<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/NCT03025035</url>
  </required_header>
  <id_info>
    <org_study_id>IIT2015-18-Mita-MK3475</org_study_id>
    <nct_id>NCT03025035</nct_id>
  </id_info>
  <brief_title>Pembrolizumab in Combination With Olaparib in Advanced BRCA-mutated or HDR-defect Breast Cancer</brief_title>
  <official_title>Open Label, Phase II Pilot Study of Immune Checkpoint Inhibition With Pembrolizumab in Combination With PARP Inhibition With Olaparib in Advanced BRCA-mutated or HDR-defect Breast Cancers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Monica Mita</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Cedars-Sinai Medical Center</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 trial will evaluate the use of immunotherapy and PARP inhibition in a population with&#xD;
      incurable advanced breast cancer associated with a germline BRCA mutation or HDR-defect. The&#xD;
      main objective is to examine overall response rate of pembrolizumab (immunotherapy) in&#xD;
      combination with Olaparib (PARP inhibitor) in advanced BRCA-mutated or Homology-directed&#xD;
      repair (HDR)-defect breast cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      There are two BRCA genes, BRCA1 and BRCA2, and they play a role in protecting cells from&#xD;
      cancer. HDR-defect is another type of gene mutation that can contribute to development and&#xD;
      progression of cancer. If one of these genes is mutated, cells may rapidly change and divide,&#xD;
      which can lead to cancer. Pembrolizumab is a drug that works with the immune system to target&#xD;
      the tumor (immunotherapy). The investigators want to know if combining pembrolizumab and&#xD;
      Olaparib therapy will be able to reduce the size and amount of cancer cells with fewer side&#xD;
      effects than standard treatment by targeting the tumor. This research study is designed to&#xD;
      test the investigational use of pembrolizumab and Olaparib in breast cancer.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 10, 2017</start_date>
  <completion_date type="Anticipated">November 8, 2024</completion_date>
  <primary_completion_date type="Anticipated">November 8, 2023</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>Overall response rate (ORR) per RECIST1.1</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Defined as complete or partial response per RECIST 1.1 criteria with assessment every 9 weeks during the first year and while on the study drug, and every 12 weeks thereafter.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression free survival (PFS), per RECIST 1.1</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>As measured by RECIST 1.1, in patients progressing after 1st line therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Calculated in months from the start of treatment to the date of death from any cause</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Benefit Rate (CBR = CR+PR+SD) per RECIST 1.1</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>As measured by RECIST 1.1, in patients progressing after 1st line therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DOR) for Complete Response (CR) and Partial Response (PR) per RECIST 1.1</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>As measured by RECIST 1.1, in patients progressing after 1st line therapy</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Pembrolizumab + Olaparib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This is an open-label, single-arm pilot study of pembrolizumab (study drug) in combination with Olaparib in 20 subjects with advanced BRCA mutation or HDR-defect associated breast cancer having progressed through at least a standard first line therapy.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>Pembrolizumab IV solution administered on Day 1 of each 3-week cycle</description>
    <arm_group_label>Pembrolizumab + Olaparib</arm_group_label>
    <other_name>Keytruda</other_name>
    <other_name>MK-3475</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Olaparib</intervention_name>
    <description>Olaparib administered orally twice a day</description>
    <arm_group_label>Pembrolizumab + Olaparib</arm_group_label>
    <other_name>Lynparza</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Be willing and able to provide written informed consent/assent for the trial&#xD;
&#xD;
          -  Be ≥18 years of age on day of signing informed consent&#xD;
&#xD;
          -  Advanced BRCA-mutated and/or HDR-defect breast cancer progressing on or after prior&#xD;
             therapy for metastatic disease or locally advanced disease; Prior therapy is defined&#xD;
             as follows: for triple negative breast cancer - progressing after at least 1 line of&#xD;
             any prior chemotherapy; for HER2 positive disease must have progressed after at least&#xD;
             two HER2 directed therapies in the metastatic setting including ado-trastuzumab&#xD;
             emtansine (T-DM1); for hormone receptor positive disease (ER, PR, or both) must have&#xD;
             progressed after a CDK4/CDK6 inhibitor plus hormonal therapy. Patients with&#xD;
             progression within 12 months from previous neoadjuvant or adjuvant treatment could be&#xD;
             enrolled in the study as 1st line therapy in metastatic setting.&#xD;
&#xD;
          -  Measurable disease by RECIST 1.1, with at least one lesion, not previously irradiated,&#xD;
             that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except&#xD;
             lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or&#xD;
             magnetic resonance imaging (MRI) and which is suitable for accurate repeated&#xD;
             measurements. Patients with non-measurable bone metastases in addition to measurable&#xD;
             disease are eligible; however patients with non-measurable bone disease as the only&#xD;
             site(s) of disease are not eligible.&#xD;
&#xD;
          -  ECOG 0 or 1&#xD;
&#xD;
          -  Documented BRCA deleterious germline or somatic mutation and/or HDR-defect.&#xD;
&#xD;
          -  FFPE tumor tissue available for analysis&#xD;
&#xD;
          -  Adequate organ function&#xD;
&#xD;
          -  Female subjects: Postmenopausal or evidence of non-childbearing status for women of&#xD;
             childbearing potential: negative urine or serum pregnancy test within 28 days of study&#xD;
             treatment and confirmed prior to treatment on day 1. Postmenopausal is defined as:&#xD;
&#xD;
               1. Amenorrheic for 1 year or more following cessation of exogenous hormonal&#xD;
                  treatments Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels&#xD;
                  in the post menopausal range for women under 50&#xD;
&#xD;
               2. radiation-induced oophorectomy with last menses &gt;1 year ago&#xD;
&#xD;
               3. chemotherapy-induced menopause with &gt;1 year interval since last menses&#xD;
&#xD;
               4. surgical sterilization (bilateral oophorectomy or hysterectomy)&#xD;
&#xD;
          -  Women of childbearing potential and their partners, who are sexually active, must&#xD;
             agree to the use of TWO highly effective forms of contraception in combination. This&#xD;
             should be started from the signing of the informed consent and continue throughout the&#xD;
             period of taking study treatment and for at least 1 month after last dose of study&#xD;
             drug(s), or they must totally/truly abstain from any form of sexual intercourse.&#xD;
&#xD;
          -  Male patients must use a condom during treatment and for 3 months after the last dose&#xD;
             of olaparib when having sexual intercourse with a pregnant woman or with a woman of&#xD;
             childbearing potential. Female partners of male patients should also use a highly&#xD;
             effective form of contraception if they are of childbearing potential&#xD;
&#xD;
          -  Patients must have a life expectancy ≥ 16 weeks&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Is currently participating or has participated in a study of investigational agent or&#xD;
             using an investigational device with 30 days of the first dose of pembrolizumab.&#xD;
&#xD;
               1. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy&#xD;
                  within 3 weeks prior to study Day 1.&#xD;
&#xD;
               2. Subjects must have recovered (i.e., ≤ Grade 1 or at baseline) from any adverse&#xD;
                  events due to a previously administered agent. Subjects with ≤ Grade 2 neuropathy&#xD;
                  are an exception to this criterion and may qualify for the study.&#xD;
&#xD;
               3. If subject received major surgery, they must have recovered adequately from the&#xD;
                  toxicity and/or complications from the intervention prior to starting therapy.&#xD;
&#xD;
          -  Is receiving systemic steroid therapy within three days prior to the first dose of&#xD;
             pembrolizumab or receiving any other form of immunosuppressive medication&#xD;
&#xD;
          -  Is expected to require any other form of systemic or localized antineoplastic therapy&#xD;
             while on trial.&#xD;
&#xD;
               1. Subjects with ER+/PR+ disease may be given endocrine therapy.&#xD;
&#xD;
               2. Subjects with HER2+ disease will be required to discontinue trastuzumab&#xD;
                  (Herceptin).&#xD;
&#xD;
          -  Has participated in another MK03475 trial.&#xD;
&#xD;
             a. Note: Patients with or without prior PARP-inhibitor exposure may be included.&#xD;
&#xD;
          -  Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,&#xD;
             clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,&#xD;
             saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.&#xD;
             ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout&#xD;
             period prior to starting olaparib is 2 weeks.&#xD;
&#xD;
          -  Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,&#xD;
             rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or&#xD;
             moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout&#xD;
             period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3&#xD;
             weeks for other agents.&#xD;
&#xD;
          -  Major surgery within 2 weeks of starting study treatment and patients must have&#xD;
             recovered from any effects of any major surgery.&#xD;
&#xD;
          -  Has known hypersensitivity to pembrolizumab or any of its excipients&#xD;
&#xD;
          -  Has a known additional malignancy that is progressing or requires active treatment.&#xD;
             Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the&#xD;
             skin, or in situ cervical cancer that has undergone potentially curative therapy.&#xD;
&#xD;
          -  Has known history of prior malignancy except if the patient has undergone potentially&#xD;
             curative therapy with no evidence of that disease recurrence for 5 years since&#xD;
             initiation of that therapy.&#xD;
&#xD;
          -  Has known active central nervous system (CNS) metastases and/or carcinomatous&#xD;
             meningitis. Subjects with previously treated brain metastases may participate provided&#xD;
             they are stable (without evidence of progression by MRI for at least four weeks prior&#xD;
             to the first dose of pembrolizumab and any neurologic symptoms have returned to&#xD;
             baseline), have no evidence of new or enlarging brain metastases, and are using no&#xD;
             steroids for at least three days prior to study medication.&#xD;
&#xD;
          -  Has evidence of interstitial lung disease or active, non-infectious pneumonitis&#xD;
&#xD;
          -  Has active tuberculosis&#xD;
&#xD;
          -  Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as&#xD;
             judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic&#xD;
             arrhythmia, congestive heart failure, QTcF prolongation &gt;500 ms, electrolyte&#xD;
             disturbances, etc.), or patients with congenital long QT syndrome.&#xD;
&#xD;
          -  Persistent toxicities (&gt;Common Terminology Criteria for Adverse Event (CTCAE) grade 2)&#xD;
             caused by previous cancer therapy, excluding alopecia.&#xD;
&#xD;
          -  Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features&#xD;
             suggestive of MDS/AML.&#xD;
&#xD;
          -  Patients unable to swallow orally administered medication and patients with&#xD;
             gastrointestinal disorders likely to interfere with absorption of the study&#xD;
             medication.&#xD;
&#xD;
          -  Patients with a known hypersensitivity to olaparib or any of the excipients of the&#xD;
             product.&#xD;
&#xD;
          -  Has received a live vaccine or live-attenuated vaccine within 30 days prior to the&#xD;
             first dose of pembrolizumab. Administration of killed vaccines is allowed.&#xD;
&#xD;
          -  Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).&#xD;
&#xD;
          -  Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA&#xD;
             [qualitative] is detected).&#xD;
&#xD;
          -  Has an active autoimmune disease that has required systemic treatment in the past 2&#xD;
             years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive&#xD;
             drugs). Subjects with vitiligo or resolved childhood asthma/atopy would be exception&#xD;
             to this rule. Subjects that require inhaled steroid or local steroid injections will&#xD;
             not be excluded from the study. Subjects with hypothyroidism not from autoimmune&#xD;
             disease and stable on hormone replacement will not be excluded from the study. Note:&#xD;
             Replacement therapy (eg., 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;
          -  Has had an allogenic tissue / solid organ transplant.&#xD;
&#xD;
          -  Previous allogenic bone marrow transplant or double umbilical cord blood&#xD;
             transplantation (dUCBT).&#xD;
&#xD;
          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality&#xD;
             that might confound the results of the trial, interfere with the subject's&#xD;
             participation for the full duration of the trial, or is not in the best interest of&#xD;
             the subject to participate, in the opinion of the treating Investigator.&#xD;
&#xD;
          -  Has known psychiatric or substance abuse disorders that would interfere with&#xD;
             cooperation with the requirements of the trial.&#xD;
&#xD;
          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the&#xD;
             projected duration of the trial, starting with the screening visit (Visit 1) through&#xD;
             120 days after the last dose of study treatment.&#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>Monica Mita, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cedars-Sinal Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Amy Oppenheim</last_name>
    <phone>310-423-3713</phone>
    <email>Amy.Oppenheim@cshs.org</email>
  </overall_contact>
  <location>
    <facility>
      <name>Cedars-Sinai Medical Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90048</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Amy Oppenheim</last_name>
      <phone>310-423-3713</phone>
      <email>Amy.Oppenheim@cshs.org</email>
    </contact>
    <investigator>
      <last_name>Monica Mita, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Philomena McAndrew, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Dorothy Park, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Alain Mita, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Maryliza El-Masry, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>January 17, 2017</study_first_submitted>
  <study_first_submitted_qc>January 17, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 19, 2017</study_first_posted>
  <last_update_submitted>June 3, 2023</last_update_submitted>
  <last_update_submitted_qc>June 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Cedars-Sinai Medical Center</investigator_affiliation>
    <investigator_full_name>Monica Mita</investigator_full_name>
    <investigator_title>Associate Professor of Medicine</investigator_title>
  </responsible_party>
  <keyword>BRCA-mutation</keyword>
  <keyword>Immune checkpoint inhibition</keyword>
  <keyword>Immunotherapy</keyword>
  <keyword>Advanced BRCA-mutated breast cancer</keyword>
  <keyword>HDR-defect</keyword>
  <keyword>PARP inhibitor</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>Olaparib</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/NCT03025035
org study id: IIT2015-18-Mita-MK3475
nct id: NCT03025035
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This trial will evaluate the use of immunotherapy and PARP inhibition in a population with
      incurable advanced breast cancer associated with a germline BRCA mutation or HDR-defect. The
      main objective is to examine overall response rate of pembrolizumab (immunotherapy) in
      combination with Olaparib (PARP inhibitor) in advanced BRCA-mutated or Homology-directed
      repair (HDR)-defect breast cancer.
There are two BRCA genes, BRCA1 and BRCA2, and they play a role in protecting cells from
      cancer. HDR-defect is another type of gene mutation that can contribute to development and
      progression of cancer. If one of these genes is mutated, cells may rapidly change and divide,
      which can lead to cancer. Pembrolizumab is a drug that works with the immune system to target
      the tumor (immunotherapy). The investigators want to know if combining pembrolizumab and
      Olaparib therapy will be able to reduce the size and amount of cancer cells with fewer side
      effects than standard treatment by targeting the tumor. This research study is designed to
      test the investigational use of pembrolizumab and Olaparib in breast cancer.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall response rate (ORR) per RECIST1.1
time frame: Up to 2 years
description: Defined as complete or partial response per RECIST 1.1 criteria with assessment every 9 weeks during the first year and while on the study drug, and every 12 weeks thereafter.
measure: Progression free survival (PFS), per RECIST 1.1
time frame: Up to 2 years
description: As measured by RECIST 1.1, in patients progressing after 1st line therapy
measure: Overall survival (OS)
time frame: Up to 2 years
description: Calculated in months from the start of treatment to the date of death from any cause
measure: Clinical Benefit Rate (CBR = CR+PR+SD) per RECIST 1.1
time frame: Up to 2 years
description: As measured by RECIST 1.1, in patients progressing after 1st line therapy
measure: Duration of Response (DOR) for Complete Response (CR) and Partial Response (PR) per RECIST 1.1
time frame: Up to 2 years
description: As measured by RECIST 1.1, in patients progressing after 1st line therapy
arm group label: Pembrolizumab + Olaparib
arm group type: Experimental
description: This is an open-label, single-arm pilot study of pembrolizumab (study drug) in combination with Olaparib in 20 subjects with advanced BRCA mutation or HDR-defect associated breast cancer having progressed through at least a standard first line therapy.
intervention type: Drug
intervention name: Pembrolizumab
description: Pembrolizumab IV solution administered on Day 1 of each 3-week cycle
arm group label: Pembrolizumab + Olaparib
other name: Keytruda
other name: MK-3475
intervention type: Drug
intervention name: Olaparib
description: Olaparib administered orally twice a day
arm group label: Pembrolizumab + Olaparib
other name: Lynparza
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Monica Mita, MD
role: Principal Investigator
affiliation: Cedars-Sinal Medical Center
last name: Amy Oppenheim
phone: 310-423-3713
email: Amy.Oppenheim@cshs.org
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Cedars-Sinai Medical Center
investigator full name: Monica Mita
investigator title: Associate Professor of Medicine
mesh term: Breast Neoplasms
mesh term: Pembrolizumab
mesh term: Olaparib
sharing ipd: No