<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/NCT03227328</url>
  </required_header>
  <id_info>
    <org_study_id>IRST174.19</org_study_id>
    <secondary_id>2016-004107-31</secondary_id>
    <nct_id>NCT03227328</nct_id>
  </id_info>
  <brief_title>CDK4/6-inhibitor or Chemotherapy, in Combination With ENDOcrine Therapy, for Advanced Breast Cancer / KENDO</brief_title>
  <acronym>KENDO</acronym>
  <official_title>Group Sequential Response Adaptive Randomized Clinical Trial of Concomitant Chemotherapy Plus Endocrine Therapy Versus Cyclin-dependent Kinase 4/6 (CDK4/6) Inhibitor Plus Endocrine Therapy for Advanced Hormone Receptor-positive, HER2-negative Breast Cancer.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Agenzia Italiana del Farmaco</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori</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>
      Prospective, open label, multicenter, group sequential response adaptive randomized phase 2&#xD;
      study, comparing two treatments for locally advanced or metastatic luminal breast cancer:&#xD;
&#xD;
        -  Arm A: concomitant cyclin-dependent Kinase 4/6 (CDK4/6) inhibitor (palbociclib,&#xD;
           ribociclib or abemaciclib) plus endocrine therapy (aromatase inhibitor [AI] or&#xD;
           fulvestrant)&#xD;
&#xD;
        -  Arm B: chemotherapy plus endocrine therapy (AI or fulvestrant, administered either&#xD;
           concomitantly from the beginning of chemotherapy or sequentially after 4-6 months of&#xD;
           chemotherapy) Treatments will continue until disease progression or toxicity or patient&#xD;
           refusal.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Group sequential response adaptive randomized clinical trial of concomitant chemotherapy plus&#xD;
      endocrine therapy versus cyclin-dependent Kinase 4/6 (CDK4/6) inhibitor plus endocrine&#xD;
      therapy for advanced hormone receptor-positive, HER2-negative breast cancer Primary&#xD;
      Objective: To compare the efficacy of concomitant CDK4/6 inhibitor plus endocrine therapy&#xD;
      versus chemotherapy plus endocrine therapy (administered either concomitantly from the&#xD;
      beginning or sequentially) in terms of progression-free survival (PFS).&#xD;
&#xD;
      Secondary objectives: To compare between treatment arms:&#xD;
&#xD;
        -  quality of life (EORTC quality of life questionnaire(QLQ) QLQ -C30 and QLQ-BR23)&#xD;
&#xD;
        -  toxicity (CTCAE version 5.0)&#xD;
&#xD;
        -  time to treatment failure&#xD;
&#xD;
        -  best response rate&#xD;
&#xD;
        -  duration of response&#xD;
&#xD;
        -  clinical benefit rate&#xD;
&#xD;
        -  overall survival (OS)&#xD;
&#xD;
        -  PFS and clinical benefit with the subsequent line of treatment after cross-over: CDK4/6&#xD;
           inhibitors plus endocrine therapy in patients treated with chemotherapy plus endocrine&#xD;
           therapy, chemotherapy (with or without endocrine therapy) in patients treated with&#xD;
           CDK4/6 inhibitors plus endocrine therapy&#xD;
&#xD;
        -  correlative biomarkers of response to CDK4/6 inhibitors and chemotherapy:&#xD;
&#xD;
             -  tissue markers (on the primary tumor and / or metastatic tissue)&#xD;
&#xD;
             -  circulating markers (e.g. CTCs, ctDNA)&#xD;
&#xD;
      The patients will be allocated according to block randomization until two events are observed&#xD;
      in each arm, and then according to the time-to-event adaptation of the group sequential&#xD;
      Doubly-adaptive Biased Coin Design (DBCD) whose allocation probabilities are computed at the&#xD;
      end of the block randomization and after around 70% and 85% of the 150 maximum patients are&#xD;
      enrolled during a 23 month period. At these last two (i.e. after 105 and 128 patients,&#xD;
      respectively), interim analysis on efficacy will be carried out allowing for early stopping.&#xD;
      At the end of the 16-month follow up, administrative censoring is introduced. Therefore, the&#xD;
      total study duration is 39 months.&#xD;
&#xD;
      Previous results on palbociclib and fulvestrant combination in second line and the&#xD;
      characteristics of our target population lead us to assume a median PFS of 8 and 12 months&#xD;
      for arm A and B, respectively. Under this scenario, for a sample size of at the most 150&#xD;
      patients, the proposed design strategy has led to a simulated power of 0.911 compared with a&#xD;
      0.717 one for the Complete Randomisation design.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">August 2, 2017</start_date>
  <completion_date type="Anticipated">July 2022</completion_date>
  <primary_completion_date type="Anticipated">February 2022</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>group sequential response adaptive Randomized, open label, multicenter,</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression Free Survival (PFS)</measure>
    <time_frame>up to 39 months</time_frame>
    <description>time from randomization until first disease progression or death; disease progression is defined according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>EORTC QLQ-C30 quality of life between the 2 arms</measure>
    <time_frame>up to 39 months</time_frame>
    <description>evaluation of EORTC QLQ-C30 Version 3.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>QLQ-BR23 quality of life between the 2 arms</measure>
    <time_frame>up to 39 months</time_frame>
    <description>evaluation of QLQ-BR23 (breast cancer specific)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>toxicity</measure>
    <time_frame>up to 39 months</time_frame>
    <description>evaluation of toxicity by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>time to treatment failure (TTF)</measure>
    <time_frame>up to 39 months</time_frame>
    <description>the time from randomization to treatment discontinuation for any reason, including disease progression, treatment toxicity, patient refuse or death.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>best objective response rate</measure>
    <time_frame>up to 39 months</time_frame>
    <description>best objective (partial or complete) response rate according to RECIST 1.1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>duration of response</measure>
    <time_frame>up to 39 months</time_frame>
    <description>time from documentation of tumor response to disease progression</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>clinical benefit rate (CBR)</measure>
    <time_frame>up to 39months</time_frame>
    <description>the percentage of patients who achieved complete response, partial response or stable disease lasting longer than 24 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>overall survival (OS)</measure>
    <time_frame>up to 39 months</time_frame>
    <description>time from randomization until death for any cause</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival (PFS)</measure>
    <time_frame>up to 39 months</time_frame>
    <description>PFS and clinical benefit with the subsequent line of treatment after cross-overtime calculated from randomization until the date of start of the subsequent treatment line</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>correlative biomarkers of response to chemotherapy and endocrine therapy</measure>
    <time_frame>up to 39 months</time_frame>
    <description>correlative biomarkers assessed on baseline tumor specimens (from primary tumor or metastatic biopsies) and blood samples collected at baseline and at different timepoints until evidence of disease progression</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">150</enrollment>
  <condition>Hormone Receptor Positive Breast Cancer</condition>
  <condition>Metastatic Breast Cancer</condition>
  <condition>Hormone Receptor Negative Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Treatment Arm A</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>concomitant cyclin-dependent Kinase 4/6 (CDK4/6) inhibitor plus endocrine therapy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment Arm B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>chemotherapy plus endocrine therapy (administered either concomitantly or sequentially)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>concomitant cyclin-dependent Kinase 4/6 (CDK4/6) inhibitor plus endocrine therapy</intervention_name>
    <description>CDK4/6 inhibitor:&#xD;
palbociclib&#xD;
ribociclib&#xD;
abemaciclib&#xD;
Endocrine therapy:&#xD;
non-steroidal or steroidal AI&#xD;
fulvestrant</description>
    <arm_group_label>Treatment Arm A</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>chemotherapy plus endocrine therapy (administered either concomitantly or sequentially)</intervention_name>
    <description>Standard Chemotherapy regimens will be classified as:&#xD;
anthracycline + taxane,&#xD;
taxane,&#xD;
anthracycline,&#xD;
capecitabine / fluoropyrimidines,&#xD;
others.&#xD;
Endocrine therapy:&#xD;
non-steroidal or steroidal AI&#xD;
fulvestrant</description>
    <arm_group_label>Treatment Arm B</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histological diagnosis of HR-positive (ER ≥10% of tumor cells), HER2-negative breast&#xD;
             cancer, determined by local laboratory on most recent available tumor tissue.&#xD;
&#xD;
          -  Locally advanced (not susceptible to locoregional therapy) or metastatic disease&#xD;
             (herein globally defined as &quot;advanced breast cancer (ABC)&quot;).&#xD;
&#xD;
          -  At least one of the following signs of disease aggressiveness:&#xD;
&#xD;
               -  The main criteria are a low expression of ER (10% ≤ ER &lt; 50%) and/or a relapse&#xD;
                  while on the first 2 years of adjuvant endocrine therapy or disease progression&#xD;
                  (PD) within the first 6 months of first-line endocrine therapy for ABC&#xD;
&#xD;
               -  Other tumor characteristics of aggressiveness that make the patient potentially&#xD;
                  candidate to chemotherapy, according to the guidelines of the Italian Association&#xD;
                  of Medical Oncology [AIOM guidelines 2017], such as: elevated Ki67 (preferably&#xD;
                  documented, if available, on a metastatic biopsy), low expression of hormone&#xD;
                  receptors (e.g. progesterone receptor &lt;20%), extended visceral involvement or&#xD;
                  visceral involvement at risk for organ failure, uncontrolled symptoms; these&#xD;
                  patients are eligible if chemotherapy is considered a suitable option by the&#xD;
                  treating physician.&#xD;
&#xD;
          -  Postmenopausal women, or premenopausal women undergoing treatment with LHRH analog, or&#xD;
             men (either receiving treatment with LHRH analog or not).&#xD;
&#xD;
          -  Measurable disease according to RECIST 1.1 criteria, or not measurable but evaluable&#xD;
             disease.&#xD;
&#xD;
          -  Any prior adjuvant chemotherapy or endocrine therapy&#xD;
&#xD;
          -  No prior chemotherapy for advanced disease.&#xD;
&#xD;
          -  Up to one prior line of endocrine therapy for ABC.&#xD;
&#xD;
          -  Age ≥ 18 years.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤2 (see Appendix A).&#xD;
&#xD;
          -  Adequate organ (renal, hepatic, bone marrow, cardiac) functions.&#xD;
&#xD;
          -  Female participants of child bearing potential and male participants whose partner is&#xD;
             of child bearing potential must be willing to use effective contraception during the&#xD;
             study period and for 4 months thereafter. Effective contraception methods include:&#xD;
             total abstinence (when this is in line with the preferred and usual lifestyle of the&#xD;
             subject); tubal ligation; male sterilization; combination of the placement of an&#xD;
             intrauterine device or intrauterine system and barrier methods of contraception with&#xD;
             spermicidal suppository.&#xD;
&#xD;
          -  Participant is willing and able to give informed consent for participation in the&#xD;
             study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any prior chemotherapy or CDK4/6 inhibitor for advanced breast cancer&#xD;
&#xD;
          -  More than 1 prior line of endocrine therapy for ABC.&#xD;
&#xD;
          -  Patients who have not recovered from adverse events due to prior therapies to grade ≤1&#xD;
             (excluding alopecia).&#xD;
&#xD;
          -  Active central nervous system metastases.&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to the drugs used in the study.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements.&#xD;
&#xD;
          -  Prior history of non-breast malignancy (except for adequately controlled basal cell&#xD;
             carcinoma of the skin, carcinoma in situ of the cervix, in situ carcinoma of the&#xD;
             bladder), unless treated with curative intent and disease free for at least 3 years.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Andrea Rocca</last_name>
    <role>Study Director</role>
    <affiliation>Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Via Maroncelli 40, 47014 Meldola, ITALY</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Oriana Nanni</last_name>
    <phone>+390543739266</phone>
    <email>oriana.nanni@irst.emr.it</email>
  </overall_contact>
  <location>
    <facility>
      <name>U.O. Oncologia Medica, P.O. Bellaria-Maggiore</name>
      <address>
        <city>Bologna</city>
        <state>BO</state>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Alba Brandes, MD</last_name>
    </contact>
    <investigator>
      <last_name>Alba Brandes, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UO Oncologia Medica IRST IRCCS</name>
      <address>
        <city>Meldola</city>
        <state>FC</state>
        <zip>47014</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Andrea Rocca</last_name>
      <phone>0543739100</phone>
      <email>andrea.rocca@irst.emr.it</email>
    </contact>
    <investigator>
      <last_name>Andrea Rocca, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Dip. Medicina Interna e Riabilitazione - U.O. Medicina Interna Oncologica, Ospedale Ramazzini</name>
      <address>
        <city>Carpi</city>
        <state>MO</state>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Fabrizio Artioli, MD</last_name>
    </contact>
    <investigator>
      <last_name>Fabrizio Artioli, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Dip. Oncologia-Ematologia - U.O. Oncologia Medica,Azienda USL di Piacenza - Ospedale Civile</name>
      <address>
        <city>Piacenza</city>
        <state>PC</state>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Luigi Cavanna, MD</last_name>
    </contact>
    <investigator>
      <last_name>Luigi Cavanna, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UOC Oncologia Medica AUSL Romagna-Ravenna</name>
      <address>
        <city>Ravenna</city>
        <state>RA</state>
        <zip>48121</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Laura Amaducci, MD</last_name>
      <email>laura.amaducci@auslromagna.it</email>
    </contact>
    <investigator>
      <last_name>Laura Amaducci, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UO Oncologia Medica AUSL Romagna-Rimini</name>
      <address>
        <city>Rimini</city>
        <state>RI</state>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Lorenzo Gianni, MD</last_name>
      <email>lorenzo.gianni@auslromagna.it</email>
    </contact>
    <investigator>
      <last_name>Lorenzo Gianni, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>A.O.U. Ospedali Riuniti Umberto I - GM Lancisi - G Salesi</name>
      <address>
        <city>Ancona</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Rossana Berardi, MD</last_name>
    </contact>
    <investigator>
      <last_name>Rossana Berardi, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>U.O. Oncologia Medica; Ist. Tumori Giovanni Paolo II - IRCCS Osp. Oncologico di Bari</name>
      <address>
        <city>Bari</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Vito Lorusso, MD</last_name>
    </contact>
    <investigator>
      <last_name>Vito Lorusso, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Terapia Molecolare e Farmaco Genomica, Azienda Socio-Sanitaria Territoriale di Cremona</name>
      <address>
        <city>Cremona</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Daniele Generali, MD</last_name>
    </contact>
    <investigator>
      <last_name>Daniele Generali, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>A.O.U. di Ferrara Arcispedale Sant'Anna</name>
      <address>
        <city>Ferrara</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Antonio Frassoldati, MD</last_name>
    </contact>
    <investigator>
      <last_name>Antonio Frassoldati, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Ospedale Civile di Guastalla - AUSL di Reggio Emilia</name>
      <address>
        <city>Guastalla</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Filippo Giovanardi, MD</last_name>
    </contact>
    <investigator>
      <last_name>Filippo Giovanardi, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>AUSL Imola</name>
      <address>
        <city>Imola</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Antonio Maestri, MD</last_name>
    </contact>
    <investigator>
      <last_name>Antonio Maestri, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Ospedale Mater Salutis - Azienda ULSS9 Scaligera</name>
      <address>
        <city>Legnago</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Andrea Bonetti, MD</last_name>
    </contact>
    <investigator>
      <last_name>Andrea Bonetti, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Ospedale di Macerata, ASUR AV3</name>
      <address>
        <city>Macerata</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Nicola Battelli, MD</last_name>
    </contact>
    <investigator>
      <last_name>Nicola Battelli, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>A.O.U. Policlinico di Modena</name>
      <address>
        <city>Modena</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Federico Piacentini, MD</last_name>
    </contact>
    <investigator>
      <last_name>Federico Piacentini</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>A.O.U. Maggiore della Carità di Novara</name>
      <address>
        <city>Novara</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Alessandra Gennari, MD</last_name>
    </contact>
    <investigator>
      <last_name>Alessandra Gennari, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>U.O. Oncologia Medica, AOU di Parma</name>
      <address>
        <city>Parma</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Antonio Musolino, MD</last_name>
    </contact>
    <investigator>
      <last_name>Antonio Musolino, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>A.O. Santa Maria della Misericordia di Perugia</name>
      <address>
        <city>Perugia</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Fausto Roila, MD</last_name>
    </contact>
    <investigator>
      <last_name>Fausto Roila, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>A.O. Arcispedale S. Maria Nuova IRCCS di Reggio Emilia</name>
      <address>
        <city>Reggio Emilia</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Giancarlo Bisagni, MD</last_name>
    </contact>
    <investigator>
      <last_name>Giancarlo Bisagni, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Ospedale di Sondrio - ASST Valtellina e Alto Lario</name>
      <address>
        <city>Sondrio</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Alessandro Bertolini, MD</last_name>
    </contact>
    <investigator>
      <last_name>Alessandro Bertolini, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>April 2020</verification_date>
  <study_first_submitted>July 19, 2017</study_first_submitted>
  <study_first_submitted_qc>July 21, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 24, 2017</study_first_posted>
  <last_update_submitted>April 20, 2020</last_update_submitted>
  <last_update_submitted_qc>April 20, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">April 21, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>HR-positive Breast Cancer</keyword>
  <keyword>metastatic breast cancer</keyword>
  <keyword>First line treatment</keyword>
  <keyword>endocrine therapy</keyword>
  <keyword>chemotherapy</keyword>
  <keyword>randomized phase III trial</keyword>
  <keyword>aromatase inhibitor</keyword>
  <keyword>HR-negative Breast Cancer</keyword>
  <keyword>CDK4/6 inhibitor</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03227328
org study id: IRST174.19
secondary id: 2016-004107-31
nct id: NCT03227328
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Prospective, open label, multicenter, group sequential response adaptive randomized phase 2
      study, comparing two treatments for locally advanced or metastatic luminal breast cancer:

        -  Arm A: concomitant cyclin-dependent Kinase 4/6 (CDK4/6) inhibitor (palbociclib,
           ribociclib or abemaciclib) plus endocrine therapy (aromatase inhibitor [AI] or
           fulvestrant)

        -  Arm B: chemotherapy plus endocrine therapy (AI or fulvestrant, administered either
           concomitantly from the beginning of chemotherapy or sequentially after 4-6 months of
           chemotherapy) Treatments will continue until disease progression or toxicity or patient
           refusal.
Group sequential response adaptive randomized clinical trial of concomitant chemotherapy plus
      endocrine therapy versus cyclin-dependent Kinase 4/6 (CDK4/6) inhibitor plus endocrine
      therapy for advanced hormone receptor-positive, HER2-negative breast cancer Primary
      Objective: To compare the efficacy of concomitant CDK4/6 inhibitor plus endocrine therapy
      versus chemotherapy plus endocrine therapy (administered either concomitantly from the
      beginning or sequentially) in terms of progression-free survival (PFS).

      Secondary objectives: To compare between treatment arms:

        -  quality of life (EORTC quality of life questionnaire(QLQ) QLQ -C30 and QLQ-BR23)

        -  toxicity (CTCAE version 5.0)

        -  time to treatment failure

        -  best response rate

        -  duration of response

        -  clinical benefit rate

        -  overall survival (OS)

        -  PFS and clinical benefit with the subsequent line of treatment after cross-over: CDK4/6
           inhibitors plus endocrine therapy in patients treated with chemotherapy plus endocrine
           therapy, chemotherapy (with or without endocrine therapy) in patients treated with
           CDK4/6 inhibitors plus endocrine therapy

        -  correlative biomarkers of response to CDK4/6 inhibitors and chemotherapy:

             -  tissue markers (on the primary tumor and / or metastatic tissue)

             -  circulating markers (e.g. CTCs, ctDNA)

      The patients will be allocated according to block randomization until two events are observed
      in each arm, and then according to the time-to-event adaptation of the group sequential
      Doubly-adaptive Biased Coin Design (DBCD) whose allocation probabilities are computed at the
      end of the block randomization and after around 70% and 85% of the 150 maximum patients are
      enrolled during a 23 month period. At these last two (i.e. after 105 and 128 patients,
      respectively), interim analysis on efficacy will be carried out allowing for early stopping.
      At the end of the 16-month follow up, administrative censoring is introduced. Therefore, the
      total study duration is 39 months.

      Previous results on palbociclib and fulvestrant combination in second line and the
      characteristics of our target population lead us to assume a median PFS of 8 and 12 months
      for arm A and B, respectively. Under this scenario, for a sample size of at the most 150
      patients, the proposed design strategy has led to a simulated power of 0.911 compared with a
      0.717 one for the Complete Randomisation design.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: group sequential response adaptive Randomized, open label, multicenter,
primary purpose: Treatment
masking: None (Open Label)
measure: Progression Free Survival (PFS)
time frame: up to 39 months
description: time from randomization until first disease progression or death; disease progression is defined according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1
measure: EORTC QLQ-C30 quality of life between the 2 arms
time frame: up to 39 months
description: evaluation of EORTC QLQ-C30 Version 3.0
measure: QLQ-BR23 quality of life between the 2 arms
time frame: up to 39 months
description: evaluation of QLQ-BR23 (breast cancer specific)
measure: toxicity
time frame: up to 39 months
description: evaluation of toxicity by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
measure: time to treatment failure (TTF)
time frame: up to 39 months
description: the time from randomization to treatment discontinuation for any reason, including disease progression, treatment toxicity, patient refuse or death.
measure: best objective response rate
time frame: up to 39 months
description: best objective (partial or complete) response rate according to RECIST 1.1
measure: duration of response
time frame: up to 39 months
description: time from documentation of tumor response to disease progression
measure: clinical benefit rate (CBR)
time frame: up to 39months
description: the percentage of patients who achieved complete response, partial response or stable disease lasting longer than 24 weeks
measure: overall survival (OS)
time frame: up to 39 months
description: time from randomization until death for any cause
measure: Progression free survival (PFS)
time frame: up to 39 months
description: PFS and clinical benefit with the subsequent line of treatment after cross-overtime calculated from randomization until the date of start of the subsequent treatment line
measure: correlative biomarkers of response to chemotherapy and endocrine therapy
time frame: up to 39 months
description: correlative biomarkers assessed on baseline tumor specimens (from primary tumor or metastatic biopsies) and blood samples collected at baseline and at different timepoints until evidence of disease progression
arm group label: Treatment Arm A
arm group type: Active Comparator
description: concomitant cyclin-dependent Kinase 4/6 (CDK4/6) inhibitor plus endocrine therapy
arm group label: Treatment Arm B
arm group type: Experimental
description: chemotherapy plus endocrine therapy (administered either concomitantly or sequentially)
intervention type: Drug
intervention name: concomitant cyclin-dependent Kinase 4/6 (CDK4/6) inhibitor plus endocrine therapy
description: CDK4/6 inhibitor:
palbociclib
ribociclib
abemaciclib
Endocrine therapy:
non-steroidal or steroidal AI
fulvestrant
arm group label: Treatment Arm A
intervention type: Drug
intervention name: chemotherapy plus endocrine therapy (administered either concomitantly or sequentially)
description: Standard Chemotherapy regimens will be classified as:
anthracycline + taxane,
taxane,
anthracycline,
capecitabine / fluoropyrimidines,
others.
Endocrine therapy:
non-steroidal or steroidal AI
fulvestrant
arm group label: Treatment Arm B
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Andrea Rocca
role: Study Director
affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Via Maroncelli 40, 47014 Meldola, ITALY
last name: Oriana Nanni
phone: +390543739266
email: oriana.nanni@irst.emr.it
facility: 
status: Not yet recruiting
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country: Italy
responsible party type: Sponsor
mesh term: Breast Neoplasms