xD;
             within the past 5 years and felt to be at low risk of recurrence should be discussed&#xD;
             with the study sponsor to determine eligibility.&#xD;
&#xD;
          -  The subject has a medical condition that requires chronic systemic steroid therapy or&#xD;
             any other form of immunosuppressive medication including disease modifiying agents, or&#xD;
             has required such therapy in the last 2 years. Replacement therapy (eg., thyroxine,&#xD;
             insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary&#xD;
             insufficiency, etc.) is not considered a form of systemic treatment.&#xD;
&#xD;
          -  The subject has an active autoimmune disease or a documented history of autoimmune&#xD;
             disease or syndrome that requires systemic steroids or immunosuppressive agents.&#xD;
&#xD;
          -  The participant is positive for Hepatitis B surface antigen, or Hepatitis C RNA.&#xD;
&#xD;
          -  Known HIV-positive participants. HIV-positive patients on combination antiretroviral&#xD;
             therapy are ineligible because of the potential for pharmacokinetic interactions with&#xD;
             pembrolizumab. In addition, these participants are at increased risk of lethal&#xD;
             infections with bone marrow suppressive therapy, i.e. nab-paclitaxel. Appropriate&#xD;
             studies will be undertaken in participants receiving combination antiretroviral&#xD;
             therapy when indicated.&#xD;
&#xD;
          -  The subject has received a live vaccine within 28 days of planned start of study&#xD;
             therapy. Note: seasonal influenza vaccines for infection are generally inactivated flu&#xD;
             vaccines and are allowed; however intranasal influenza vaccines (i.e. Flu-Mist ®) are&#xD;
             live 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>Sara Tolaney, MD MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dana-Farber Cancer Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Beth Israel Deaconess Medical Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana-Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>January 23, 2017</study_first_submitted>
  <study_first_submitted_qc>January 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 26, 2017</study_first_posted>
  <last_update_submitted>July 25, 2022</last_update_submitted>
  <last_update_submitted_qc>July 25, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">July 26, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Dana-Farber Cancer Institute</investigator_affiliation>
    <investigator_full_name>Sara Tolaney</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Breast Cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
    <mesh_term>Trastuzumab</mesh_term>
    <mesh_term>Ado-Trastuzumab Emtansine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>May 17, 2023</submitted>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03032107
org study id: 16-492
nct id: NCT03032107
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This research study is studying a combination of drugs as a possible treatment for metastatic
      breast cancer.

      The interventions involved in this study are:

        -  Pembrolizumab

        -  Trastuzumab emtansine (also called T-DM1)
This research study is a Phase I clinical trial, which tests the safety of an investigational
      intervention and also tries to define the appropriate dose of the investigational
      intervention to use for further studies. "Investigational" means that the intervention is
      being studied. It also means that the FDA (U.S. Food and Drug Administration) has not
      approved the combination of Pembrolizumab and T-DM1 for use in patients, including people
      with your type of cancer.

      This study will determine what amount (or dose) of Pembrolizumab and of T-DM1 is safe for
      people to take and what effects, good or bad, this combination may have on participants and
      their disease.

      The FDA has not approved Pembrolizumab for this specific disease but it has been approved in
      the United Sates for the treatment of other types of cancer.

      The FDA has approved Trastuzumab emtansine (T-DM1) as a treatment option for this type of
      breast cancer

      The combination of Pembrolizumab and T-DM1 is investigational. It is thought that together
      these drugs to help get the immune system to attack tumor cells and kill cancer cells that
      have the HER2 protein. However, it is not known if giving the two study drugs at the same
      time will have a better anti-cancer effect than giving each treatment on its own.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
time frame: 21 days
description: The number and type of DLTs as defined in the protocol that occur during the first 21 days of treatment and all maximum grade of all treatment-related adverse events using CTCAE v4.0 will be used to identify a safe and tolerable dose
measure: Objective Response Rate
time frame: 2 years
measure: Progression Free Survival
time frame: 2 years
measure: Duration Of Response
time frame: 2 years
measure: Disease Control Rate
time frame: 18 weeks
measure: Overall Survival Rate
time frame: 5 years
arm group label: Pembrolizumab Combine With Trastuzumab Emtansine
arm group type: Experimental
description: Pembrolizumab will be administered intravenousely in clinic on day 1 of each 3-week cycle
Pembrolizumab will be administered prior to T-DM1 administration
Pembrolizumab will be given at a predetermine dose
T-DM1 will be administered intravenousely in clinic on day 1 of each 3-week cycle
T-DM1 will be given at a predetermine dose
intervention type: Drug
intervention name: T-DM1
description: -T-DM1 will be administered intravenousely in clinic on day 1 of each 3-week cycle
arm group label: Pembrolizumab Combine With Trastuzumab Emtansine
other name: Trastuzumab emtansine
intervention type: Drug
intervention name: Pembrolizumab
description: -Pembrolizumab will be administered intravenousely in clinic on day 1 of each 3-week cycle
arm group label: Pembrolizumab Combine With Trastuzumab Emtansine
other name: Keytruda
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Sara Tolaney, MD MPH
role: Principal Investigator
affiliation: Dana-Farber Cancer Institute
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Dana-Farber Cancer Institute
investigator full name: Sara Tolaney
investigator title: Principal Investigator
mesh term: Breast Neoplasms
mesh term: Pembrolizumab
mesh term: Trastuzumab
mesh term: Ado-Trastuzumab Emtansine
sharing ipd: No
submitted: May 17, 2023