<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/NCT02213042</url>
  </required_header>
  <id_info>
    <org_study_id>117165</org_study_id>
    <secondary_id>2014-001220-30</secondary_id>
    <secondary_id>CLAP016A2206</secondary_id>
    <nct_id>NCT02213042</nct_id>
  </id_info>
  <brief_title>Evaluation of Biomarkers Associated With Response to Subsequent Therapies in Subjects With HER2-Positive Metastatic Breast Cancer</brief_title>
  <official_title>An Open-Label, Phase II, Study to Evaluate Biomarkers Associated With Response to Subsequent Therapies in Subjects With HER2-Positive Metastatic Breast Cancer Receiving Treatment With Trastuzumab in Combination With Lapatinib or Chemotherapy (EGF117165)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Novartis</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This was a multicenter, open-label, Phase II study in subjects with Human epidermal growth&#xD;
      factor receptor (HER2)-positive metastatic breast cancer who received at least 2 prior lines&#xD;
      of anti-HER2-targeted therapies of which at least one included a Trastuzumab-containing&#xD;
      regimen. This study was a post-approval commitment with regulatory authorities. It was&#xD;
      designed to evaluate whether treatment with Dual blockade promoted changes to biomarkers&#xD;
      associated with immunomodulation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study was designed to address the post-authorization measures as agreed with the&#xD;
      Committee for Medicinal Products for Human Use (CHMP). Recruitment of subjects into this&#xD;
      study was challenging, and following agreement with the European Medicines Agency (EMA)&#xD;
      enrollment into this study was halted after the enrollment of 42 of the 225 planned subjects.&#xD;
&#xD;
      The primary endpoint of the study evaluated changes in expression of biomarkers associated&#xD;
      with immunomodulation between a pre-treatment biopsy and the disease progression biopsy.&#xD;
      Secondary efficacy endpoints included overall response rate, clinical benefit rate and&#xD;
      progression-free survival (PFS), as well as safety/tolerability. All subjects received study&#xD;
      treatment until disease progression, death, unacceptable toxicity, or subject withdrawal. In&#xD;
      case of disease progression during the treatment period, the subject was followed-up for 30&#xD;
      days for safety evaluation. In case of study treatment discontinuation for any reasons other&#xD;
      than disease progression, the subject was followed-up for safety and efficacy assessments&#xD;
      until disease progression, new anticancer therapy, death, withdrawal of consent or end of&#xD;
      study, whichever came first.&#xD;
&#xD;
      This study supported a better understanding of the rapidly accumulating evidence for the&#xD;
      importance of the immune microenvironment in HER2-positive breast cancer and the observed&#xD;
      immunomodulation in the neoadjuvant setting could be confirmed in the advanced setting and&#xD;
      supported the putative mechanism of action of HER2 dual blockade and its potential function&#xD;
      on the tumor microenvironment. No formal comparisons between treatment arms were undertaken.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Primary analysis was completed in 2018 and continued minimal data collection from the one&#xD;
    participant active in the study was not expected to add meaningful knowledge to the&#xD;
    understanding of lapatinib&#xD;
  </why_stopped>
  <start_date type="Actual">October 24, 2014</start_date>
  <completion_date type="Actual">June 4, 2020</completion_date>
  <primary_completion_date type="Actual">June 4, 2020</primary_completion_date>
  <phase>Phase 2</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>
    <intervention_model_description>Participants were randomized to Arms A and B but randomized to Arm C.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>This was a two-cohort, three-arm, open-label Phase II study to evaluate the changes in the expression of biomarkers between pre-treatment and progression biopsy in subjects with Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Subjects were allocated to 1 of 2 cohorts depending on the molecular subtype of their biopsy.&#xD;
Cohort 1 HER2 -enriched included HER2-positive subjects with a HER2-Enriched molecular subtype, and were randomized in a 1:1 ratio to receive either trastuzumab in combination with lapatinib (Arm A) or trastuzumab in combination with chemotherapy (Arm B).&#xD;
Cohort 2 non-HER2-enriched, included HER2-positive subjects with luminal A, luminal B, and basal-like molecular subtypes and were to receive trastuzumab in combination with lapatinib (Arm C). Subjects with hormone receptor (ER and/or PgR)-positive MBC in this arm were required to be treated with an AI of the Investigator's choice.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Fold Change in Expression Profile of Genes and/or Proteins for Arm A (LAP+TRAS±AI (HER2-Enriched)) From Screening to Approx. 3.5 Years</measure>
    <time_frame>At screening and at disease progression, assessed up to approx. 3.5 years</time_frame>
    <description>Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available.&#xD;
For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Fold Change in Expression Profile of Genes and /or Proteins for Arm B (TRAS+CHEM±AI (HER2-Enriched)) From Screening to Approx. 3.5 Years</measure>
    <time_frame>At screening and at disease progression, assessed up to approx. 3.5 years</time_frame>
    <description>Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available.&#xD;
For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Fold Change in Expression Profile of Genes and /or Proteins for Arm C (Non-HER2- Enriched) From Screening to Approx. 3.5 Years</measure>
    <time_frame>At screening and at disease progression, assessed up to approx. 3.5 years</time_frame>
    <description>Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available.&#xD;
For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival (PFS)</measure>
    <time_frame>From randomization to disease progression or death, up to approx. 5.6 years</time_frame>
    <description>PFS was defined as the time from the date of randomization (for Arm A and B) / treatment start date (for Arm C) to the date of the first documented disease progression or death due to any cause, whichever was earlier. If a subject had not progressed or died at the analysis cutoff date, PFS was censored at the time of the last adequate tumor assessment. PFS was summarized using Kaplan-Meier estimates.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate (ORR)</measure>
    <time_frame>From enrollment/randomization to the end of study, approximately 5.6 years</time_frame>
    <description>Overall response rate was defined as the percentage of subjects achieving either a confirmed complete response (CR) or partial response (PR) and was calculated from the Investigator's assessment of response per RECIST 1.1 criteria. . The confirmed CR or PR was derived using the following rules: confirmed CR - at least two determinations of CR at least 4 weeks apart before disease progression; confirmed PR - at least two determinations of PR or better at least 4 weeks apart before progression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Benefit Rate (CBR)</measure>
    <time_frame>From enrollment/randomization the end of study, approximately 5.6 years</time_frame>
    <description>CBR is defined as percentage of subjects with a complete response (CR), partial response (PR), or maintaining stable disease (SD) for at least 24 weeks while on study according to the investigator assessment of response per RECIST 1.1 criteria. CR and PR are confirmed responses derived using the following rules: Confirmed CR - at least 2 determinations of CR at least 4 weeks apart before disease progression. Confirmed PR - at least 2 determinations of PR or better at least 4 weeks apart before progression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Association Between Biomarkers and PFS</measure>
    <time_frame>From randomization to disease progression or death, up to approx. 5.6 years</time_frame>
    <description>Describe if changes of biomarker expression at disease progression from baseline correlate with PFS.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">42</enrollment>
  <condition>Neoplasms, Breast</condition>
  <arm_group>
    <arm_group_label>Lapatinib 1000mg + Trastuzumab in HER2 Enriched</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Trastuzumab in HER2 Enriched</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lapatinib</intervention_name>
    <description>Lapatinib is available as 250-mg orange tablets. Subjects randomized to the Lapatinib plus Trastuzumab arm received 1000 mg per day of Lapatinib, so wre instructed to take 4 x 250 mg tablets per day. Lapatinib was to be taken either 1 hour (or more) before a meal or 1 hour (or more) after a meal</description>
    <arm_group_label>Lapatinib 1000mg + Trastuzumab in HER2 Enriched</arm_group_label>
    <arm_group_label>Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Trastuzumab</intervention_name>
    <description>Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized powder for IV administration. Trastuzumab was administered on Day 1 of the start of Lapatinib or in conjunction with the first cycle of chemotherapy, as an 8 mg/kg loading dose. Subsequently, Trastuzumab was administered q3weekly as a 6 mg/kg maintenance dose. At the discretion of the investigator, weekly Trastuzumab could be given in either of the three treatment arms (loading dose 4mg/kg followed by weekly administration of 2mg/kg).</description>
    <arm_group_label>Lapatinib 1000mg + Trastuzumab in HER2 Enriched</arm_group_label>
    <arm_group_label>Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched</arm_group_label>
    <arm_group_label>Trastuzumab in HER2 Enriched</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aromatase Inhibitors (AIs)</intervention_name>
    <description>Subjects who were hormone receptor-positive were required to receive an aromatase inhibitor as combination treatment; however the choice of the aromatase inhibitor selected for each patient was determined by the patients' investigator. The AIs the Investigator could choose from were anastrozole, exemestane, and letrozole and dosing was per product information.</description>
    <arm_group_label>Lapatinib 1000mg + Trastuzumab in HER2 Enriched</arm_group_label>
    <arm_group_label>Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched</arm_group_label>
    <arm_group_label>Trastuzumab in HER2 Enriched</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed written informed consent&#xD;
&#xD;
          -  Female &gt;=18 years&#xD;
&#xD;
          -  Histologically or cytologically confirmed invasive breast cancer with distant&#xD;
             metastasis&#xD;
&#xD;
          -  Subjects must have at least one measurable lesion per RECIST 1.1&#xD;
&#xD;
          -  Note: Biopsied lesions should not be used as target lesions.&#xD;
&#xD;
          -  Documentation of HER2 overexpression or gene amplification, in the invasive component&#xD;
             of either the primary tumor or metastatic disease site as defined as: 3+ by&#xD;
             Immunohistochemistry (IHC) and/or&#xD;
&#xD;
          -  HER2/neu gene amplification by fluorescence, chromogenic, or silver in situ&#xD;
             hybridization [FISH, CISH or SISH;&gt;=6 HER2/neu gene copies per nucleus or a FISH,&#xD;
             CISH, or SISH test ratio (HER2 gene copies to chromosome 17 signals) of &gt;=2.0 OR&#xD;
             HER2/chromosome 17 ratio &lt;=2.0 with average HER2 copy number &gt;=6 signals/cell nucleus]&#xD;
&#xD;
          -  Centrally determined HER2-positive, hormone receptor status, breast molecular subtype&#xD;
             by Prediction Analysis of Microarray 50 (PAM50) on the pre-treatment biopsy of&#xD;
             metastatic lesion obtained during screening&#xD;
&#xD;
          -  Note: Biopsied lesions should not be used as target lesions.&#xD;
&#xD;
          -  Progression on at least 2 lines of anti-HER2-targeted therapies for metastatic breast&#xD;
             cancer (MBC)&#xD;
&#xD;
          -  Documented radiological disease progression during the most recent treatment regimen&#xD;
             for metastatic disease&#xD;
&#xD;
          -  Most recent treatment regimen for metastatic disease must include Trastuzumab and&#xD;
             chemotherapy.&#xD;
&#xD;
          -  Note: Trastuzumab emtansine (T-DM1) is considered acceptable as prior&#xD;
             Trastuzumab/chemotherapy regimen&#xD;
&#xD;
          -  Agreement to provide 2 tumor biopsies&#xD;
&#xD;
          -  Prior treatment with pertuzumab, Lapatinib, and/or Trastuzumab emtansine is allowed;&#xD;
             however, the last treatment for MBC must not include Trastuzumab in combination with&#xD;
             pertuzumab.&#xD;
&#xD;
          -  Subjects with radiographically stable Central nervous system (CNS) metastases, defined&#xD;
             as radiographically stable on the previous 2 brain imaging scans, asymptomatic, and&#xD;
             off systemic steroids and anticonvulsants for at least 1 month are eligible; treatment&#xD;
             with prophylactic anticonvulsants is permitted unless listed under Prohibited&#xD;
             Medications&#xD;
&#xD;
          -  Discontinuation of all prior chemotherapy, immunotherapy, or biological therapy at&#xD;
             least 3 weeks prior to the first dose of investigational product is required.&#xD;
&#xD;
          -  Note: Discontinuation of Trastuzumab is not necessary.&#xD;
&#xD;
          -  All treatment related toxicities, except alopecia, must have recovered to Grade 1 or&#xD;
             better (Common Terminology Criteria for Adverse Events (CTCAE); version 4.0) prior to&#xD;
             administration of the first dose of study treatment.&#xD;
&#xD;
          -  Baseline Left ventricular ejection fraction (LVEF) &gt;=50% as measured by Echocardiogram&#xD;
             (ECHO) or Multigated acquisition (MUGA) and above the testing institution's lower&#xD;
             limit of normal&#xD;
&#xD;
          -  QT interval corrected (QTc) &lt;450 millisecond (msec) or QTc &lt;480 msec for patients with&#xD;
             bundle branch block.&#xD;
&#xD;
          -  The QTc is the QT interval corrected for heart rate according to either Bazett's&#xD;
             formula (QTcB)&#xD;
&#xD;
          -  Fridericia's formula (QTcF), or another method, machine or manual overread.&#xD;
&#xD;
          -  For subject eligibility and withdrawal, QT correction formula QTcB will be used.&#xD;
&#xD;
          -  For purposes of this data analysis, Bazett's formula will be used as the primary&#xD;
             method of calculating the corrected QT interval. The QTc should be based on either a&#xD;
             single Electrocardiogram (ECG) or an average of 3 sequential ECGs obtained within 24&#xD;
             hours of each other.&#xD;
&#xD;
          -  The QTc should be based on single or averaged QTc values of triplicate ECGs obtained&#xD;
             over a brief recording period.&#xD;
&#xD;
          -  Women of childbearing potential must have a negative serum pregnancy test within 7&#xD;
             days prior to the first dose of study treatment and agree to use effective&#xD;
             contraception, during the study and for 30 days following the last dose of study&#xD;
             treatment.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1&#xD;
&#xD;
          -  Completion of screening and baseline assessments&#xD;
&#xD;
          -  Able to swallow and retain orally administered medication and does not have any&#xD;
             clinically significant gastrointestinal abnormalities that may alter absorption such&#xD;
             as malabsorption syndrome or major resection of the stomach or bowels.&#xD;
&#xD;
          -  At least 4 weeks must have elapsed since the last surgery and 2 weeks must have&#xD;
             elapsed since radiotherapy&#xD;
&#xD;
          -  Adequate baseline organ function as defined below&#xD;
&#xD;
          -  Screening laboratory values should be used to confirm subject eligibility. Laboratory&#xD;
             results may be retested if necessary to confirm eligibility.&#xD;
&#xD;
          -  Hematologic(These values must be independent of growth factor support and stable for&#xD;
             at least one week post transfusion)&#xD;
&#xD;
          -  Absolute neutrophil count &gt;=1.5 x 10^9/litre (L)&#xD;
&#xD;
          -  Hemoglobin &gt;=9.0 grams/decilitre(g/dL) (after transfusion if needed)&#xD;
&#xD;
          -  Platelets&gt;=100 x 10^9/L&#xD;
&#xD;
          -  Hepatic&#xD;
&#xD;
          -  Albumin &gt;=2.5 g/dL&#xD;
&#xD;
          -  Serum bilirubin &lt;=1.25 x upper limit of normal (ULN)( These values must be independent&#xD;
             of growth factor support and stable for at least one week post transfusion)&#xD;
&#xD;
          -  Alanine aminotransferase; and, Aspartate aminotransferase AST and ALT&lt;=2.5 x ULN&#xD;
&#xD;
          -  Renal&#xD;
&#xD;
          -  Calculate creatinine clearance &gt;=40 millilitre/ minute (mL/min) (With the exception of&#xD;
             those subjects who have Gilbert's syndrome; the bilirubin in these subjects should be&#xD;
             at their baseline)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Lactating female&#xD;
&#xD;
          -  Note: Women with potential to have children must be willing to practice acceptable&#xD;
             methods of birth control during the study&#xD;
&#xD;
          -  Bone-only disease and/or disease that cannot be biopsied.&#xD;
&#xD;
          -  Unstable CNS metastases or leptomeningeal carcinomatosis not considered&#xD;
             radiographically stable&#xD;
&#xD;
          -  Note: Subjects with radiographically stable CNS metastases are defined as&#xD;
             radiographically stable on the previous 2 brain imaging studies, asymptomatic, and off&#xD;
             systemic steroids and anticonvulsants for at least 1 month; treatment with&#xD;
             prophylactic anticonvulsants is permitted unless listed under prohibited medications&#xD;
&#xD;
          -  Any serious and/or unstable pre-existing medical, psychiatric disorder, or other&#xD;
             conditions including concurrent disease that could interfere with subject's safety,&#xD;
             obtaining informed consent, or compliance with the study procedures.&#xD;
&#xD;
          -  Serious cardiac illness or medical condition including but not confined to:&#xD;
             Uncontrolled arrhythmias (e.g. ventricular tachycardia, high-grade atrioventricular&#xD;
             (AV)-block, supraventricular arrhythmias which are not adequately rate-controlled);&#xD;
&#xD;
          -  Angina pectoris requiring antianginal medication&#xD;
&#xD;
          -  History of congestive heart failure or systolic dysfunction (LVEF &lt;50%)&#xD;
&#xD;
          -  Documented myocardial infarction &lt;6 months from study entry&#xD;
&#xD;
          -  Evidence of transmural infarction on ECG&#xD;
&#xD;
          -  Poorly controlled hypertension (e.g. systolic &gt;160milimiter (mm) Mercury (Hg) or&#xD;
             diastolic &gt;100mm Hg)&#xD;
&#xD;
          -  Clinically significant valvular heart disease&#xD;
&#xD;
          -  Current active hepatic or biliary disease (with exception of subjects with Gilbert's&#xD;
             syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease&#xD;
             per investigator assessment)&#xD;
&#xD;
          -  Any clinically significant gastrointestinal abnormalities that may alter absorption&#xD;
             such as malabsorption syndrome or major resection of the stomach or bowels as well as&#xD;
             subjects with ulcerative colitis are also excluded&#xD;
&#xD;
          -  Any prohibited medication&#xD;
&#xD;
          -  Prior treatment with Trastuzumab in combination with Lapatinib or prior treatment with&#xD;
             an irreversible inhibitor of the intracellular domain of the HER2 receptor such as&#xD;
             neratinib&#xD;
&#xD;
          -  Last treatment for metastatic disease including Trastuzumab in combination with&#xD;
             pertuzumab&#xD;
&#xD;
          -  Administration of an investigational drug within 30 days or 5 half-lives, whichever is&#xD;
             longer, preceding the first dose of study treatment&#xD;
&#xD;
          -  A known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs&#xD;
             chemically related to any of the study drugs or their excipients that, in the opinion&#xD;
             of the investigator or medical monitor, contraindicates participation&#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>Novartis Pharmaceuticals</last_name>
    <role>Study Director</role>
    <affiliation>Novartis Pharmaceuticals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Mobile</city>
        <state>Alabama</state>
        <zip>36608</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Berazategui</city>
        <state>Buenos Aires</state>
        <zip>B1880BBF</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Ciudad Autonoma de Buenos Aires</city>
        <state>Buenos Aires</state>
        <zip>C1125ABD</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Viedma</city>
        <state>Río Negro</state>
        <zip>R8500ACE</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Rosario</city>
        <state>Santa Fe</state>
        <zip>S2000KZE</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Ciudad Autonoma de Buenos Aires</city>
        <zip>C1025ABI</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Cordoba</city>
        <zip>X5004FHP</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>La Rioja</city>
        <zip>F5300COE</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>San Miguel de Tucuman</city>
        <zip>T4000IAK</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Salzburg</city>
        <zip>A-5020</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Wien</city>
        <zip>1090</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Salvador</city>
        <state>Bahía</state>
        <zip>41825-010</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Belo Horizonte</city>
        <state>Minas Gerais</state>
        <zip>30130-090</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Porto Alegre</city>
        <state>Rio Grande Do Sul</state>
        <zip>90430-090</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Porto Alegre</city>
        <state>Rio Grande Do Sul</state>
        <zip>90470-340</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Porto Alegre</city>
        <state>Rio Grande Do Sul</state>
        <zip>90610-000</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Itajai</city>
        <state>Santa Catarina</state>
        <zip>88301220</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Barretos</city>
        <state>São Paulo</state>
        <zip>14784-400</zip>
        <country>Brazil</country>
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    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Sao Paulo</city>
        <state>São Paulo</state>
        <zip>01236030</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Sao Paulo</city>
        <state>São Paulo</state>
        <zip>01317-001</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Sao Jose do Rio Preto</city>
        <zip>15090-000</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Pok Fu Lam</city>
        <country>Hong Kong</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Pokfulam</city>
        <country>Hong Kong</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Milano</city>
        <state>Lombardia</state>
        <zip>20133</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Milano</city>
        <state>Lombardia</state>
        <zip>20141</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Mexico</city>
        <zip>06760</zip>
        <country>Mexico</country>
      </address>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Arequipa</city>
        <country>Peru</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Lima</city>
        <zip>Lima 34</zip>
        <country>Peru</country>
      </address>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Cebu</city>
        <zip>6000</zip>
        <country>Philippines</country>
      </address>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Manila</city>
        <zip>1000</zip>
        <country>Philippines</country>
      </address>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Kazan</city>
        <zip>420029</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Moscow</city>
        <zip>115 478</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Ryazan</city>
        <zip>390011</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>St. Petersburg</city>
        <zip>197022</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>St. Petersburg</city>
        <zip>197758</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Volzhskiy</city>
        <zip>404130</zip>
        <country>Russian Federation</country>
      </address>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Barcelona</city>
        <zip>08035</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Barcelona</city>
        <zip>08036</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Donostia</city>
        <zip>20014</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Madrid</city>
        <zip>28034</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Madrid</city>
        <zip>28040</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Madrid</city>
        <zip>28041</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Malaga</city>
        <zip>29010</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Sevilla</city>
        <zip>41013</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Valencia</city>
        <zip>46010</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Valencia</city>
        <zip>46015</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Bangkok</city>
        <zip>10330</zip>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Chiangmai</city>
        <zip>50200</zip>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Phitsanulok</city>
        <zip>65000</zip>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Argentina</country>
    <country>Austria</country>
    <country>Brazil</country>
    <country>Hong Kong</country>
    <country>Italy</country>
    <country>Mexico</country>
    <country>Peru</country>
    <country>Philippines</country>
    <country>Russian Federation</country>
    <country>Spain</country>
    <country>Thailand</country>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2021</verification_date>
  <study_first_submitted>August 7, 2014</study_first_submitted>
  <study_first_submitted_qc>August 7, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 11, 2014</study_first_posted>
  <results_first_submitted>June 1, 2021</results_first_submitted>
  <results_first_submitted_qc>August 20, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">September 16, 2021</results_first_posted>
  <disposition_first_submitted>May 3, 2021</disposition_first_submitted>
  <disposition_first_submitted_qc>May 4, 2021</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">May 7, 2021</disposition_first_posted>
  <last_update_submitted>September 17, 2021</last_update_submitted>
  <last_update_submitted_qc>September 17, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 13, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>CLAP016A2206</keyword>
  <keyword>biomarker</keyword>
  <keyword>Lapatinib</keyword>
  <keyword>Prosigna</keyword>
  <keyword>ErbB2</keyword>
  <keyword>PAM50</keyword>
  <keyword>HER2</keyword>
  <keyword>HER2-overexpressing metastatic breast cancer</keyword>
  <keyword>HER2-enriched</keyword>
  <keyword>Trastuzumab</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>Trastuzumab</mesh_term>
    <mesh_term>Lapatinib</mesh_term>
    <mesh_term>Aromatase Inhibitors</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.&#xD;
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com</ipd_description>
    <ipd_url>http://www.clinicalstudydatarequest.com</ipd_url>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>May 15, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/42/NCT02213042/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>November 10, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/42/NCT02213042/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Overall, 225 subjects were planned and 42 subjects were enrolled in this study</recruitment_details>
      <pre_assignment_details>This study was designed to address the post-authorization measures as agreed with the Committee for Medicinal Products for Human Use (CHMP). Recruitment of subjects into this study was challenging, and following agreement with the European Medicines Agency (EMA) enrollment into this study was halted after the enrollment of 42 of the 225 planned subjects.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>LAP+TRAS±AI (HER2-Enriched) - Arm A</title>
          <description>Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.</description>
        </group>
        <group group_id="P2">
          <title>TRAS+CHEM±AI (HER2-Enriched) - Arm B</title>
          <description>Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.</description>
        </group>
        <group group_id="P3">
          <title>Non-HER2- Enriched - Arm C</title>
          <description>Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
                <participants group_id="P2" count="15"/>
                <participants group_id="P3" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Total Deaths</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
                <participants group_id="P2" count="15"/>
                <participants group_id="P3" count="10"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Disease progression (incl. death due to disease progression)</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
                <participants group_id="P2" count="13"/>
                <participants group_id="P3" count="8"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Investigator discretion</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Full Analysis Set (FAS): Consisted of all subjects who were randomized to study Arm A or Arm B or assigned to study Arm C, irrespective of whether they actually received study treatment.</population>
      <group_list>
        <group group_id="B1">
          <title>LAP+TRAS±AI (HER2-Enriched) - Arm A</title>
          <description>Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.</description>
        </group>
        <group group_id="B2">
          <title>TRAS+CHEM±AI (HER2-Enriched) - Arm B</title>
          <description>Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.</description>
        </group>
        <group group_id="B3">
          <title>Non-HER2- Enriched - Arm C</title>
          <description>Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="17"/>
            <count group_id="B2" value="15"/>
            <count group_id="B3" value="10"/>
            <count group_id="B4" value="42"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age, Customized</title>
          <units>Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>&lt; 65 years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>&gt;= 65 years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="10"/>
                    <measurement group_id="B4" value="42"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Caucasian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="10"/>
                    <measurement group_id="B4" value="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>African American</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Asian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Native Hawaiian or Pacific Islander</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Fold Change in Expression Profile of Genes and/or Proteins for Arm A (LAP+TRAS±AI (HER2-Enriched)) From Screening to Approx. 3.5 Years</title>
        <description>Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available.&#xD;
For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.</description>
        <time_frame>At screening and at disease progression, assessed up to approx. 3.5 years</time_frame>
        <population>Evaluable Set: Included all subjects in Arm A who received the study treatment and had both baseline and progression tumor biopsies available, with evaluable data for at least 1 biomarker.</population>
        <group_list>
          <group group_id="O1">
            <title>LAP+TRAS±AI (HER2-Enriched) - Arm A</title>
            <description>Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.</description>
          </group>
        </group_list>
        <measure>
          <title>Fold Change in Expression Profile of Genes and/or Proteins for Arm A (LAP+TRAS±AI (HER2-Enriched)) From Screening to Approx. 3.5 Years</title>
          <description>Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available.&#xD;
For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.</description>
          <population>Evaluable Set: Included all subjects in Arm A who received the study treatment and had both baseline and progression tumor biopsies available, with evaluable data for at least 1 biomarker.</population>
          <units>Ratio of gene expression level</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Membrane spanning 4-domains A1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.25" lower_limit="0.078" upper_limit="0.589"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>POU class 2 associating factor 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.32" lower_limit="0.183" upper_limit="0.543"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CD19+</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.35" lower_limit="0.106" upper_limit="0.904"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Interleukin 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.36" lower_limit="0.033" upper_limit="0.832"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>G antigen 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.43" lower_limit="0.030" upper_limit="0.901"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ubiquitin specific peptidase 9, Y-linked</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.50" lower_limit="0.321" upper_limit="0.770"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Thy-1 cell surface antigen</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.50" lower_limit="0.113" upper_limit="0.902"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Chemerin chemokine-like receptor 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.51" lower_limit="0.345" upper_limit="0.862"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Major histocompatibility complex, class II, DR beta 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.51" lower_limit="0.320" upper_limit="0.984"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Collectin subfamily member 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.51" lower_limit="0.151" upper_limit="0.794"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Complement C3b/C4b receptor 1 (Knops blood group)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.51" lower_limit="0.227" upper_limit="0.901"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CD33 molecule</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.56" lower_limit="0.458" upper_limit="0.826"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>B-cell linker</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.56" lower_limit="0.326" upper_limit="0.874"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Interleukin 12A</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.57" lower_limit="0.228" upper_limit="0.892"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CD163+</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.57" lower_limit="0.417" upper_limit="0.911"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>C-C motif chemokine ligand 8</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.58" lower_limit="0.138" upper_limit="0.954"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Chemokine (C-C motif) receptor 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.59" lower_limit="0.501" upper_limit="0.792"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>POU class 2 homeobox 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.60" lower_limit="0.440" upper_limit="0.944"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cyclin dependent kinase inhibitor 1A</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.62" lower_limit="0.453" upper_limit="0.873"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CD27 molecule</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.62" lower_limit="0.357" upper_limit="0.886"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Lymphocyte antigen 86</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.63" lower_limit="0.383" upper_limit="0.906"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TNF superfamily member 8</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.64" lower_limit="0.476" upper_limit="0.879"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CD34+</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.67" lower_limit="0.558" upper_limit="0.863"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Integrin subunit alpha 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.68" lower_limit="0.470" upper_limit="0.827"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>C-type lectin domain containing 7A</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.69" lower_limit="0.326" upper_limit="0.944"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CD180 molecule</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.70" lower_limit="0.347" upper_limit="0.869"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Integrin subunit alpha M</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.72" lower_limit="0.411" upper_limit="0.957"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Toll like receptor 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.72" lower_limit="0.511" upper_limit="0.836"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Autophagy related 10</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.73" lower_limit="0.662" upper_limit="0.864"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>C-C motif chemokine ligand 3 like 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.74" lower_limit="0.499" upper_limit="0.996"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Bone marrow stromal cell antigen 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.75" lower_limit="0.345" upper_limit="0.922"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CD22+</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.76" lower_limit="0.629" upper_limit="0.936"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CD37 molecule</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.76" lower_limit="0.553" upper_limit="0.884"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>NEG_A</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.77" lower_limit="0.674" upper_limit="0.949"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Sperm auto antigenic protein 17</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.79" lower_limit="0.697" upper_limit="0.968"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CD200 molecule</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.79" lower_limit="0.598" upper_limit="0.945"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TNF receptor associated factor 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.82" lower_limit="0.718" upper_limit="0.962"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Interferon alpha and beta receptor subunit 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.10" lower_limit="1.036" upper_limit="1.124"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TNF receptor associated factor 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.21" lower_limit="1.016" upper_limit="1.332"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Fold Change in Expression Profile of Genes and /or Proteins for Arm B (TRAS+CHEM±AI (HER2-Enriched)) From Screening to Approx. 3.5 Years</title>
        <description>Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available.&#xD;
For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.</description>
        <time_frame>At screening and at disease progression, assessed up to approx. 3.5 years</time_frame>
        <population>Evaluable Set: Included all subjects in Arm B who received the study treatment and had both baseline and progression tumor biopsies available, with evaluable data for at least 1 biomarker.</population>
        <group_list>
          <group group_id="O1">
            <title>TRAS+CHEM±AI (HER2-Enriched) - Arm B</title>
            <description>Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.</description>
          </group>
        </group_list>
        <measure>
          <title>Fold Change in Expression Profile of Genes and /or Proteins for Arm B (TRAS+CHEM±AI (HER2-Enriched)) From Screening to Approx. 3.5 Years</title>
          <description>Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available.&#xD;
For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.</description>
          <population>Evaluable Set: Included all subjects in Arm B who received the study treatment and had both baseline and progression tumor biopsies available, with evaluable data for at least 1 biomarker.</population>
          <units>Ratio of gene expression level</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>C-type lectin domain containing 5A</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.16" lower_limit="0.020" upper_limit="0.440"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Interferon induced transmembrane protein 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.25" lower_limit="0.183" upper_limit="0.421"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Fibronectin 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.27" lower_limit="0.077" upper_limit="0.393"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>C-C motif chemokine ligand 7</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.27" lower_limit="-0.064" upper_limit="0.888"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Triggering receptor expressed on myeloid cells 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.27" lower_limit="-0.018" upper_limit="0.959"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Plasminogen activator, urokinase</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.27" lower_limit="0.112" upper_limit="0.545"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Interleukin 22 receptor subunit alpha 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.28" lower_limit="0.192" upper_limit="0.425"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>C-C motif chemokine ligand 8</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.28" lower_limit="0.044" upper_limit="0.699"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Tumor necrosis factor (ligand) superfamily member 4 gene</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.31" lower_limit="0.147" upper_limit="0.651"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Major histocompatibility complex, Class I-related</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.32" lower_limit="0.139" upper_limit="0.832"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cathepsin L</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.32" lower_limit="0.066" upper_limit="0.820"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SPP-1 (Osteopontin)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.33" lower_limit="0.076" upper_limit="0.501"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Thy-1 cell surface antigen</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.34" lower_limit="0.157" upper_limit="0.648"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Transforming growth factor beta 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.35" lower_limit="0.120" upper_limit="0.504"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hepatitis A virus cellular receptor 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.36" lower_limit="0.138" upper_limit="0.614"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Bone marrow stromal cell antigen 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.37" lower_limit="0.133" upper_limit="0.864"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>C-type lectin domain containing 7A</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.37" lower_limit="0.166" upper_limit="0.570"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>C-X-C motif chemokine ligand 5</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.38" lower_limit="0.040" upper_limit="0.943"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Collagen type III alpha 1 chain</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.40" lower_limit="0.130" upper_limit="0.685"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Complement C1s</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.41" lower_limit="0.088" upper_limit="0.717"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>IFIT1 gene</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.41" lower_limit="0.148" upper_limit="0.921"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Major histocompatibility complex, class I, G</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.41" lower_limit="0.147" upper_limit="0.698"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Tumour necrosis factor gene</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.42" lower_limit="0.108" upper_limit="0.945"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Integrin subunit beta 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.43" lower_limit="0.231" upper_limit="0.864"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Pro-melanin concentrating hormone</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.43" lower_limit="0.081" upper_limit="0.972"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CD86+</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.44" lower_limit="0.102" upper_limit="0.700"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>FCGR3A SNP rs396991</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.44" lower_limit="0.107" upper_limit="0.696"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TNF receptor superfamily member 10c</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.44" lower_limit="0.165" upper_limit="0.925"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Integrin subunit alpha M</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.45" lower_limit="0.166" upper_limit="0.797"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TNF receptor superfamily member 11b</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.45" lower_limit="0.114" upper_limit="0.923"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Platelet derived growth factor C</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.45" lower_limit="0.231" upper_limit="0.797"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Mannan binding lectin serine peptidase 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.46" lower_limit="0.304" upper_limit="0.896"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Recombination activating 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.46" lower_limit="0.394" upper_limit="0.597"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Interleukin 22</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.47" lower_limit="0.229" upper_limit="0.609"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Tumor necrosis factor (ligand) superfamily member 13b gene</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.47" lower_limit="0.179" upper_limit="0.697"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>BMI1 proto-oncogene, polycomb ring finger</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.47" lower_limit="0.322" upper_limit="0.735"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CXCL10 gene</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.48" lower_limit="0.074" upper_limit="0.986"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Leukocyte immunoglobulin like receptor B1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.48" lower_limit="0.142" upper_limit="0.747"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>MX1 gene</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.48" lower_limit="0.155" upper_limit="0.781"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Tumor necrosis factor (ligand) superfamily member 11 gene</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.48" lower_limit="0.227" upper_limit="0.798"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cathepsin S</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.49" lower_limit="0.138" upper_limit="0.807"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Interferon induced transmembrane protein 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.49" lower_limit="0.245" upper_limit="0.887"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LYN proto-oncogene, Src family tyrosine kinase</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.50" lower_limit="0.360" upper_limit="0.685"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Platelet derived growth factor receptor beta</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.50" lower_limit="0.160" upper_limit="0.801"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>OAS3 gene</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.50" lower_limit="0.284" upper_limit="0.899"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CD58 molecule</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.50" lower_limit="0.398" upper_limit="0.619"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>complement C3a receptor 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.51" lower_limit="0.147" upper_limit="0.949"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Chemokine (C-C motif) receptor 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.52" lower_limit="0.159" upper_limit="0.815"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Interleukin 24 gene</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.52" lower_limit="0.161" upper_limit="0.706"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Chemokine (C-X-C motif) receptor 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.53" lower_limit="0.295" upper_limit="0.629"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Strawberry notch homolog 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.13" lower_limit="1.045" upper_limit="1.300"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Zinc finger protein 205</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.42" lower_limit="1.144" upper_limit="1.815"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Fas associated via death domain</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.58" lower_limit="1.107" upper_limit="2.043"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CD3e molecule associated protein</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.67" lower_limit="1.244" upper_limit="2.075"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Baculoviral IAP repeat containing 5</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.73" lower_limit="1.003" upper_limit="2.635"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Interleukin 17 receptor B</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.01" lower_limit="1.151" upper_limit="2.975"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Fold Change in Expression Profile of Genes and /or Proteins for Arm C (Non-HER2- Enriched) From Screening to Approx. 3.5 Years</title>
        <description>Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available.&#xD;
For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.</description>
        <time_frame>At screening and at disease progression, assessed up to approx. 3.5 years</time_frame>
        <population>Evaluable Set: Included all subjects in Arm C who received the study treatment and had both baseline and progression tumor biopsies available, with evaluable data for at least 1 biomarker.</population>
        <group_list>
          <group group_id="O1">
            <title>Non-HER2- Enriched - Arm C</title>
            <description>Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.</description>
          </group>
        </group_list>
        <measure>
          <title>Fold Change in Expression Profile of Genes and /or Proteins for Arm C (Non-HER2- Enriched) From Screening to Approx. 3.5 Years</title>
          <description>Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available.&#xD;
For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.</description>
          <population>Evaluable Set: Included all subjects in Arm C who received the study treatment and had both baseline and progression tumor biopsies available, with evaluable data for at least 1 biomarker.</population>
          <units>Ratio of gene expression level</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Triggering receptor expressed on myeloid cells 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.50" lower_limit="0.294" upper_limit="0.995"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Interleukin 1 receptor, type 1 gene</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.58" lower_limit="1.235" upper_limit="2.328"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Complement component 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.13" lower_limit="1.011" upper_limit="3.567"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Coagulation factor XII</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.69" lower_limit="1.062" upper_limit="4.229"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression-free Survival (PFS)</title>
        <description>PFS was defined as the time from the date of randomization (for Arm A and B) / treatment start date (for Arm C) to the date of the first documented disease progression or death due to any cause, whichever was earlier. If a subject had not progressed or died at the analysis cutoff date, PFS was censored at the time of the last adequate tumor assessment. PFS was summarized using Kaplan-Meier estimates.</description>
        <time_frame>From randomization to disease progression or death, up to approx. 5.6 years</time_frame>
        <population>Full Analysis Set (FAS): Consisted of all subjects who were randomized to study Arm A or Arm B or assigned to study Arm C, irrespective of whether they actually received study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>LAP+TRAS±AI (HER2-Enriched) - Arm A</title>
            <description>Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.</description>
          </group>
          <group group_id="O2">
            <title>TRAS+CHEM±AI (HER2-Enriched) - Arm B</title>
            <description>Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.</description>
          </group>
          <group group_id="O3">
            <title>Non-HER2- Enriched - Arm C</title>
            <description>Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression-free Survival (PFS)</title>
          <description>PFS was defined as the time from the date of randomization (for Arm A and B) / treatment start date (for Arm C) to the date of the first documented disease progression or death due to any cause, whichever was earlier. If a subject had not progressed or died at the analysis cutoff date, PFS was censored at the time of the last adequate tumor assessment. PFS was summarized using Kaplan-Meier estimates.</description>
          <population>Full Analysis Set (FAS): Consisted of all subjects who were randomized to study Arm A or Arm B or assigned to study Arm C, irrespective of whether they actually received study treatment.</population>
          <units>Months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="15"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.0" lower_limit="2.10" upper_limit="10.60"/>
                    <measurement group_id="O2" value="7.2" lower_limit="2.10" upper_limit="14.80"/>
                    <measurement group_id="O3" value="6.0" lower_limit="1.60" upper_limit="8.30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Response Rate (ORR)</title>
        <description>Overall response rate was defined as the percentage of subjects achieving either a confirmed complete response (CR) or partial response (PR) and was calculated from the Investigator's assessment of response per RECIST 1.1 criteria. . The confirmed CR or PR was derived using the following rules: confirmed CR - at least two determinations of CR at least 4 weeks apart before disease progression; confirmed PR - at least two determinations of PR or better at least 4 weeks apart before progression.</description>
        <time_frame>From enrollment/randomization to the end of study, approximately 5.6 years</time_frame>
        <population>Full Analysis Set (FAS): Consisted of all subjects who were randomized to study Arm A or Arm B or assigned to study Arm C, irrespective of whether they actually received study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>LAP+TRAS±AI (HER2-Enriched) - Arm A</title>
            <description>Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.</description>
          </group>
          <group group_id="O2">
            <title>TRAS+CHEM±AI (HER2-Enriched) - Arm B</title>
            <description>Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.</description>
          </group>
          <group group_id="O3">
            <title>Non-HER2- Enriched - Arm C</title>
            <description>Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Response Rate (ORR)</title>
          <description>Overall response rate was defined as the percentage of subjects achieving either a confirmed complete response (CR) or partial response (PR) and was calculated from the Investigator's assessment of response per RECIST 1.1 criteria. . The confirmed CR or PR was derived using the following rules: confirmed CR - at least two determinations of CR at least 4 weeks apart before disease progression; confirmed PR - at least two determinations of PR or better at least 4 weeks apart before progression.</description>
          <population>Full Analysis Set (FAS): Consisted of all subjects who were randomized to study Arm A or Arm B or assigned to study Arm C, irrespective of whether they actually received study treatment.</population>
          <units>Percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="15"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="35.3" lower_limit="14.2" upper_limit="61.7"/>
                    <measurement group_id="O2" value="33.3" lower_limit="11.8" upper_limit="61.6"/>
                    <measurement group_id="O3" value="30.0" lower_limit="6.7" upper_limit="65.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clinical Benefit Rate (CBR)</title>
        <description>CBR is defined as percentage of subjects with a complete response (CR), partial response (PR), or maintaining stable disease (SD) for at least 24 weeks while on study according to the investigator assessment of response per RECIST 1.1 criteria. CR and PR are confirmed responses derived using the following rules: Confirmed CR - at least 2 determinations of CR at least 4 weeks apart before disease progression. Confirmed PR - at least 2 determinations of PR or better at least 4 weeks apart before progression.</description>
        <time_frame>From enrollment/randomization the end of study, approximately 5.6 years</time_frame>
        <population>Full Analysis Set (FAS): Consisted of all subjects who were randomized to study Arm A or Arm B or assigned to study Arm C, irrespective of whether they actually received study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>LAP+TRAS±AI (HER2-Enriched) - Arm A</title>
            <description>Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.</description>
          </group>
          <group group_id="O2">
            <title>TRAS+CHEM±AI (HER2-Enriched) - Arm B</title>
            <description>Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.</description>
          </group>
          <group group_id="O3">
            <title>Non-HER2- Enriched - Arm C</title>
            <description>Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.</description>
          </group>
        </group_list>
        <measure>
          <title>Clinical Benefit Rate (CBR)</title>
          <description>CBR is defined as percentage of subjects with a complete response (CR), partial response (PR), or maintaining stable disease (SD) for at least 24 weeks while on study according to the investigator assessment of response per RECIST 1.1 criteria. CR and PR are confirmed responses derived using the following rules: Confirmed CR - at least 2 determinations of CR at least 4 weeks apart before disease progression. Confirmed PR - at least 2 determinations of PR or better at least 4 weeks apart before progression.</description>
          <population>Full Analysis Set (FAS): Consisted of all subjects who were randomized to study Arm A or Arm B or assigned to study Arm C, irrespective of whether they actually received study treatment.</population>
          <units>Percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="15"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="35.3" lower_limit="14.2" upper_limit="61.7"/>
                    <measurement group_id="O2" value="46.7" lower_limit="21.3" upper_limit="73.4"/>
                    <measurement group_id="O3" value="30.0" lower_limit="6.7" upper_limit="65.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Association Between Biomarkers and PFS</title>
        <description>Describe if changes of biomarker expression at disease progression from baseline correlate with PFS.</description>
        <time_frame>From randomization to disease progression or death, up to approx. 5.6 years</time_frame>
        <population>The number of patients with available biomarker data at both baseline and at progression is very small within each treatment arm (Arm A: n=7, Arm B: n=5, Arm C: n=5). This number of subjects is insufficient for an analysis to establish a relationship between the changes in biomarker at disease progression and progression free survival and would be statistically inappropriate to fit a model correlating changes in biomarkers with progression free survival with so few patients.</population>
        <group_list>
          <group group_id="O1">
            <title>LAP+TRAS±AI (HER2-Enriched) - Arm A</title>
            <description>Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.</description>
          </group>
          <group group_id="O2">
            <title>TRAS+CHEM±AI (HER2-Enriched) - Arm B</title>
            <description>Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.</description>
          </group>
          <group group_id="O3">
            <title>Non-HER2- Enriched - Arm C</title>
            <description>Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.</description>
          </group>
        </group_list>
        <measure>
          <title>Association Between Biomarkers and PFS</title>
          <description>Describe if changes of biomarker expression at disease progression from baseline correlate with PFS.</description>
          <population>The number of patients with available biomarker data at both baseline and at progression is very small within each treatment arm (Arm A: n=7, Arm B: n=5, Arm C: n=5). This number of subjects is insufficient for an analysis to establish a relationship between the changes in biomarker at disease progression and progression free survival and would be statistically inappropriate to fit a model correlating changes in biomarkers with progression free survival with so few patients.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Post-Hoc</type>
        <title>All-Collected Deaths</title>
        <description>On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 168 weeks for Lapatinib, (treatment duration ranged from 151 to 164 weeks), 164 weeks for Trastuzumab (treatment duration ranged from 0 to 160 weeks), 168 weeks for Aromatase Inhibitors (treatment duration ranged from 9 to 164 weeks).&#xD;
Deaths post treatment survival follow up were collected after the on- treatment period, up to approx. 5.6 years.</description>
        <time_frame>On-treatment deaths: up to approx. 168 weeks, Total deaths: up to approx. 5.6 years</time_frame>
        <population>Clinical Database Population: All treated participants.</population>
        <group_list>
          <group group_id="O1">
            <title>LAP+TRAS±AI (HER2-Enriched) - Arm A</title>
            <description>Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.</description>
          </group>
          <group group_id="O2">
            <title>TRAS+CHEM±AI (HER2-Enriched) - Arm B</title>
            <description>Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.</description>
          </group>
          <group group_id="O3">
            <title>Non-HER2- Enriched - Arm C</title>
            <description>Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.</description>
          </group>
        </group_list>
        <measure>
          <title>All-Collected Deaths</title>
          <description>On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 168 weeks for Lapatinib, (treatment duration ranged from 151 to 164 weeks), 164 weeks for Trastuzumab (treatment duration ranged from 0 to 160 weeks), 168 weeks for Aromatase Inhibitors (treatment duration ranged from 9 to 164 weeks).&#xD;
Deaths post treatment survival follow up were collected after the on- treatment period, up to approx. 5.6 years.</description>
          <population>Clinical Database Population: All treated participants.</population>
          <units>Participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="15"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Total Deaths</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11"/>
                    <measurement group_id="O2" value="9"/>
                    <measurement group_id="O3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>On-treatment deaths</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 168 weeks for lapatinib, for a maximum duration of 164 weeks for trastuzumab and for a maximum duration of 168 weeks for aromatase inhibitors (anastrozole, letrozole and exemestane.)</time_frame>
      <desc>Adverse Event: Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.</desc>
      <group_list>
        <group group_id="E1">
          <title>LAP+TRAS±AI (HER2-Enriched) - Arm A</title>
          <description>Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.</description>
        </group>
        <group group_id="E2">
          <title>TRAS+CHEM±AI (HER2-Enriched) • ArmB</title>
          <description>Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.</description>
        </group>
        <group group_id="E3">
          <title>Non-HER2-Enriched - Arm C</title>
          <description>Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (20.1)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Cardiac arrest</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Escherichia sepsis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypoalbuminaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypoglycaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypomagnesaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hyponatraemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Metabolic disorder</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Breast neoplasm</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Chronic obstructive pulmonary disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (20.1)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Leukopenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Lymphopenia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Left ventricular dysfunction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Ventricular extrasystoles</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Eyelid oedema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Visual impairment</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Face oedema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Mucosal inflammation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Paronychia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Incision site pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Rib fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Blood alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Blood sodium decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Ejection fraction decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Weight increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hyperkalaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypermagnesaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypoalbuminaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypocalcaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Musculoskeletal chest pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Cancer pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Tumour pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Neuropathy peripheral</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Neurotoxicity</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Catarrh</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pleurisy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dermatitis acneiform</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Nail discolouration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Nail disorder</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Nail dystrophy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Palmar-plantar erythrodysaesthesia syndrome</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Skin toxicity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Lymphoedema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="15"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Study Director</name_or_title>
      <organization>Novartis Pharmaceuticals</organization>
      <phone>862-778-8300</phone>
      <email>novartis.email@novartis.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02213042
org study id: 117165
secondary id: 2014-001220-30
secondary id: CLAP016A2206
nct id: NCT02213042
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This was a multicenter, open-label, Phase II study in subjects with Human epidermal growth
      factor receptor (HER2)-positive metastatic breast cancer who received at least 2 prior lines
      of anti-HER2-targeted therapies of which at least one included a Trastuzumab-containing
      regimen. This study was a post-approval commitment with regulatory authorities. It was
      designed to evaluate whether treatment with Dual blockade promoted changes to biomarkers
      associated with immunomodulation.
This study was designed to address the post-authorization measures as agreed with the
      Committee for Medicinal Products for Human Use (CHMP). Recruitment of subjects into this
      study was challenging, and following agreement with the European Medicines Agency (EMA)
      enrollment into this study was halted after the enrollment of 42 of the 225 planned subjects.

      The primary endpoint of the study evaluated changes in expression of biomarkers associated
      with immunomodulation between a pre-treatment biopsy and the disease progression biopsy.
      Secondary efficacy endpoints included overall response rate, clinical benefit rate and
      progression-free survival (PFS), as well as safety/tolerability. All subjects received study
      treatment until disease progression, death, unacceptable toxicity, or subject withdrawal. In
      case of disease progression during the treatment period, the subject was followed-up for 30
      days for safety evaluation. In case of study treatment discontinuation for any reasons other
      than disease progression, the subject was followed-up for safety and efficacy assessments
      until disease progression, new anticancer therapy, death, withdrawal of consent or end of
      study, whichever came first.

      This study supported a better understanding of the rapidly accumulating evidence for the
      importance of the immune microenvironment in HER2-positive breast cancer and the observed
      immunomodulation in the neoadjuvant setting could be confirmed in the advanced setting and
      supported the putative mechanism of action of HER2 dual blockade and its potential function
      on the tumor microenvironment. No formal comparisons between treatment arms were undertaken.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Participants were randomized to Arms A and B but randomized to Arm C.
primary purpose: Treatment
masking: None (Open Label)
masking description: This was a two-cohort, three-arm, open-label Phase II study to evaluate the changes in the expression of biomarkers between pre-treatment and progression biopsy in subjects with Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Subjects were allocated to 1 of 2 cohorts depending on the molecular subtype of their biopsy.
Cohort 1 HER2 -enriched included HER2-positive subjects with a HER2-Enriched molecular subtype, and were randomized in a 1:1 ratio to receive either trastuzumab in combination with lapatinib (Arm A) or trastuzumab in combination with chemotherapy (Arm B).
Cohort 2 non-HER2-enriched, included HER2-positive subjects with luminal A, luminal B, and basal-like molecular subtypes and were to receive trastuzumab in combination with lapatinib (Arm C). Subjects with hormone receptor (ER and/or PgR)-positive MBC in this arm were required to be treated with an AI of the Investigator's choice.
measure: Fold Change in Expression Profile of Genes and/or Proteins for Arm A (LAP+TRAS±AI (HER2-Enriched)) From Screening to Approx. 3.5 Years
time frame: At screening and at disease progression, assessed up to approx. 3.5 years
description: Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available.
For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.
measure: Fold Change in Expression Profile of Genes and /or Proteins for Arm B (TRAS+CHEM±AI (HER2-Enriched)) From Screening to Approx. 3.5 Years
time frame: At screening and at disease progression, assessed up to approx. 3.5 years
description: Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available.
For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.
measure: Fold Change in Expression Profile of Genes and /or Proteins for Arm C (Non-HER2- Enriched) From Screening to Approx. 3.5 Years
time frame: At screening and at disease progression, assessed up to approx. 3.5 years
description: Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available.
For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.
measure: Progression-free Survival (PFS)
time frame: From randomization to disease progression or death, up to approx. 5.6 years
description: PFS was defined as the time from the date of randomization (for Arm A and B) / treatment start date (for Arm C) to the date of the first documented disease progression or death due to any cause, whichever was earlier. If a subject had not progressed or died at the analysis cutoff date, PFS was censored at the time of the last adequate tumor assessment. PFS was summarized using Kaplan-Meier estimates.
measure: Overall Response Rate (ORR)
time frame: From enrollment/randomization to the end of study, approximately 5.6 years
description: Overall response rate was defined as the percentage of subjects achieving either a confirmed complete response (CR) or partial response (PR) and was calculated from the Investigator's assessment of response per RECIST 1.1 criteria. . The confirmed CR or PR was derived using the following rules: confirmed CR - at least two determinations of CR at least 4 weeks apart before disease progression; confirmed PR - at least two determinations of PR or better at least 4 weeks apart before progression.
measure: Clinical Benefit Rate (CBR)
time frame: From enrollment/randomization the end of study, approximately 5.6 years
description: CBR is defined as percentage of subjects with a complete response (CR), partial response (PR), or maintaining stable disease (SD) for at least 24 weeks while on study according to the investigator assessment of response per RECIST 1.1 criteria. CR and PR are confirmed responses derived using the following rules: Confirmed CR - at least 2 determinations of CR at least 4 weeks apart before disease progression. Confirmed PR - at least 2 determinations of PR or better at least 4 weeks apart before progression.
measure: Association Between Biomarkers and PFS
time frame: From randomization to disease progression or death, up to approx. 5.6 years
description: Describe if changes of biomarker expression at disease progression from baseline correlate with PFS.
arm group label: Lapatinib 1000mg + Trastuzumab in HER2 Enriched
arm group type: Active Comparator
description: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.
arm group label: Trastuzumab in HER2 Enriched
arm group type: Active Comparator
description: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.
arm group label: Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched
arm group type: Active Comparator
description: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.
intervention type: Drug
intervention name: Lapatinib
description: Lapatinib is available as 250-mg orange tablets. Subjects randomized to the Lapatinib plus Trastuzumab arm received 1000 mg per day of Lapatinib, so wre instructed to take 4 x 250 mg tablets per day. Lapatinib was to be taken either 1 hour (or more) before a meal or 1 hour (or more) after a meal
arm group label: Lapatinib 1000mg + Trastuzumab in HER2 Enriched
arm group label: Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched
intervention type: Biological
intervention name: Trastuzumab
description: Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized powder for IV administration. Trastuzumab was administered on Day 1 of the start of Lapatinib or in conjunction with the first cycle of chemotherapy, as an 8 mg/kg loading dose. Subsequently, Trastuzumab was administered q3weekly as a 6 mg/kg maintenance dose. At the discretion of the investigator, weekly Trastuzumab could be given in either of the three treatment arms (loading dose 4mg/kg followed by weekly administration of 2mg/kg).
arm group label: Lapatinib 1000mg + Trastuzumab in HER2 Enriched
arm group label: Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched
arm group label: Trastuzumab in HER2 Enriched
intervention type: Drug
intervention name: Aromatase Inhibitors (AIs)
description: Subjects who were hormone receptor-positive were required to receive an aromatase inhibitor as combination treatment; however the choice of the aromatase inhibitor selected for each patient was determined by the patients' investigator. The AIs the Investigator could choose from were anastrozole, exemestane, and letrozole and dosing was per product information.
arm group label: Lapatinib 1000mg + Trastuzumab in HER2 Enriched
arm group label: Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched
arm group label: Trastuzumab in HER2 Enriched
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Novartis Pharmaceuticals
role: Study Director
affiliation: Novartis Pharmaceuticals
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country: Argentina
country: Austria
country: Brazil
country: Hong Kong
country: Italy
country: Mexico
country: Peru
country: Philippines
country: Russian Federation
country: Spain
country: Thailand
country: United States
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Trastuzumab
mesh term: Lapatinib
mesh term: Aromatase Inhibitors
sharing ipd: Yes
ipd description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
ipd url: http://www.clinicalstudydatarequest.com
provided document: 
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reported events: 
certain agreements: 
point of contact: 