<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/NCT03811418</url>
  </required_header>
  <id_info>
    <org_study_id>iOM-110383</org_study_id>
    <secondary_id>2017-004749-25</secondary_id>
    <nct_id>NCT03811418</nct_id>
  </id_info>
  <brief_title>A Study to Compare Pertuzumab + Trastuzumab + Vinorelbine vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-positive Metastatic Breast Cancer</brief_title>
  <acronym>ATTILA</acronym>
  <official_title>Phase III Study to Compare Trastuzumab-biosimilar (Kanjinti®) Plus Pertuzumab Plus Vinorelbine With Trastuzumab-biosimilar (Kanjinti®) Plus Pertuzumab Plus Docetaxel as First-line Treatment for HER2-positive Advanced Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>iOMEDICO AG</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Arbeitsgemeinschaft fur Internistische Onkologie</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Amgen</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>iOMEDICO AG</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a randomized, open-label, two-arm, phase III trial in Germany to investigate whether&#xD;
      vinorelbine-based triple combination presents a less toxic treatment option than&#xD;
      docetaxel-based triple combination in patients with HER2-positive advanced breast cancer who&#xD;
      have not previously received any systemic treatment in the metastatic setting.&#xD;
&#xD;
      The primary objective of the study is to compare patient-reported quality of life in the two&#xD;
      treatment arms. Patients will be followed-up for survival until death or end of study after&#xD;
      at least 79 deaths occured in each arm, whatever comes first.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Study approved with treatment regimen based on current guidelines. However, reimbursement of&#xD;
    IMP was not feasible.&#xD;
  </why_stopped>
  <start_date type="Anticipated">January 2019</start_date>
  <completion_date type="Anticipated">April 2019</completion_date>
  <primary_completion_date type="Anticipated">April 2019</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Patient-reported health-related quality of life (QoL): FACT-B</measure>
    <time_frame>Baseline to week 18</time_frame>
    <description>Area under the curve (AUC) in the Functional Assessment of Cancer Therapy - Breast (FACT-B) questionnaire subscale Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) after 18 weeks (irrespective of disease or treatment situation at that time point). Higher AUC indicates better quality of life.&#xD;
To calculate the TOI-PFB the three subscales Physical well-being (PWB - 7 statements), Functional well-being (FWB - 7 statements) and breast cancer subscale (BCS - 10 statements) are summed up. In all subscales each statement will be rated by the patient from 0 (not at all) - 4 (very much). Therefore ranges of subscales are: PWB 0 - 28; FWB 0 - 28; BCS 0 - 40; TOI-PFB 0 - 96; higher values indicate better quality of life.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS) assessed by the investigator</measure>
    <time_frame>Baseline, every 12 weeks after randomization (maximum up to 76 months)</time_frame>
    <description>PFS is defined as time from randomization to date of progressive disease or death, whichever comes first. It will be analyzed using Kaplan-Meier method. Data will be censored at date of last contact for patients alive without progressive disease at database lock. If subsequent treatment was started prior to progressive disease, then data will be censored at the onset of this treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Time from randomization to date of death (maximum up to approximately 76 months)</time_frame>
    <description>OS is defined as time from randomization to date of death. It will be analyzed using Kaplan-Meier method. Data will be censored at date of last contact for patients alive at database cut/lock.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall response rate (ORR)</measure>
    <time_frame>Baseline, every 12 weeks after randomization (maximum up to 76 months)</time_frame>
    <description>Overall response rate is defined as the proportion of patients achieving a complete or partial remission as best response.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical benefit rate (CBR)</measure>
    <time_frame>Baseline, every 12 weeks after randomization (maximum up to 76 months)</time_frame>
    <description>CBR is defined as proportion of patients achieving a complete or partial remission or a stable disease lasting at least 24 weeks.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to treatment failure (TTF)</measure>
    <time_frame>Baseline, every 12 weeks after randomization (maximum up to 56 months)</time_frame>
    <description>TTF is defined as time from randomization to discontinuation of all study medications. Date of discontinuation is the earliest end of last cycle (= 20 days after first administration of a study drug in the last cycle) OR progressive disease after last administration of any study drug OR death OR start of a subsequent treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of (Serious) Adverse events ((S)AEs)</measure>
    <time_frame>From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)</time_frame>
    <description>Type, frequency and severity of adverse events (including those from the pre- and post-treatment periods) will be listed according to Common Toxicity Criteria for Adverse Events (CTCAE).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood count: Hemoglobin</measure>
    <time_frame>From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)</time_frame>
    <description>The amount of hemoglobin in the blood will be measured in g/dL as per clinical routine and will be displayed using by-patient listings.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood count: Platelet Count</measure>
    <time_frame>From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)</time_frame>
    <description>The number of platelets in the blood will be counted as per clinical routine and will be displayed using by-patient listings.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood count: Leukocytes</measure>
    <time_frame>From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)</time_frame>
    <description>The number of leukocytes in the blood will be counted as per clinical routine and will be displayed using by-patient listings.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood count: Absolute Neutrophil Count</measure>
    <time_frame>From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)</time_frame>
    <description>The absolute neutrophil count will be determined as per clinical routine and will be displayed using by-patient listings.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety monitoring (coagulation): Coagulation (INR)</measure>
    <time_frame>From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)</time_frame>
    <description>Coagulation (INR) as per clinical routine will be displayed using by-patient listings.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical chemistry: Alkaline Phosphatase</measure>
    <time_frame>From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)</time_frame>
    <description>Alkaline phosphatase will be measured in U/L as per clinical routine and will be displayed using by-patient listings.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical chemistry: Alanine transaminase (ALT)</measure>
    <time_frame>From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)</time_frame>
    <description>ALT will be measured in U/L as per clinical routine and will be displayed using by-patient listings.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical chemistry: Aspartate transaminase (AST)</measure>
    <time_frame>From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)</time_frame>
    <description>AST will be measured in U/L as per clinical routine and will be displayed using by-patient listings.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical chemistry: Bilirubin total</measure>
    <time_frame>From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)</time_frame>
    <description>Total bilirubin will be measured in mg/dL as per clinical routine and will be displayed using by-patient listings.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical chemistry: Creatinine (Serum)</measure>
    <time_frame>From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)</time_frame>
    <description>Serum creatinine will be measured in µmol/L as per clinical routine and will be displayed using by-patient listings.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left Ventricular Ejection Fraction (LVEF) monitoring</measure>
    <time_frame>LVEF at baseline, every three months thereafter until end of treatment, then every six months for 24 months thereafter (maximum up to 76 months)</time_frame>
    <description>Incidence of clinically relevant LVEF levels. Change from baseline at each assessment time point, worst-on-treatment will be displayed using descriptive statistics.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient-reported health-related quality of life (QoL): Trial Outcome Index-Physical/Functional/Breast (TOI-PFB)</measure>
    <time_frame>Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).</time_frame>
    <description>AUC in TOI-PFB at 12, 18, 24 and 36 months.&#xD;
Area under the curve (AUC) in the Functional Assessment of Cancer Therapy - Breast (FACT-B) questionnaire subscale Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) after 12, 18, 24 and 36 months (irrespective of disease or treatment situation at that time point). Higher AUC indicates better quality of life.&#xD;
To calculate the TOI-PFB the three subscales Physical well-being (PWB - 7 statements), Functional well-being (FWB - 7 statements) and breast cancer subscale (BCS - 10 statements) are summed up. In all subscales each statement will be rated by the patient from 0 (not at all) - 4 (very much). Therefore ranges of subscales are: PWB 0 - 28; FWB 0 - 28; BCS 0 - 40; TOI-PFB 0 - 96; higher values indicate better quality of life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient-reported health-related quality of life (QoL): FACT-B TOI-PFB</measure>
    <time_frame>Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).</time_frame>
    <description>Time to decline by 5 points in the Functional Assessment of Cancer Therapy - Breast (FACT-B) questionnaire subscale Trial Outcome Index-Physical/Functional/Breast (TOI-PFB).&#xD;
To calculate the TOI-PFB the three subscales Physical well-being (PWB - 7 statements), Functional well-being (FWB - 7 statements) and breast cancer subscale (BCS - 10 statements) are summed up. In all subscales each statement will be rated by the patient from 0 (not at all) - 4 (very much). Therefore ranges of subscales are: PWB 0 - 28; FWB 0 - 28; BCS 0 - 40; TOI-PFB 0 - 96; decline of scale indicates worsening quality of life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient-reported health-related quality of life (QoL): FACT-B total score</measure>
    <time_frame>Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).</time_frame>
    <description>Change from baseline in the FACT-B total score for all questionnaire timepoints. To calculate FACT-B total score patient ratings from 0 (not at all) - 4 (very much) to each of the 37 questionnaire statement are summed up. Total score range: 0 - 148. Higher values indicate better quality of life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient-reported health-related quality of life (QoL): FACT-B subscale physical well-being (PWB)</measure>
    <time_frame>Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).</time_frame>
    <description>Change from baseline in the FACT-B subscale PWB for all questionnaire timepoints. PWB subscale consists of 7 statements leading to a scale range of 0-28. Higher values indicate better quality of life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient-reported health-related quality of life (QoL): FACT-B subscale social/family well-being (SWB)</measure>
    <time_frame>Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).</time_frame>
    <description>Change from baseline in the FACT-B subscale SWB for all questionnaire timepoints. SWB subscale consists of 8 statements leading to a scale range of 0-32. Higher values indicate better quality of life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient-reported health-related quality of life (QoL): FACT-B subscale emotional well-being (EWB)</measure>
    <time_frame>Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).</time_frame>
    <description>Change from baseline in the FACT-B subscale EWB for all questionnaire timepoints. EWB subscale consists of 6 statements leading to a scale range of 0-24. Higher values indicate better quality of life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient-reported health-related quality of life (QoL): FACT-B subscale functional well-being (FWB)</measure>
    <time_frame>Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).</time_frame>
    <description>Change from baseline in the FACT-B subscale FWB for all questionnaire timepoints. FWB subscale consists of 7 statements leading to a scale range of 0-28. Higher values indicate better quality of life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient-reported health-related quality of life (QoL): FACT-B breast cancer subscale (BCS)</measure>
    <time_frame>Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).</time_frame>
    <description>Change from baseline in the FACT-B BCS score for all questionnaire timepoints. BCS consists of 10 statements leading to a score range of 0-40. Higher values indicate better quality of life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient-reported health-related quality of life (QoL): FACT-B breast cancer subscale (BCS) score decline</measure>
    <time_frame>Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).</time_frame>
    <description>Time to decline by 2 points in the FACT-B BCS score. BCS consists of 10 statements leading to a score range of 0-40. BCS score decline indicates worsening quality of life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient-reported health-related quality of life (QoL): FACT/GOG-Ntx4 subscale</measure>
    <time_frame>Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).</time_frame>
    <description>Change from baseline in the FACT/GOG-Ntx4 subscale for all questionnaire timepoints. FACT/GOG-Ntx4 subscale consists of 11 statements leading to a scale range of 0-44. Higher values indicate better quality of life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exploratory endpoint: Treatment costs</measure>
    <time_frame>From randomization until end of treatment (maximum up to 56 months).</time_frame>
    <description>Treatment costs (drug costs)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exploratory endpoints: Duration of hospitalizations</measure>
    <time_frame>From randomization until end of treatment (maximum up to 57 months).</time_frame>
    <description>Total duration of hospitalizations (per patients)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exploratory endpoints: Number of hospitalizations</measure>
    <time_frame>From randomization until end of treatment (maximum up to 57 months).</time_frame>
    <description>Number of hospitalizations (in-patient stays)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exploratory endpoints: Reasons for hospitalizations</measure>
    <time_frame>From randomization until end of treatment (maximum up to 57 months).</time_frame>
    <description>Reasons for hospitalizations</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exploratory endpoints: Febrile infections</measure>
    <time_frame>From randomization until end of treatment (maximum up to 57 months).</time_frame>
    <description>Incidence of febrile infections</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exploratory endpoints: Employment status</measure>
    <time_frame>From randomization until end of treatment (maximum up to 56 months).</time_frame>
    <description>Employment status (kind and duration of sick leaves)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Advanced Breast Cancer</condition>
  <condition>HER2-positive Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Kanjinti/Pertuzumab plus Vinorelbine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will receive Kanjinti® (trastuzumab-biosimilar) plus pertuzumab plus vinorelbine.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Kanjinti/Pertuzumab plus Docetaxel</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients will receive Kanjinti® (trastuzumab-biosimilar) plus pertuzumab plus docetaxel.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Trastuzumab</intervention_name>
    <description>administered as combined therapy with pertuzumab and vinorelbine or docetaxel.&#xD;
Trastuzumab will be administered as an IV loading dose of 8 milligrams per kilogram (mg/kg) on day 1 of cycle 1 (1 cycle length = 21 days), and 6 mg/kg Q3W on day 1 of subsequent cycles until progressive disease, intolerable toxicity, or death.</description>
    <arm_group_label>Kanjinti/Pertuzumab plus Docetaxel</arm_group_label>
    <arm_group_label>Kanjinti/Pertuzumab plus Vinorelbine</arm_group_label>
    <other_name>Kanjinti®</other_name>
    <other_name>ABP 980</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pertuzumab</intervention_name>
    <description>administered as combined therapy with Kanjinti® and vinorelbine or docetaxel.&#xD;
Pertuzumab will be administered as an IV loading dose of 840 milligrams (mg) on day 1 of cycle 1 (1 cycle length = 21 days), and 420 mg Q3W on day 1 of subsequent cycles until progressive disease, intolerable toxicity, or death.</description>
    <arm_group_label>Kanjinti/Pertuzumab plus Docetaxel</arm_group_label>
    <arm_group_label>Kanjinti/Pertuzumab plus Vinorelbine</arm_group_label>
    <other_name>Perjeta®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vinorelbine</intervention_name>
    <description>administered as combined therapy with Kanjinti® and pertuzumab.&#xD;
Vinorelbine will be administered as an IV dose of 25 milligrams per kilogram (mg/kg) on days 1 and 8 of cycle 1 (1 cycle length = 21 days), and 25mg/kg up to 30 mg/kg (as per treating physician discretion) Q3W on day 1 of subsequent cycles until progressive disease, intolerable toxicity, or death.</description>
    <arm_group_label>Kanjinti/Pertuzumab plus Vinorelbine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Docetaxel</intervention_name>
    <description>administered as combined therapy with Kanjinti® and pertuzumab.&#xD;
Docetaxel will be administered as an IV dose of 75 milligrams per square meter (mg/m^2) on day 1 of cycle 1 (1 cycle length = 21 days), and 75 mg/m^2 (up to 100 mg/m^2 as per treating physician discretion) Q3W on day 1 of subsequent cycles until progressive disease, intolerable toxicity, or death.</description>
    <arm_group_label>Kanjinti/Pertuzumab plus Docetaxel</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed and dated written informed consent prior to beginning of protocol-specific&#xD;
             procedures.&#xD;
&#xD;
          -  Histologically or cytologically confirmed adenocarcinoma of the breast. Locally&#xD;
             advanced and inoperable or metastatic disease.&#xD;
&#xD;
          -  HER2-positive disease, defined as IHC status HER2+++ or CISH/FISH status positive.&#xD;
&#xD;
          -  Female patients aged ≥ 18 years.&#xD;
&#xD;
          -  In case of adjuvant treatment, disease-free interval of at least 12 months after&#xD;
             completion of adjuvant treatment (excluding hormonal therapy).&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1.&#xD;
&#xD;
          -  Left Ventricular Ejection Fraction (LVEF) ≥ 50%.&#xD;
&#xD;
          -  For women with childbearing potential, defined as physiologically capable of becoming&#xD;
             pregnant:&#xD;
&#xD;
               -  Negative pregnancy test.&#xD;
&#xD;
               -  Agreement to use an effective form of contraception during study treatment and&#xD;
                  for 7 months after the last dose of study treatment.&#xD;
&#xD;
          -  Life expectancy of at least 12 weeks.&#xD;
&#xD;
          -  Adequate organ and bone marrow function&#xD;
&#xD;
          -  Fluent in spoken and written German and willing to answer the questionnaires&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previous systemic treatment in palliative intention (chemotherapy, hormonal therapy&#xD;
             and / or biological therapy)&#xD;
&#xD;
          -  Persistent peripheral sensory or motor neuropathy grade 2 or higher (NCI CTCAE v5.0)&#xD;
&#xD;
          -  Evidence of central nervous system metastases. CT or MRI of the brain is only&#xD;
             mandatory in case of clinical suspicion of brain metastases&#xD;
&#xD;
          -  Current uncontrolled hypertension (systolic &gt; 150 mmHg and / or diastolic &gt; 100 mmHg)&#xD;
             or clinically significant cardiovascular disease&#xD;
&#xD;
          -  History of LVEF &lt; 50% during or after prior (neo)adjuvant therapy with trastuzumab&#xD;
&#xD;
          -  Current severe, uncontrolled systemic disease (e.g. cardiovascular, pulmonary, or&#xD;
             metabolic disease, wound healing disorder, ulcers, or bone fractures, or severe&#xD;
             fungal, bacterial or viral infection)&#xD;
&#xD;
          -  Major surgery within 28 days prior to start of study medication, or anticipation of&#xD;
             the need for major surgery during the course of study treatment&#xD;
&#xD;
          -  Current known infection with HIV, HBV, or HCV (testing not required)&#xD;
&#xD;
          -  Dyspnea at rest due to complications of advanced malignancy, or other diseases&#xD;
             requiring continuous oxygen therapy.&#xD;
&#xD;
          -  Known hypersensitivity to any of the study medications or to excipients of recombinant&#xD;
             human or humanized antibodies.&#xD;
&#xD;
          -  Participation in investigational studies within 30 days or five half-lives of the&#xD;
             respective IMP, whichever is longer, prior randomization.&#xD;
&#xD;
          -  Pregnant or lactating women.&#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>Anja Welt, Dr.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Essen University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>iOMEDICO AG</name>
      <address>
        <city>Freiburg</city>
        <state>Baden-Wuerttemberg</state>
        <zip>79106</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <reference>
    <citation>Andersson M, Lidbrink E, Bjerre K, Wist E, Enevoldsen K, Jensen AB, Karlsson P, Tange UB, Sorensen PG, Moller S, Bergh J, Langkjer ST. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol. 2011 Jan 20;29(3):264-71. doi: 10.1200/JCO.2010.30.8213. Epub 2010 Dec 13.</citation>
    <PMID>21149659</PMID>
  </reference>
  <reference>
    <citation>Andersson M, Lopez-Vega JM, Petit T, Zamagni C, Easton V, Kamber J, Restuccia E, Perez EA. Efficacy and Safety of Pertuzumab and Trastuzumab Administered in a Single Infusion Bag, Followed by Vinorelbine: VELVET Cohort 2 Final Results. Oncologist. 2017 Oct;22(10):1160-1168. doi: 10.1634/theoncologist.2017-0079. Epub 2017 Jun 7.</citation>
    <PMID>28592618</PMID>
  </reference>
  <reference>
    <citation>Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. doi: 10.1056/NEJMoa1113216. Epub 2011 Dec 7.</citation>
    <PMID>22149875</PMID>
  </reference>
  <reference>
    <citation>Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, Gelman R, Winer EP. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007 Sep 1;110(5):965-72. doi: 10.1002/cncr.22885.</citation>
    <PMID>17614302</PMID>
  </reference>
  <reference>
    <citation>Cortes J, Baselga J, Im YH, Im SA, Pivot X, Ross G, Clark E, Knott A, Swain SM. Health-related quality-of-life assessment in CLEOPATRA, a phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast cancer. Ann Oncol. 2013 Oct;24(10):2630-2635. doi: 10.1093/annonc/mdt274. Epub 2013 Jul 17.</citation>
    <PMID>23868905</PMID>
  </reference>
  <reference>
    <citation>Perez EA, Lopez-Vega JM, Petit T, Zamagni C, Easton V, Kamber J, Restuccia E, Andersson M. Safety and efficacy of vinorelbine in combination with pertuzumab and trastuzumab for first-line treatment of patients with HER2-positive locally advanced or metastatic breast cancer: VELVET Cohort 1 final results. Breast Cancer Res. 2016 Dec 13;18(1):126. doi: 10.1186/s13058-016-0773-6.</citation>
    <PMID>27955684</PMID>
  </reference>
  <reference>
    <citation>Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortes J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. doi: 10.1056/NEJMoa1413513.</citation>
    <PMID>25693012</PMID>
  </reference>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>December 13, 2018</study_first_submitted>
  <study_first_submitted_qc>January 17, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 22, 2019</study_first_posted>
  <last_update_submitted>November 25, 2019</last_update_submitted>
  <last_update_submitted_qc>November 25, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">November 26, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>advanced breast cancer</keyword>
  <keyword>HER2-positive</keyword>
  <keyword>metastatic</keyword>
  <keyword>inoperable</keyword>
  <keyword>female</keyword>
  <keyword>quality of life</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>Docetaxel</mesh_term>
    <mesh_term>Trastuzumab</mesh_term>
    <mesh_term>Vinorelbine</mesh_term>
    <mesh_term>Pertuzumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03811418
org study id: iOM-110383
secondary id: 2017-004749-25
nct id: NCT03811418
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is a randomized, open-label, two-arm, phase III trial in Germany to investigate whether
      vinorelbine-based triple combination presents a less toxic treatment option than
      docetaxel-based triple combination in patients with HER2-positive advanced breast cancer who
      have not previously received any systemic treatment in the metastatic setting.

      The primary objective of the study is to compare patient-reported quality of life in the two
      treatment arms. Patients will be followed-up for survival until death or end of study after
      at least 79 deaths occured in each arm, whatever comes first.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: None (Open Label)
measure: Patient-reported health-related quality of life (QoL): FACT-B
time frame: Baseline to week 18
description: Area under the curve (AUC) in the Functional Assessment of Cancer Therapy - Breast (FACT-B) questionnaire subscale Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) after 18 weeks (irrespective of disease or treatment situation at that time point). Higher AUC indicates better quality of life.
To calculate the TOI-PFB the three subscales Physical well-being (PWB - 7 statements), Functional well-being (FWB - 7 statements) and breast cancer subscale (BCS - 10 statements) are summed up. In all subscales each statement will be rated by the patient from 0 (not at all) - 4 (very much). Therefore ranges of subscales are: PWB 0 - 28; FWB 0 - 28; BCS 0 - 40; TOI-PFB 0 - 96; higher values indicate better quality of life.
measure: Progression-free survival (PFS) assessed by the investigator
time frame: Baseline, every 12 weeks after randomization (maximum up to 76 months)
description: PFS is defined as time from randomization to date of progressive disease or death, whichever comes first. It will be analyzed using Kaplan-Meier method. Data will be censored at date of last contact for patients alive without progressive disease at database lock. If subsequent treatment was started prior to progressive disease, then data will be censored at the onset of this treatment.
measure: Overall survival (OS)
time frame: Time from randomization to date of death (maximum up to approximately 76 months)
description: OS is defined as time from randomization to date of death. It will be analyzed using Kaplan-Meier method. Data will be censored at date of last contact for patients alive at database cut/lock.
measure: Overall response rate (ORR)
time frame: Baseline, every 12 weeks after randomization (maximum up to 76 months)
description: Overall response rate is defined as the proportion of patients achieving a complete or partial remission as best response.
measure: Clinical benefit rate (CBR)
time frame: Baseline, every 12 weeks after randomization (maximum up to 76 months)
description: CBR is defined as proportion of patients achieving a complete or partial remission or a stable disease lasting at least 24 weeks.
measure: Time to treatment failure (TTF)
time frame: Baseline, every 12 weeks after randomization (maximum up to 56 months)
description: TTF is defined as time from randomization to discontinuation of all study medications. Date of discontinuation is the earliest end of last cycle (= 20 days after first administration of a study drug in the last cycle) OR progressive disease after last administration of any study drug OR death OR start of a subsequent treatment.
measure: Incidence of (Serious) Adverse events ((S)AEs)
time frame: From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
description: Type, frequency and severity of adverse events (including those from the pre- and post-treatment periods) will be listed according to Common Toxicity Criteria for Adverse Events (CTCAE).
measure: Blood count: Hemoglobin
time frame: From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
description: The amount of hemoglobin in the blood will be measured in g/dL as per clinical routine and will be displayed using by-patient listings.
measure: Blood count: Platelet Count
time frame: From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
description: The number of platelets in the blood will be counted as per clinical routine and will be displayed using by-patient listings.
measure: Blood count: Leukocytes
time frame: From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
description: The number of leukocytes in the blood will be counted as per clinical routine and will be displayed using by-patient listings.
measure: Blood count: Absolute Neutrophil Count
time frame: From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
description: The absolute neutrophil count will be determined as per clinical routine and will be displayed using by-patient listings.
measure: Safety monitoring (coagulation): Coagulation (INR)
time frame: From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
description: Coagulation (INR) as per clinical routine will be displayed using by-patient listings.
measure: Clinical chemistry: Alkaline Phosphatase
time frame: From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
description: Alkaline phosphatase will be measured in U/L as per clinical routine and will be displayed using by-patient listings.
measure: Clinical chemistry: Alanine transaminase (ALT)
time frame: From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
description: ALT will be measured in U/L as per clinical routine and will be displayed using by-patient listings.
measure: Clinical chemistry: Aspartate transaminase (AST)
time frame: From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
description: AST will be measured in U/L as per clinical routine and will be displayed using by-patient listings.
measure: Clinical chemistry: Bilirubin total
time frame: From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
description: Total bilirubin will be measured in mg/dL as per clinical routine and will be displayed using by-patient listings.
measure: Clinical chemistry: Creatinine (Serum)
time frame: From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
description: Serum creatinine will be measured in µmol/L as per clinical routine and will be displayed using by-patient listings.
measure: Left Ventricular Ejection Fraction (LVEF) monitoring
time frame: LVEF at baseline, every three months thereafter until end of treatment, then every six months for 24 months thereafter (maximum up to 76 months)
description: Incidence of clinically relevant LVEF levels. Change from baseline at each assessment time point, worst-on-treatment will be displayed using descriptive statistics.
measure: Patient-reported health-related quality of life (QoL): Trial Outcome Index-Physical/Functional/Breast (TOI-PFB)
time frame: Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).
description: AUC in TOI-PFB at 12, 18, 24 and 36 months.
Area under the curve (AUC) in the Functional Assessment of Cancer Therapy - Breast (FACT-B) questionnaire subscale Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) after 12, 18, 24 and 36 months (irrespective of disease or treatment situation at that time point). Higher AUC indicates better quality of life.
To calculate the TOI-PFB the three subscales Physical well-being (PWB - 7 statements), Functional well-being (FWB - 7 statements) and breast cancer subscale (BCS - 10 statements) are summed up. In all subscales each statement will be rated by the patient from 0 (not at all) - 4 (very much). Therefore ranges of subscales are: PWB 0 - 28; FWB 0 - 28; BCS 0 - 40; TOI-PFB 0 - 96; higher values indicate better quality of life.
measure: Patient-reported health-related quality of life (QoL): FACT-B TOI-PFB
time frame: Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).
description: Time to decline by 5 points in the Functional Assessment of Cancer Therapy - Breast (FACT-B) questionnaire subscale Trial Outcome Index-Physical/Functional/Breast (TOI-PFB).
To calculate the TOI-PFB the three subscales Physical well-being (PWB - 7 statements), Functional well-being (FWB - 7 statements) and breast cancer subscale (BCS - 10 statements) are summed up. In all subscales each statement will be rated by the patient from 0 (not at all) - 4 (very much). Therefore ranges of subscales are: PWB 0 - 28; FWB 0 - 28; BCS 0 - 40; TOI-PFB 0 - 96; decline of scale indicates worsening quality of life.
measure: Patient-reported health-related quality of life (QoL): FACT-B total score
time frame: Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).
description: Change from baseline in the FACT-B total score for all questionnaire timepoints. To calculate FACT-B total score patient ratings from 0 (not at all) - 4 (very much) to each of the 37 questionnaire statement are summed up. Total score range: 0 - 148. Higher values indicate better quality of life
measure: Patient-reported health-related quality of life (QoL): FACT-B subscale physical well-being (PWB)
time frame: Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).
description: Change from baseline in the FACT-B subscale PWB for all questionnaire timepoints. PWB subscale consists of 7 statements leading to a scale range of 0-28. Higher values indicate better quality of life
measure: Patient-reported health-related quality of life (QoL): FACT-B subscale social/family well-being (SWB)
time frame: Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).
description: Change from baseline in the FACT-B subscale SWB for all questionnaire timepoints. SWB subscale consists of 8 statements leading to a scale range of 0-32. Higher values indicate better quality of life
measure: Patient-reported health-related quality of life (QoL): FACT-B subscale emotional well-being (EWB)
time frame: Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).
description: Change from baseline in the FACT-B subscale EWB for all questionnaire timepoints. EWB subscale consists of 6 statements leading to a scale range of 0-24. Higher values indicate better quality of life
measure: Patient-reported health-related quality of life (QoL): FACT-B subscale functional well-being (FWB)
time frame: Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).
description: Change from baseline in the FACT-B subscale FWB for all questionnaire timepoints. FWB subscale consists of 7 statements leading to a scale range of 0-28. Higher values indicate better quality of life
measure: Patient-reported health-related quality of life (QoL): FACT-B breast cancer subscale (BCS)
time frame: Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).
description: Change from baseline in the FACT-B BCS score for all questionnaire timepoints. BCS consists of 10 statements leading to a score range of 0-40. Higher values indicate better quality of life
measure: Patient-reported health-related quality of life (QoL): FACT-B breast cancer subscale (BCS) score decline
time frame: Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).
description: Time to decline by 2 points in the FACT-B BCS score. BCS consists of 10 statements leading to a score range of 0-40. BCS score decline indicates worsening quality of life.
measure: Patient-reported health-related quality of life (QoL): FACT/GOG-Ntx4 subscale
time frame: Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).
description: Change from baseline in the FACT/GOG-Ntx4 subscale for all questionnaire timepoints. FACT/GOG-Ntx4 subscale consists of 11 statements leading to a scale range of 0-44. Higher values indicate better quality of life
measure: Exploratory endpoint: Treatment costs
time frame: From randomization until end of treatment (maximum up to 56 months).
description: Treatment costs (drug costs)
measure: Exploratory endpoints: Duration of hospitalizations
time frame: From randomization until end of treatment (maximum up to 57 months).
description: Total duration of hospitalizations (per patients)
measure: Exploratory endpoints: Number of hospitalizations
time frame: From randomization until end of treatment (maximum up to 57 months).
description: Number of hospitalizations (in-patient stays)
measure: Exploratory endpoints: Reasons for hospitalizations
time frame: From randomization until end of treatment (maximum up to 57 months).
description: Reasons for hospitalizations
measure: Exploratory endpoints: Febrile infections
time frame: From randomization until end of treatment (maximum up to 57 months).
description: Incidence of febrile infections
measure: Exploratory endpoints: Employment status
time frame: From randomization until end of treatment (maximum up to 56 months).
description: Employment status (kind and duration of sick leaves)
arm group label: Kanjinti/Pertuzumab plus Vinorelbine
arm group type: Experimental
description: Patients will receive Kanjinti® (trastuzumab-biosimilar) plus pertuzumab plus vinorelbine.
arm group label: Kanjinti/Pertuzumab plus Docetaxel
arm group type: Active Comparator
description: Patients will receive Kanjinti® (trastuzumab-biosimilar) plus pertuzumab plus docetaxel.
intervention type: Drug
intervention name: Trastuzumab
description: administered as combined therapy with pertuzumab and vinorelbine or docetaxel.
Trastuzumab will be administered as an IV loading dose of 8 milligrams per kilogram (mg/kg) on day 1 of cycle 1 (1 cycle length = 21 days), and 6 mg/kg Q3W on day 1 of subsequent cycles until progressive disease, intolerable toxicity, or death.
arm group label: Kanjinti/Pertuzumab plus Docetaxel
arm group label: Kanjinti/Pertuzumab plus Vinorelbine
other name: Kanjinti®
other name: ABP 980
intervention type: Drug
intervention name: Pertuzumab
description: administered as combined therapy with Kanjinti® and vinorelbine or docetaxel.
Pertuzumab will be administered as an IV loading dose of 840 milligrams (mg) on day 1 of cycle 1 (1 cycle length = 21 days), and 420 mg Q3W on day 1 of subsequent cycles until progressive disease, intolerable toxicity, or death.
arm group label: Kanjinti/Pertuzumab plus Docetaxel
arm group label: Kanjinti/Pertuzumab plus Vinorelbine
other name: Perjeta®
intervention type: Drug
intervention name: Vinorelbine
description: administered as combined therapy with Kanjinti® and pertuzumab.
Vinorelbine will be administered as an IV dose of 25 milligrams per kilogram (mg/kg) on days 1 and 8 of cycle 1 (1 cycle length = 21 days), and 25mg/kg up to 30 mg/kg (as per treating physician discretion) Q3W on day 1 of subsequent cycles until progressive disease, intolerable toxicity, or death.
arm group label: Kanjinti/Pertuzumab plus Vinorelbine
intervention type: Drug
intervention name: Docetaxel
description: administered as combined therapy with Kanjinti® and pertuzumab.
Docetaxel will be administered as an IV dose of 75 milligrams per square meter (mg/m^2) on day 1 of cycle 1 (1 cycle length = 21 days), and 75 mg/m^2 (up to 100 mg/m^2 as per treating physician discretion) Q3W on day 1 of subsequent cycles until progressive disease, intolerable toxicity, or death.
arm group label: Kanjinti/Pertuzumab plus Docetaxel
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Anja Welt, Dr.
role: Principal Investigator
affiliation: Essen University Hospital
facility: 
country: Germany
citation: Andersson M, Lidbrink E, Bjerre K, Wist E, Enevoldsen K, Jensen AB, Karlsson P, Tange UB, Sorensen PG, Moller S, Bergh J, Langkjer ST. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol. 2011 Jan 20;29(3):264-71. doi: 10.1200/JCO.2010.30.8213. Epub 2010 Dec 13.
PMID: 21149659
citation: Andersson M, Lopez-Vega JM, Petit T, Zamagni C, Easton V, Kamber J, Restuccia E, Perez EA. Efficacy and Safety of Pertuzumab and Trastuzumab Administered in a Single Infusion Bag, Followed by Vinorelbine: VELVET Cohort 2 Final Results. Oncologist. 2017 Oct;22(10):1160-1168. doi: 10.1634/theoncologist.2017-0079. Epub 2017 Jun 7.
PMID: 28592618
citation: Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. doi: 10.1056/NEJMoa1113216. Epub 2011 Dec 7.
PMID: 22149875
citation: Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, Gelman R, Winer EP. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007 Sep 1;110(5):965-72. doi: 10.1002/cncr.22885.
PMID: 17614302
citation: Cortes J, Baselga J, Im YH, Im SA, Pivot X, Ross G, Clark E, Knott A, Swain SM. Health-related quality-of-life assessment in CLEOPATRA, a phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast cancer. Ann Oncol. 2013 Oct;24(10):2630-2635. doi: 10.1093/annonc/mdt274. Epub 2013 Jul 17.
PMID: 23868905
citation: Perez EA, Lopez-Vega JM, Petit T, Zamagni C, Easton V, Kamber J, Restuccia E, Andersson M. Safety and efficacy of vinorelbine in combination with pertuzumab and trastuzumab for first-line treatment of patients with HER2-positive locally advanced or metastatic breast cancer: VELVET Cohort 1 final results. Breast Cancer Res. 2016 Dec 13;18(1):126. doi: 10.1186/s13058-016-0773-6.
PMID: 27955684
citation: Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortes J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. doi: 10.1056/NEJMoa1413513.
PMID: 25693012
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Docetaxel
mesh term: Trastuzumab
mesh term: Vinorelbine
mesh term: Pertuzumab
sharing ipd: No