<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/NCT03280563</url>
  </required_header>
  <id_info>
    <org_study_id>CO39611</org_study_id>
    <secondary_id>2017-000335-14</secondary_id>
    <nct_id>NCT03280563</nct_id>
  </id_info>
  <brief_title>A Study of Multiple Immunotherapy-Based Treatment Combinations in Hormone Receptor (HR)-Positive Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Breast Cancer</brief_title>
  <acronym>MORPHEUS HR+BC</acronym>
  <official_title>A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Hormone Receptor-Positive HER2-Negative Breast Cancer (MORPHEUS-HR+ Breast Cancer)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hoffmann-La Roche</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hoffmann-La Roche</source>
  <oversight_info>
    <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 designed to evaluate the efficacy, safety, and pharmacokinetics of several&#xD;
      immunotherapy-based combination treatments in participants with inoperable locally advanced&#xD;
      or metastatic HR-positive, HER2-negative breast cancer who have progressed during or&#xD;
      following treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor in the first- or&#xD;
      second-line setting, such as palbociclib, ribociclib, or abemaciclib. The study will be&#xD;
      performed in two stages. During Stage 1, participants will be randomized to fulvestrant&#xD;
      (control) or an atezolizumab-containing doublet or triplet combination. Those who experience&#xD;
      disease progression, loss of clinical benefit, or unacceptable toxicity may be eligible to&#xD;
      receive a new triplet combination treatment in Stage 2 until loss of clinical benefit or&#xD;
      unacceptable toxicity. New treatment arms may be added and/or existing treatment arms may be&#xD;
      closed during the course of the study on the basis of ongoing clinical efficacy and safety as&#xD;
      well as the current treatments available.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">December 26, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2024</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of Participants with Objective Response during Stage 1 According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1</measure>
    <time_frame>From baseline until disease progression or loss of clinical benefit (up to 6 years overall)</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-Free Survival during Stage 1 According to RECIST v1.1</measure>
    <time_frame>From randomization until disease progression or death from any cause (up to 6 years overall)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants with Clinical Benefit during Stage 1 According to RECIST v1.1</measure>
    <time_frame>From baseline until disease progression or loss of clinical benefit (up to 6 years overall)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival during Stage 1</measure>
    <time_frame>From randomization until death from any cause (up to 6 years overall)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants Alive at 18 Months during Stage 1</measure>
    <time_frame>18 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response during Stage 1 According to RECIST v1.1</measure>
    <time_frame>From first objective response until disease progression or death from any cause (up to 6 years overall)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants with Adverse Events (AEs) during Stage 1</measure>
    <time_frame>From baseline until 30 days after last dose or initiation of new systemic anti-cancer therapy (up to 6 years overall)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants with AEs during Stage 2</measure>
    <time_frame>From baseline until 30 days after last dose or initiation of new systemic anti-cancer therapy (up to 6 years overall)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Atezolizumab Serum Concentration during Stage 1</measure>
    <time_frame>Predose (0 hours [h]) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 21-28 days); postdose (30 min) (infusion = 30-60 min) on Day 1 of Cycle 1; at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Entinostat Serum and Plasma Concentration during Stage 1</measure>
    <time_frame>Serum predose (0 h) and plasma postdose (2-4 h) on Day 1 of Cycle 1; plasma predose (0 h) on Day 1 of Cycle 2 (cycle = 21 days)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fulvestrant Plasma Concentration during Stage 1</measure>
    <time_frame>Predose (0 h) on Day 1 of Cycles 2-3 (cycle = 28 days)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ipatasertib Plasma Concentration during Stage 1</measure>
    <time_frame>Predose (0 h) and postdose (1, 2, 4, 6 h) on Day 15 of Cycle 1; postdose (1-3 h) on Day 15 of Cycle 3</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Atezolizumab Serum Concentration during Stage 2</measure>
    <time_frame>Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 21-28 days); postdose (30 min) (infusion = 30-60 min) on Day 1 of Cycle 1; at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bevacizumab Serum Concentration during Stage 2</measure>
    <time_frame>Predose (0 h) and postdose (30 min) (infusion = 30-90 min) on Day 1 of Cycles 1, 3 (cycle = 21-28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exemestane Plasma Concentration during Stage 2</measure>
    <time_frame>Predose (0 h) on Day 1 of Cycle 2 (cycle = 21 days)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fulvestrant Plasma Concentration during Stage 2</measure>
    <time_frame>Predose (0 h) on Day 1 of Cycles 2-3 (cycle = 28 days)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tamoxifen Plasma Concentration during Stage 2</measure>
    <time_frame>Predose (0 h) on Day 1 of Cycle 2 (cycle = 21 days)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab during Stage 1</measure>
    <time_frame>Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants with ADAs to Atezolizumab during Stage 2</measure>
    <time_frame>Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 21-28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants with ADAs to Bevacizumab during Stage 2</measure>
    <time_frame>Predose (0 h) on Day 1 of Cycles 1, 3 (cycle = 21-28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Abemaciclib Plasma Concentration during Stage 1</measure>
    <time_frame>Predose (0 h), Postdose (30 minutes post infusion), and 4-8 hours after dose on Day 1 Cycle 1; Predose on Day 15 Cycle 1 and Day 1 of Cycles 2 and 3</time_frame>
  </secondary_outcome>
  <number_of_arms>8</number_of_arms>
  <enrollment type="Actual">138</enrollment>
  <condition>Breast Neoplasms</condition>
  <arm_group>
    <arm_group_label>Stage 1: Fulvestrant</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants will receive fulvestrant until unacceptable toxicity or disease progression according to RECIST v1.1.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Stage 1: Atezolizumab + Entinostat</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive doublet combination treatment with atezolizumab plus entinostat until unacceptable toxicity or loss of clinical benefit as determined by the investigator.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Stage 1: Atezolizumab + Fulvestrant</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive doublet combination treatment with atezolizumab plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Stage 1: Atezolizumab + Ipatasertib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive doublet combination treatment with atezolizumab plus ipatasertib until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Prior to enrollment into this arm, the first 6 participants in the study will complete a safety run-in with atezolizumab plus ipatasertib.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Stage 1: Atezolizumab + Ipatasertib + Fulvestrant</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive triplet combination treatment with atezolizumab plus ipatasertib plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Prior to enrollment into this arm, the first 6 participants in the study will complete a safety run-in with atezolizumab plus ipatasertib.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Those who progress or experience unacceptable toxicity during treatment in Stage 1 may be eligible to enter Stage 2. Participants will receive triplet combination therapy with atezolizumab plus bevacizumab plus one of three endocrine therapies (fulvestrant, exemestane, or tamoxifen) selected by the physician. Treatment in Stage 2 will continue until unacceptable toxicity or loss of clinical benefit as determined by the investigator.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Stage 1: Mandatory On-Treatment Biopsy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>For experimental combination arms that demonstrate clinical activity during the preliminary phase, the Sponsor may open enrollment into a separate mandatory on-treatment biopsy cohort for that combination.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Stage 1: Atezolizumab + Abemaciclib + Fulvestrant</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive triplet combination treatment with atezolizumab plus abemaciclib plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody</intervention_name>
    <description>Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with entinostat in Stage 1, or exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.</description>
    <arm_group_label>Stage 1: Atezolizumab + Abemaciclib + Fulvestrant</arm_group_label>
    <arm_group_label>Stage 1: Atezolizumab + Entinostat</arm_group_label>
    <arm_group_label>Stage 1: Atezolizumab + Fulvestrant</arm_group_label>
    <arm_group_label>Stage 1: Atezolizumab + Ipatasertib</arm_group_label>
    <arm_group_label>Stage 1: Atezolizumab + Ipatasertib + Fulvestrant</arm_group_label>
    <arm_group_label>Stage 1: Mandatory On-Treatment Biopsy</arm_group_label>
    <arm_group_label>Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy</arm_group_label>
    <other_name>Tecentriq</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bevacizumab</intervention_name>
    <description>Bevacizumab will be given as 10 milligrams per kilogram (mg/kg) via IV infusion on Days 1 and 15 of each 28-day cycle in the regimen containing fulvestrant. When given with exemestane or tamoxifen, bevacizumab will be given as 15 mg/kg via IV infusion on Day 1 of each 21-day cycle.</description>
    <arm_group_label>Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy</arm_group_label>
    <other_name>Avastin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Entinostat</intervention_name>
    <description>Entinostat will be given as 5 mg orally once a week on Days 1, 8 and 15 of each 21-day cycle.</description>
    <arm_group_label>Stage 1: Atezolizumab + Entinostat</arm_group_label>
    <arm_group_label>Stage 1: Mandatory On-Treatment Biopsy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Exemestane</intervention_name>
    <description>Exemestane will be given as 25 mg orally QD in each 21-day cycle.</description>
    <arm_group_label>Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fulvestrant</intervention_name>
    <description>Fulvestrant will be given as 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle.</description>
    <arm_group_label>Stage 1: Atezolizumab + Abemaciclib + Fulvestrant</arm_group_label>
    <arm_group_label>Stage 1: Atezolizumab + Fulvestrant</arm_group_label>
    <arm_group_label>Stage 1: Atezolizumab + Ipatasertib + Fulvestrant</arm_group_label>
    <arm_group_label>Stage 1: Fulvestrant</arm_group_label>
    <arm_group_label>Stage 1: Mandatory On-Treatment Biopsy</arm_group_label>
    <arm_group_label>Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipatasertib</intervention_name>
    <description>Ipatasertib will be given as 400 mg orally QD on Days 1-21 of each 28-day cycle.</description>
    <arm_group_label>Stage 1: Atezolizumab + Ipatasertib</arm_group_label>
    <arm_group_label>Stage 1: Atezolizumab + Ipatasertib + Fulvestrant</arm_group_label>
    <arm_group_label>Stage 1: Mandatory On-Treatment Biopsy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tamoxifen</intervention_name>
    <description>Tamoxifen will be given as 20 mg orally QD in each 21-day cycle.</description>
    <arm_group_label>Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Abemaciclib</intervention_name>
    <description>Abemaciclib will be given as 150mg twice daily during each 28-day cycle.</description>
    <arm_group_label>Stage 1: Atezolizumab + Abemaciclib + Fulvestrant</arm_group_label>
    <arm_group_label>Stage 1: Mandatory On-Treatment Biopsy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria for Both Stages:&#xD;
&#xD;
          -  Measurable disease per RECIST v1.1&#xD;
&#xD;
          -  Adequate hematologic and end organ function&#xD;
&#xD;
          -  Disease progression during or after first- or second-line hormonal therapy with CDK4/6&#xD;
             inhibitor&#xD;
&#xD;
        Inclusion Criteria for Stage 1:&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1&#xD;
&#xD;
          -  Metastatic or inoperable, locally advanced, histologically or cytologically confirmed&#xD;
             invasive HR-positive HER2-negative breast cancer&#xD;
&#xD;
          -  Recommended for endocrine therapy, and cytotoxic chemotherapy not indicated at study&#xD;
             entry&#xD;
&#xD;
          -  Recurrence or progression following most recent systemic breast cancer therapy&#xD;
&#xD;
          -  Disease progression during or after first- or second-line hormonal therapy for locally&#xD;
             advanced or metastatic disease&#xD;
&#xD;
          -  Postmenopausal according to protocol-defined criteria&#xD;
&#xD;
          -  Life expectancy &gt;3 months&#xD;
&#xD;
          -  Available tumor specimen for determination of PD-L1 status&#xD;
&#xD;
        Inclusion Criteria for Stage 2:&#xD;
&#xD;
          -  ECOG performance status of 0-2&#xD;
&#xD;
          -  Ability to initiate treatment within 3 months after disease progression or&#xD;
             unacceptable toxicity on a Stage 1 regimen&#xD;
&#xD;
        Exclusion Criteria for Both Stages:&#xD;
&#xD;
          -  Significant or uncontrolled comorbid disease as specified in the protocol&#xD;
&#xD;
          -  Uncontrolled tumor-related pain&#xD;
&#xD;
          -  Autoimmune disease except for stable/controlled hypothyroidism, Type 1 diabetes&#xD;
             mellitus, or certain dermatologic conditions&#xD;
&#xD;
          -  Positive human immunodeficiency virus test&#xD;
&#xD;
          -  Active hepatitis B or C&#xD;
&#xD;
          -  Active tuberculosis&#xD;
&#xD;
          -  Severe infection within 4 weeks and/or antibiotics within 2 weeks prior to study&#xD;
             treatment&#xD;
&#xD;
          -  Prior allogeneic stem cell or solid organ transplantation&#xD;
&#xD;
          -  History of malignancy other than breast cancer within 2 years prior to screening&#xD;
             except those with negligible risk of metastasis/death&#xD;
&#xD;
          -  History of or known hypersensitivity to study drug or excipients&#xD;
&#xD;
          -  For patients entering Stage 2, recovery from all immunotherapy-related adverse events&#xD;
             to Grade 1 or better or to baseline at the time of consent&#xD;
&#xD;
        Exclusion Criteria for Stage 1:&#xD;
&#xD;
          -  Prior fulvestrant or cytotoxic chemotherapy for metastatic breast cancer, or certain&#xD;
             other agents as specified in the protocol&#xD;
&#xD;
          -  Unresolved AEs from prior anti-cancer therapy&#xD;
&#xD;
          -  Eligibility only for the control arm&#xD;
&#xD;
          -  Prior treatment with inhibitors as specified in the protocol&#xD;
&#xD;
        Exclusion Criteria for Stage 2:&#xD;
&#xD;
          -  Unacceptable toxicity with atezolizumab during Stage 1&#xD;
&#xD;
          -  Uncontrolled cardiovascular disease or coagulation disorder, including use of&#xD;
             anticoagulants as specified in the protocol&#xD;
&#xD;
          -  Significant abdominal or intestinal manifestations within 6 months prior to treatment&#xD;
&#xD;
          -  Grade 2 or higher proteinuria&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Clinical Trials</last_name>
    <role>Study Director</role>
    <affiliation>Hoffmann-La Roche</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Alabama at Birmingham</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35249</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <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>
  </location>
  <location>
    <facility>
      <name>UCSF Helen Diller Family CCC</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94158</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stanford Cancer Institute</name>
      <address>
        <city>Stanford</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center</name>
      <address>
        <city>Torrance</city>
        <state>California</state>
        <zip>90502</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Wellness Oncology and Hematology - Main Office</name>
      <address>
        <city>West Hills</city>
        <state>California</state>
        <zip>91307</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwest Georgia Oncology Centers PC - Marietta</name>
      <address>
        <city>Marietta</city>
        <state>Georgia</state>
        <zip>30060</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rush University Medical Center - Chicago</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Johns Hopkins Sidney Kimmel Comprehensive Cancer Center</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Levine Cancer Institute</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>28204</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Ohio State University Comprehensive Cancer Center</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43221</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Providence Cancer Center</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97231</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UPMC Pinnacle Health System</name>
      <address>
        <city>Harrisburg</city>
        <state>Pennsylvania</state>
        <zip>17102</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Thomas Jefferson University Hospital</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Univ of Pittsburgh Sch of Med; Magee-Womens Hospital</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sarah Cannon Research Institute</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Houston Methodist Hospital; Department of Pharmacy</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwest Medical Specialties, PLLC; Research Department</name>
      <address>
        <city>Tacoma</city>
        <state>Washington</state>
        <zip>98405</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rambam Medical Center</name>
      <address>
        <city>Haifa</city>
        <zip>3109601</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Shaare Zedek Medical Center</name>
      <address>
        <city>Jerusalem</city>
        <zip>9103102</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rabin Medical Center-Beilinson Campus; Davidof Institute</name>
      <address>
        <city>Petach Tikva</city>
        <zip>4941492</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sheba Medical Center</name>
      <address>
        <city>Ramat Gan</city>
        <zip>5262100</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tel Aviv Sourasky Medical Center; Pharmacy</name>
      <address>
        <city>Tel Aviv</city>
        <zip>6423906</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National Cancer Center</name>
      <address>
        <city>Goyang-si</city>
        <zip>10408</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seoul National University Hospital</name>
      <address>
        <city>Seoul</city>
        <zip>03080</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Ulsan College of Medicine - Asan Medical Center</name>
      <address>
        <city>Seoul</city>
        <zip>05505</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Israel</country>
    <country>Korea, Republic of</country>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>September 11, 2017</study_first_submitted>
  <study_first_submitted_qc>September 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 12, 2017</study_first_posted>
  <last_update_submitted>September 14, 2023</last_update_submitted>
  <last_update_submitted_qc>September 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <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>Tamoxifen</mesh_term>
    <mesh_term>Bevacizumab</mesh_term>
    <mesh_term>Atezolizumab</mesh_term>
    <mesh_term>Fulvestrant</mesh_term>
    <mesh_term>Exemestane</mesh_term>
    <mesh_term>Entinostat</mesh_term>
    <mesh_term>Ipatasertib</mesh_term>
    <mesh_term>Antibodies</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03280563
org study id: CO39611
secondary id: 2017-000335-14
nct id: NCT03280563
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
This study is designed to evaluate the efficacy, safety, and pharmacokinetics of several
      immunotherapy-based combination treatments in participants with inoperable locally advanced
      or metastatic HR-positive, HER2-negative breast cancer who have progressed during or
      following treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor in the first- or
      second-line setting, such as palbociclib, ribociclib, or abemaciclib. The study will be
      performed in two stages. During Stage 1, participants will be randomized to fulvestrant
      (control) or an atezolizumab-containing doublet or triplet combination. Those who experience
      disease progression, loss of clinical benefit, or unacceptable toxicity may be eligible to
      receive a new triplet combination treatment in Stage 2 until loss of clinical benefit or
      unacceptable toxicity. New treatment arms may be added and/or existing treatment arms may be
      closed during the course of the study on the basis of ongoing clinical efficacy and safety as
      well as the current treatments available.
allocation: Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Percentage of Participants with Objective Response during Stage 1 According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1
time frame: From baseline until disease progression or loss of clinical benefit (up to 6 years overall)
measure: Progression-Free Survival during Stage 1 According to RECIST v1.1
time frame: From randomization until disease progression or death from any cause (up to 6 years overall)
measure: Percentage of Participants with Clinical Benefit during Stage 1 According to RECIST v1.1
time frame: From baseline until disease progression or loss of clinical benefit (up to 6 years overall)
measure: Overall Survival during Stage 1
time frame: From randomization until death from any cause (up to 6 years overall)
measure: Percentage of Participants Alive at 18 Months during Stage 1
time frame: 18 months
measure: Duration of Response during Stage 1 According to RECIST v1.1
time frame: From first objective response until disease progression or death from any cause (up to 6 years overall)
measure: Percentage of Participants with Adverse Events (AEs) during Stage 1
time frame: From baseline until 30 days after last dose or initiation of new systemic anti-cancer therapy (up to 6 years overall)
measure: Percentage of Participants with AEs during Stage 2
time frame: From baseline until 30 days after last dose or initiation of new systemic anti-cancer therapy (up to 6 years overall)
measure: Atezolizumab Serum Concentration during Stage 1
time frame: Predose (0 hours [h]) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 21-28 days); postdose (30 min) (infusion = 30-60 min) on Day 1 of Cycle 1; at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
measure: Entinostat Serum and Plasma Concentration during Stage 1
time frame: Serum predose (0 h) and plasma postdose (2-4 h) on Day 1 of Cycle 1; plasma predose (0 h) on Day 1 of Cycle 2 (cycle = 21 days)
measure: Fulvestrant Plasma Concentration during Stage 1
time frame: Predose (0 h) on Day 1 of Cycles 2-3 (cycle = 28 days)
measure: Ipatasertib Plasma Concentration during Stage 1
time frame: Predose (0 h) and postdose (1, 2, 4, 6 h) on Day 15 of Cycle 1; postdose (1-3 h) on Day 15 of Cycle 3
measure: Atezolizumab Serum Concentration during Stage 2
time frame: Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 21-28 days); postdose (30 min) (infusion = 30-60 min) on Day 1 of Cycle 1; at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
measure: Bevacizumab Serum Concentration during Stage 2
time frame: Predose (0 h) and postdose (30 min) (infusion = 30-90 min) on Day 1 of Cycles 1, 3 (cycle = 21-28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
measure: Exemestane Plasma Concentration during Stage 2
time frame: Predose (0 h) on Day 1 of Cycle 2 (cycle = 21 days)
measure: Fulvestrant Plasma Concentration during Stage 2
time frame: Predose (0 h) on Day 1 of Cycles 2-3 (cycle = 28 days)
measure: Tamoxifen Plasma Concentration during Stage 2
time frame: Predose (0 h) on Day 1 of Cycle 2 (cycle = 21 days)
measure: Percentage of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab during Stage 1
time frame: Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
measure: Percentage of Participants with ADAs to Atezolizumab during Stage 2
time frame: Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 21-28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
measure: Percentage of Participants with ADAs to Bevacizumab during Stage 2
time frame: Predose (0 h) on Day 1 of Cycles 1, 3 (cycle = 21-28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
measure: Abemaciclib Plasma Concentration during Stage 1
time frame: Predose (0 h), Postdose (30 minutes post infusion), and 4-8 hours after dose on Day 1 Cycle 1; Predose on Day 15 Cycle 1 and Day 1 of Cycles 2 and 3
arm group label: Stage 1: Fulvestrant
arm group type: Active Comparator
description: Participants will receive fulvestrant until unacceptable toxicity or disease progression according to RECIST v1.1.
arm group label: Stage 1: Atezolizumab + Entinostat
arm group type: Experimental
description: Participants will receive doublet combination treatment with atezolizumab plus entinostat until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
arm group label: Stage 1: Atezolizumab + Fulvestrant
arm group type: Experimental
description: Participants will receive doublet combination treatment with atezolizumab plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
arm group label: Stage 1: Atezolizumab + Ipatasertib
arm group type: Experimental
description: Participants will receive doublet combination treatment with atezolizumab plus ipatasertib until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Prior to enrollment into this arm, the first 6 participants in the study will complete a safety run-in with atezolizumab plus ipatasertib.
arm group label: Stage 1: Atezolizumab + Ipatasertib + Fulvestrant
arm group type: Experimental
description: Participants will receive triplet combination treatment with atezolizumab plus ipatasertib plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Prior to enrollment into this arm, the first 6 participants in the study will complete a safety run-in with atezolizumab plus ipatasertib.
arm group label: Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy
arm group type: Experimental
description: Those who progress or experience unacceptable toxicity during treatment in Stage 1 may be eligible to enter Stage 2. Participants will receive triplet combination therapy with atezolizumab plus bevacizumab plus one of three endocrine therapies (fulvestrant, exemestane, or tamoxifen) selected by the physician. Treatment in Stage 2 will continue until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
arm group label: Stage 1: Mandatory On-Treatment Biopsy
arm group type: Experimental
description: For experimental combination arms that demonstrate clinical activity during the preliminary phase, the Sponsor may open enrollment into a separate mandatory on-treatment biopsy cohort for that combination.
arm group label: Stage 1: Atezolizumab + Abemaciclib + Fulvestrant
arm group type: Experimental
description: Participants will receive triplet combination treatment with atezolizumab plus abemaciclib plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
intervention type: Drug
intervention name: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
description: Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with entinostat in Stage 1, or exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.
arm group label: Stage 1: Atezolizumab + Abemaciclib + Fulvestrant
arm group label: Stage 1: Atezolizumab + Entinostat
arm group label: Stage 1: Atezolizumab + Fulvestrant
arm group label: Stage 1: Atezolizumab + Ipatasertib
arm group label: Stage 1: Atezolizumab + Ipatasertib + Fulvestrant
arm group label: Stage 1: Mandatory On-Treatment Biopsy
arm group label: Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy
other name: Tecentriq
intervention type: Drug
intervention name: Bevacizumab
description: Bevacizumab will be given as 10 milligrams per kilogram (mg/kg) via IV infusion on Days 1 and 15 of each 28-day cycle in the regimen containing fulvestrant. When given with exemestane or tamoxifen, bevacizumab will be given as 15 mg/kg via IV infusion on Day 1 of each 21-day cycle.
arm group label: Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy
other name: Avastin
intervention type: Drug
intervention name: Entinostat
description: Entinostat will be given as 5 mg orally once a week on Days 1, 8 and 15 of each 21-day cycle.
arm group label: Stage 1: Atezolizumab + Entinostat
arm group label: Stage 1: Mandatory On-Treatment Biopsy
intervention type: Drug
intervention name: Exemestane
description: Exemestane will be given as 25 mg orally QD in each 21-day cycle.
arm group label: Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy
intervention type: Drug
intervention name: Fulvestrant
description: Fulvestrant will be given as 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle.
arm group label: Stage 1: Atezolizumab + Abemaciclib + Fulvestrant
arm group label: Stage 1: Atezolizumab + Fulvestrant
arm group label: Stage 1: Atezolizumab + Ipatasertib + Fulvestrant
arm group label: Stage 1: Fulvestrant
arm group label: Stage 1: Mandatory On-Treatment Biopsy
arm group label: Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy
intervention type: Drug
intervention name: Ipatasertib
description: Ipatasertib will be given as 400 mg orally QD on Days 1-21 of each 28-day cycle.
arm group label: Stage 1: Atezolizumab + Ipatasertib
arm group label: Stage 1: Atezolizumab + Ipatasertib + Fulvestrant
arm group label: Stage 1: Mandatory On-Treatment Biopsy
intervention type: Drug
intervention name: Tamoxifen
description: Tamoxifen will be given as 20 mg orally QD in each 21-day cycle.
arm group label: Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy
intervention type: Drug
intervention name: Abemaciclib
description: Abemaciclib will be given as 150mg twice daily during each 28-day cycle.
arm group label: Stage 1: Atezolizumab + Abemaciclib + Fulvestrant
arm group label: Stage 1: Mandatory On-Treatment Biopsy
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Clinical Trials
role: Study Director
affiliation: Hoffmann-La Roche
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country: Israel
country: Korea, Republic of
country: United States
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Tamoxifen
mesh term: Bevacizumab
mesh term: Atezolizumab
mesh term: Fulvestrant
mesh term: Exemestane
mesh term: Entinostat
mesh term: Ipatasertib
mesh term: Antibodies