<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/NCT02216786</url>
  </required_header>
  <id_info>
    <org_study_id>009175QM</org_study_id>
    <nct_id>NCT02216786</nct_id>
  </id_info>
  <brief_title>A Randomized Study of AZD2014 in Combination With Fulvestrant in Metastatic or Advanced Breast Cancer</brief_title>
  <acronym>MANTA</acronym>
  <official_title>A Randomized Phase II Study of Fulvestrant in Combination With the Dual mTOR Inhibitor AZD2014 or Everolimus or Fulvestrant Alone in Estrogen Receptor-positive Advanced or Metastatic Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Queen Mary University of London</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Queen Mary University of London</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is an open-label, multicentre, 4-arm randomised phase II trial of fulvestrant + AZD2014&#xD;
      versus fulvestrant + everolimus versus fulvestrant alone in patients with ER-positive,&#xD;
      HER2-negative advanced or metastatic breast cancer, whose disease relapsed during treatment&#xD;
      with (or within 12 months after discontinuation of) an AI in the adjuvant setting or&#xD;
      progressed during treatment with an AI in the metastatic setting. Patients will be randomised&#xD;
      (2:3:3:2) to one of the four treatment arms:&#xD;
&#xD;
        -  Fulvestrant&#xD;
&#xD;
        -  Fulvestrant + AZD2014 (continuous daily schedule)&#xD;
&#xD;
        -  Fulvestrant + AZD2014 (intermittent schedule - 2 days on, 5 days off)&#xD;
&#xD;
        -  Fulvestrant + everolimus&#xD;
&#xD;
      Randomization will be stratified by the following criteria:&#xD;
&#xD;
        -  Measurable disease (vs. non-measurable).&#xD;
&#xD;
        -  Sensitivity to prior endocrine therapy (sensitive versus resistant)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an open-label, multicentre, 4-arm randomised phase II trial of fulvestrant + AZD2014&#xD;
      versus fulvestrant + everolimus versus fulvestrant alone in patients with ER-positive,&#xD;
      HER2-negative advanced or metastatic breast cancer, whose disease relapsed during treatment&#xD;
      with (or within 12 months after discontinuation of) an AI in the adjuvant setting or&#xD;
      progressed during treatment with an AI in the metastatic setting. Patients will be randomised&#xD;
      (2:3:3:2) to one of the four treatment arms:&#xD;
&#xD;
        -  Fulvestrant&#xD;
&#xD;
        -  Fulvestrant + AZD2014 (continuous daily schedule)&#xD;
&#xD;
        -  Fulvestrant + AZD2014 (intermittent schedule - 2 days on, 5 days off)&#xD;
&#xD;
        -  Fulvestrant + everolimus&#xD;
&#xD;
      Randomization will be stratified by the following criteria:&#xD;
&#xD;
        -  Measurable disease (vs. non-measurable).&#xD;
&#xD;
        -  Sensitivity to prior endocrine therapy (sensitive versus resistant) Sensitivity to prior&#xD;
           endocrine therapy is defined as (i) at least 24 months of endocrine therapy before&#xD;
           recurrence in the adjuvant setting or (ii) a complete or partial response to prior&#xD;
           metastatic endocrine treatment, or (iii) stabilization for at least 24 weeks of&#xD;
           endocrine therapy for advanced disease.&#xD;
&#xD;
      Treatment will be continued until disease progression unless there is evidence of&#xD;
      unacceptable toxicity or if the patient requests to be withdrawn from the study. If one of&#xD;
      the treatments (fulvestrant or mTOR inhibitor) is discontinued prior to disease progression,&#xD;
      patients should be continued on single agent treatment until progression, evidence of&#xD;
      unacceptable toxicity or if the patient requests to be withdrawn from the study.&#xD;
&#xD;
      At the time of documented disease progression (using RECIST 1.1), patients randomised to&#xD;
      receive fulvestrant + everolimus who still meet eligibility criteria may be permitted to&#xD;
      receive open-label crossover treatment with fulvestrant + AZD2014. Crossover therapy must&#xD;
      begin no later than 28 days after the clinic visit at which progression was determined.&#xD;
      Patients will receive crossover therapy until progression, intolerable toxicity, elective&#xD;
      withdrawal from the study, or until the completion or termination of the study, whichever&#xD;
      occurs first.&#xD;
&#xD;
      Tumour evaluations will be performed before the initiation of treatment, every 8 weeks during&#xD;
      the first 40 weeks and every 12 weeks thereafter until disease progression.&#xD;
&#xD;
      The study will also assess the relationship between the anticipated anti-tumour activity of&#xD;
      the treatment regimen and biological characteristics of patients' tumour at baseline&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">January 2014</start_date>
  <completion_date type="Anticipated">July 31, 2020</completion_date>
  <primary_completion_date type="Anticipated">July 31, 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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression-free survival</measure>
    <time_frame>Date of randomisation to date of first documented progression, assessed up to 100 weeks</time_frame>
    <description>Defined as the time from the date of randomisation to the date of first documented tumour progression based on investigator assessment (using RECIST 1.1) or death from any cause, whichever occurs first.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival</measure>
    <time_frame>time from the date of randomisation to the date of first documented tumour progression, assessed up to 100 weeks</time_frame>
    <description>Progression-free survival, defined as the time from the date of randomisation to the date of first documented tumour progression as assessed by an independent review facility [IRF] (using RECIST 1.1) or death from any cause, whichever occurs first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response</measure>
    <time_frame>Time from date of randomisation to documented objective response, assessed up to 60 months</time_frame>
    <description>Time from date of randomisation to documented objective response, defined as a complete or partial response, based on investigator and IRF assessment (using RECIST 1.1)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Average change (%) in tumour size</measure>
    <time_frame>16 weeks after baseline</time_frame>
    <description>Average change (%) in tumour size at 16 weeks compared to baseline, based on investigator and IRF assessment using RECIST 1.1; tumour size is defined as the sum of the longest diameters of the target (i.e. measurable tumour) lesions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Benefit (CB)</measure>
    <time_frame>Date of randomisation to 24 weeks.</time_frame>
    <description>Clinical Benefit (CB), defined as number of patients with complete or partial response or stable disease maintained ≥24 weeks, based on investigator and IRF assessment using RECIST 1.1.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">333</enrollment>
  <condition>Estrogen Receptor Positive Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Fulvestrant and AZD2014 (continuous)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Experimental arm</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Everolimus and Fulvestrant</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Comparator arm</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Fulvestrant</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Control 1</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Fulvestrant +AZD2014 (intermittent)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Experimental arm</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AZD2014</intervention_name>
    <description>Oral tablet</description>
    <arm_group_label>Fulvestrant +AZD2014 (intermittent)</arm_group_label>
    <arm_group_label>Fulvestrant and AZD2014 (continuous)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Everolimus</intervention_name>
    <description>Oral tablet</description>
    <arm_group_label>Everolimus and Fulvestrant</arm_group_label>
    <other_name>Afinitor</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fulvestrant</intervention_name>
    <description>Im injection</description>
    <arm_group_label>Everolimus and Fulvestrant</arm_group_label>
    <arm_group_label>Fulvestrant</arm_group_label>
    <arm_group_label>Fulvestrant +AZD2014 (intermittent)</arm_group_label>
    <arm_group_label>Fulvestrant and AZD2014 (continuous)</arm_group_label>
    <other_name>Faslodex</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          1. Written informed consent prior to admission to this study&#xD;
&#xD;
          2. Women, age ≥18 years&#xD;
&#xD;
          3. Histologically confirmed breast cancer&#xD;
&#xD;
          4. Metastatic or locally recurrent disease; locally recurrent disease must not be&#xD;
             amenable to resection with curative intent (patients who are considered suitable for&#xD;
             surgical or ablative techniques following potential down-staging with study treatment&#xD;
             are not eligible).&#xD;
&#xD;
          5. Patients must have:&#xD;
&#xD;
               1. at least one lesion, not previously irradiated, that can be measured accurately&#xD;
                  at baseline as ≥ 10mm in the longest diameter (except lymph nodes which must have&#xD;
                  short axis ≥ 15mm) with computed tomography (CT) or magnetic resonance imaging&#xD;
                  (MRI) which is suitable for accurate repeated measurements, or&#xD;
&#xD;
               2. lytic or mixed (lytic + sclerotic) bone lesions in the absence of measurable&#xD;
                  disease as defined above; patients with sclerotic/osteoblastic bone lesions only&#xD;
                  in the absence of measurable disease are not eligible&#xD;
&#xD;
          6. Radiological or clinical evidence of recurrence or progression&#xD;
&#xD;
          7. ER-positive disease&#xD;
&#xD;
          8. HER2-negative disease with 0, 1+ or 2+ intensity on IHC and no evidence of&#xD;
             amplification on ISH.&#xD;
&#xD;
          9. Formalin fixed, paraffin embedded tumour sample from the primary and/or recurrent&#xD;
             cancer must be available for central testing&#xD;
&#xD;
         10. Postmenopausal women.&#xD;
&#xD;
         11. Disease refractory to aromatase inhibitors (AI)&#xD;
&#xD;
         12. Haematologic and biochemical indices within acceptable limits&#xD;
&#xD;
         13. ECOG performance status 0-2&#xD;
&#xD;
         14. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant),&#xD;
             including any female who has had a hysterectomy, bilateral oophorectomy, bilateral&#xD;
             tubular ligation or is post-menopausal (total cessation of menses for ≥ 1 year&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          1. Presence of life-threatening metastatic visceral disease, defined as extensive hepatic&#xD;
             involvement or any degree of brain or leptomeningeal involvement (past or present), or&#xD;
             symptomatic pulmonary lymphangitic spread. Patients with discrete pulmonary&#xD;
             parenchymal metastases are eligible, provided their respiratory function is not&#xD;
             compromised as a result of disease.&#xD;
&#xD;
          2. More than one line of prior chemotherapy for metastatic breast cancer&#xD;
&#xD;
          3. Prior chemotherapy, biological therapy, androgens, thalidomide, immunotherapy, other&#xD;
             anticancer agents or any investigational agents within 14 days of starting study&#xD;
             treatment (not including palliative radiotherapy at focal sites), radiotherapy with a&#xD;
             wide field of radiation (greater than or equal to 30% marrow or whole pelvis or spine)&#xD;
             within 4 weeks of starting study treatment, or strontium-90 (or other&#xD;
             radiopharmaceuticals) within the past 3 months or major surgery within 4 weeks prior&#xD;
             to entry into the study (excluding the placement of vascular access); with the&#xD;
             exception of alopecia, all unresolved toxicities from prior treatment should be no&#xD;
             greater than CTCAE grade 1 at the time of starting study treatment&#xD;
&#xD;
          4. Prior treatment with fulvestrant or everolimus&#xD;
&#xD;
          5. Prior treatment with PI3K inhibitors, Akt inhibitors or other mTOR inhibitors.&#xD;
&#xD;
          6. Patients receiving concomitant immunosuppressive agents or chronic systemic&#xD;
             corticosteroids (≥10 mg prednisolone or an equivalent dose of other anti-inflammatory&#xD;
             corticosteroids) use for ≥28 days at the time of study entry except in cases outlined&#xD;
             below: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways&#xD;
             diseases), eye drops or local injections (e.g. intra-articular) are allowed. Patients&#xD;
             on stable low dose of corticosteroids for at least two weeks before randomisation are&#xD;
             allowed&#xD;
&#xD;
          7. Current refractory nausea and vomiting, chronic gastrointestinal disease or inability&#xD;
             to swallow the formulated product or previous significant bowel resection that would&#xD;
             preclude adequate absorption of the study medication&#xD;
&#xD;
          8. Clinically significant pulmonary dysfunction&#xD;
&#xD;
          9. Significant cardiovascular disease&#xD;
&#xD;
         10. QTc prolongation defined as a QTc interval &gt;470 msecs or other significant ECG&#xD;
             abnormalities including 2nd degree (type II) or 3rd degree AV block or bradycardia&#xD;
             (ventricular rate &lt;50 beats/min)&#xD;
&#xD;
         11. Concomitant medications known to prolong QT interval, or with factors that increase&#xD;
             the risk of QTc prolongation or risk of arrhythmic events (such as heart failure,&#xD;
             hypokalaemia, congenital long QT syndrome, family history of long QT syndrome, or&#xD;
             unexplained sudden death under 40 years of age)&#xD;
&#xD;
         12. Clinically significant abnormalities of glucose metabolism&#xD;
&#xD;
         13. Exposure to potent or moderate inhibitors or inducers of CYP3A4/5 within 2 weeks&#xD;
             before the first dose of study treatment&#xD;
&#xD;
         14. Exposure to potent or moderate inhibitors or inducers of CYP2C8 within 1 week before&#xD;
             the first dose of study treatment.&#xD;
&#xD;
         15. Application of haemopoietic growth factors (e.g. G-CSF, GM-CSF) within 2 weeks before&#xD;
             receiving study drug&#xD;
&#xD;
         16. Any other disease, metabolic dysfunction, physical examination finding, or clinical&#xD;
             laboratory finding that, in the investigator's opinion, gives reasonable suspicion of&#xD;
             a disease or condition that contraindicates the use of an investigational drug, may&#xD;
             affect the interpretation of the results, render the patient at high risk from&#xD;
             treatment complications or interferes with obtaining informed consent.&#xD;
&#xD;
         17. History of hypersensitivity to active or inactive excipients of AZD2014 or everolimus&#xD;
             or drugs with a similar chemical structure or class to AZD2014 or everolimus&#xD;
&#xD;
         18. History of hypersensitivity to active or inactive excipients of fulvestrant and/or&#xD;
             castor oil.&#xD;
&#xD;
         19. Patients presenting with anaemia symptoms (haemoglobin ≤ 90 g/L).&#xD;
&#xD;
         20. Currently receiving (and are unwilling to discontinue) oestrogen replacement therapy&#xD;
             (last dose ≤ 7 days prior to randomisation)&#xD;
&#xD;
         21. Psychological, familial, sociological or geographical conditions that do not permit&#xD;
             compliance with the study protocol.&#xD;
&#xD;
         22. Detained persons or prisoners&#xD;
&#xD;
         23. Pregnant or nursing women (including no breast feeding from two weeks before the first&#xD;
             dose of study medication, till 8 weeks after the last dose of study medication).&#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>Peter Schmid, Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>Queen Mary's University of London</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>ICO Paul Papin</name>
      <address>
        <city>Angers</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Sainte Catherine</name>
      <address>
        <city>Avignon</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Antoine Lacassagne Centre De Lutte Contre Le Cancer De Nice</name>
      <address>
        <city>Nice</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Center Private Saint-Grégoire</name>
      <address>
        <city>Saint-Grégoire</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Paul Strauss</name>
      <address>
        <city>Strasbourg</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinic Health House</name>
      <address>
        <city>Tbilisi</city>
        <country>Georgia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institute of Clinical Oncology</name>
      <address>
        <city>Tbilisi</city>
        <country>Georgia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>S. Khechinashvili University Clinic</name>
      <address>
        <city>Tbilisi</city>
        <country>Georgia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tbilisi Cancer Center</name>
      <address>
        <city>Tbilisi</city>
        <country>Georgia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Frauenärztliche Gemeinschaftspraxis - Onkologie</name>
      <address>
        <city>Braunschweig</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kliniken Essen-Mitte Senologie</name>
      <address>
        <city>Essen</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinik für Gynäkologie &amp; Geburtshilfe/Brustzentrum</name>
      <address>
        <city>Frankfurt</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Praxis für interdisziplinäre Onkologie &amp; Hämatologie</name>
      <address>
        <city>Freiburg</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MediProjekt GbR Hannover</name>
      <address>
        <city>Hannöver</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>SLK-Kliniken Heilbronn GmbH</name>
      <address>
        <city>Heilbronn</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dokusan GmbH</name>
      <address>
        <city>Herne</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Vincentius Kliniken</name>
      <address>
        <city>Karlsruhe</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Schwerpunktpraxis Hämatologie / Onkologie MVZ Lahr</name>
      <address>
        <city>Lahr</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinikum Neumarkt</name>
      <address>
        <city>Neumarkt</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Onkologische Praxis</name>
      <address>
        <city>Oldenburg</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Praxis für Innere Medizin</name>
      <address>
        <city>Singen</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MVZ Klinik Dr. Hancken GmbH</name>
      <address>
        <city>Stade</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mutterhaus der Borromäerinnen</name>
      <address>
        <city>Trier</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Schwarzwald Baar Klinikum, Villingen-Schwenningen</name>
      <address>
        <city>Villingen-Schwenningen</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Uzsoki Street Hospital</name>
      <address>
        <city>Budapest</city>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bacs-Kiskun County Hospital</name>
      <address>
        <city>Kalocsa</city>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pecs, Institute of Oncology</name>
      <address>
        <city>Pécs</city>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Zala County Szent Rafael Hospital</name>
      <address>
        <city>Zalaegerszeg</city>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National Cancer Center South Korea</name>
      <address>
        <city>Goyang</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Korea University Medical Center Guro Hospital</name>
      <address>
        <city>Seoul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Yonsei University Health System</name>
      <address>
        <city>Seoul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital da Luz</name>
      <address>
        <city>Lisboa</city>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ipo Porto</name>
      <address>
        <city>Porto</city>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Center of Oncology Euroclinic</name>
      <address>
        <city>Bucharest</city>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oncology Center Sf Nectarie</name>
      <address>
        <city>Caracal</city>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cluj County Clinical Emergency Hospital, Clinical Department of Medical Oncology</name>
      <address>
        <city>Cluj-Napoca</city>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oncology Institute &quot;Prof. Dr. Ion Chiricuta&quot;</name>
      <address>
        <city>Cluj-Napoca</city>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oncology Center Oncolab Craiova</name>
      <address>
        <city>Craiova</city>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitari Vall D'Hebron</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Instituto Oncologico Dr. Rosell</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Consorcio Hospitalario Provincial de Castellon</name>
      <address>
        <city>Castelló</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cafeteria Hospital San Pedro de Alcantara</name>
      <address>
        <city>Cáceres</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Ico Josep Trueta</name>
      <address>
        <city>Girona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Arnau de Vilanova</name>
      <address>
        <city>Lleida</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clinico Universitario San Carlos</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Son Espases</name>
      <address>
        <city>Palma De Mallorca</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Son Llàtzer</name>
      <address>
        <city>Palma</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario de Canarias</name>
      <address>
        <city>San Cristobal de la Laguna</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitari Sant Joan de Reus</name>
      <address>
        <city>Tarragona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Wansbeck General Hospital</name>
      <address>
        <city>Ashington</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Princess of Wales Hospital</name>
      <address>
        <city>Bridgend</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Sussex County Hospital</name>
      <address>
        <city>Brighton</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kent and Canterbury Hospital</name>
      <address>
        <city>Canterbury</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cumberland Infirmary</name>
      <address>
        <city>Carlisle</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Broomfield Hospital</name>
      <address>
        <city>Chelmsford</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital of North Durham</name>
      <address>
        <city>Durham</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Calderdale Royal Hospital</name>
      <address>
        <city>Halifax</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Huddersfield Royal Infirmary</name>
      <address>
        <city>Huddersfield</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kidderminster Hospital</name>
      <address>
        <city>Kidderminster</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Glamorgan Hospital</name>
      <address>
        <city>Llantrisant</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queen Mary University of London</name>
      <address>
        <city>London</city>
        <zip>EC1M6BQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Charring Cross Hospital</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>King's College Hospital</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mount Vernon Hospital</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queen Elizabeth Hospital, Woolwich</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Bartholomew's Hospital</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Royal Free Hospital</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Kent Oncology Centre</name>
      <address>
        <city>Maidstone</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>North Tyneside General Hospital</name>
      <address>
        <city>North Shields</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nottingham City Hospital</name>
      <address>
        <city>Nottingham</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Derriford Hospital</name>
      <address>
        <city>Plymouth</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Weston Park Hospital</name>
      <address>
        <city>Sheffield</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Solihull Hospital</name>
      <address>
        <city>Solihull</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Southend University Hospital</name>
      <address>
        <city>Southend-on-Sea</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Stoke University Hospital</name>
      <address>
        <city>Stoke-on-Trent</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>King's Mill Hospital</name>
      <address>
        <city>Sutton in Ashfield</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Great Western Hospital</name>
      <address>
        <city>Swindon</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Wrexham Maelor</name>
      <address>
        <city>Wrexham</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Yeovil District Hospital</name>
      <address>
        <city>Yeovil</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
    <country>Georgia</country>
    <country>Germany</country>
    <country>Hungary</country>
    <country>Korea, Republic of</country>
    <country>Portugal</country>
    <country>Romania</country>
    <country>Spain</country>
    <country>United Kingdom</country>
  </location_countries>
  <results_reference>
    <citation>Schmid P, Zaiss M, Harper-Wynne C, Ferreira M, Dubey S, Chan S, Makris A, Nemsadze G, Brunt AM, Kuemmel S, Ruiz I, Perello A, Kendall A, Brown J, Kristeleit H, Conibear J, Saura C, Grenier J, Mahr K, Schenker M, Sohn J, Lee KS, Shepherd CJ, Oelmann E, Sarker SJ, Prendergast A, Marosics P, Moosa A, Lawrence C, Coetzee C, Mousa K, Cortes J. Fulvestrant Plus Vistusertib vs Fulvestrant Plus Everolimus vs Fulvestrant Alone for Women With Hormone Receptor-Positive Metastatic Breast Cancer: The MANTA Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019 Nov 1;5(11):1556-1564. doi: 10.1001/jamaoncol.2019.2526. Erratum In: JAMA Oncol. 2021 Feb 1;7(2):312.</citation>
    <PMID>31465093</PMID>
  </results_reference>
  <verification_date>February 2020</verification_date>
  <study_first_submitted>March 12, 2014</study_first_submitted>
  <study_first_submitted_qc>August 14, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 15, 2014</study_first_posted>
  <last_update_submitted>February 24, 2020</last_update_submitted>
  <last_update_submitted_qc>February 24, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">February 25, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Everolimus</mesh_term>
    <mesh_term>Fulvestrant</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02216786
org study id: 009175QM
nct id: NCT02216786
lead sponsor: 
collaborator: 
has dmc: Yes
This is an open-label, multicentre, 4-arm randomised phase II trial of fulvestrant + AZD2014
      versus fulvestrant + everolimus versus fulvestrant alone in patients with ER-positive,
      HER2-negative advanced or metastatic breast cancer, whose disease relapsed during treatment
      with (or within 12 months after discontinuation of) an AI in the adjuvant setting or
      progressed during treatment with an AI in the metastatic setting. Patients will be randomised
      (2:3:3:2) to one of the four treatment arms:

        -  Fulvestrant

        -  Fulvestrant + AZD2014 (continuous daily schedule)

        -  Fulvestrant + AZD2014 (intermittent schedule - 2 days on, 5 days off)

        -  Fulvestrant + everolimus

      Randomization will be stratified by the following criteria:

        -  Measurable disease (vs. non-measurable).

        -  Sensitivity to prior endocrine therapy (sensitive versus resistant)
This is an open-label, multicentre, 4-arm randomised phase II trial of fulvestrant + AZD2014
      versus fulvestrant + everolimus versus fulvestrant alone in patients with ER-positive,
      HER2-negative advanced or metastatic breast cancer, whose disease relapsed during treatment
      with (or within 12 months after discontinuation of) an AI in the adjuvant setting or
      progressed during treatment with an AI in the metastatic setting. Patients will be randomised
      (2:3:3:2) to one of the four treatment arms:

        -  Fulvestrant

        -  Fulvestrant + AZD2014 (continuous daily schedule)

        -  Fulvestrant + AZD2014 (intermittent schedule - 2 days on, 5 days off)

        -  Fulvestrant + everolimus

      Randomization will be stratified by the following criteria:

        -  Measurable disease (vs. non-measurable).

        -  Sensitivity to prior endocrine therapy (sensitive versus resistant) Sensitivity to prior
           endocrine therapy is defined as (i) at least 24 months of endocrine therapy before
           recurrence in the adjuvant setting or (ii) a complete or partial response to prior
           metastatic endocrine treatment, or (iii) stabilization for at least 24 weeks of
           endocrine therapy for advanced disease.

      Treatment will be continued until disease progression unless there is evidence of
      unacceptable toxicity or if the patient requests to be withdrawn from the study. If one of
      the treatments (fulvestrant or mTOR inhibitor) is discontinued prior to disease progression,
      patients should be continued on single agent treatment until progression, evidence of
      unacceptable toxicity or if the patient requests to be withdrawn from the study.

      At the time of documented disease progression (using RECIST 1.1), patients randomised to
      receive fulvestrant + everolimus who still meet eligibility criteria may be permitted to
      receive open-label crossover treatment with fulvestrant + AZD2014. Crossover therapy must
      begin no later than 28 days after the clinic visit at which progression was determined.
      Patients will receive crossover therapy until progression, intolerable toxicity, elective
      withdrawal from the study, or until the completion or termination of the study, whichever
      occurs first.

      Tumour evaluations will be performed before the initiation of treatment, every 8 weeks during
      the first 40 weeks and every 12 weeks thereafter until disease progression.

      The study will also assess the relationship between the anticipated anti-tumour activity of
      the treatment regimen and biological characteristics of patients' tumour at baseline
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression-free survival
time frame: Date of randomisation to date of first documented progression, assessed up to 100 weeks
description: Defined as the time from the date of randomisation to the date of first documented tumour progression based on investigator assessment (using RECIST 1.1) or death from any cause, whichever occurs first.
measure: Progression-free survival
time frame: time from the date of randomisation to the date of first documented tumour progression, assessed up to 100 weeks
description: Progression-free survival, defined as the time from the date of randomisation to the date of first documented tumour progression as assessed by an independent review facility [IRF] (using RECIST 1.1) or death from any cause, whichever occurs first.
measure: Objective response
time frame: Time from date of randomisation to documented objective response, assessed up to 60 months
description: Time from date of randomisation to documented objective response, defined as a complete or partial response, based on investigator and IRF assessment (using RECIST 1.1)
measure: Average change (%) in tumour size
time frame: 16 weeks after baseline
description: Average change (%) in tumour size at 16 weeks compared to baseline, based on investigator and IRF assessment using RECIST 1.1; tumour size is defined as the sum of the longest diameters of the target (i.e. measurable tumour) lesions
measure: Clinical Benefit (CB)
time frame: Date of randomisation to 24 weeks.
description: Clinical Benefit (CB), defined as number of patients with complete or partial response or stable disease maintained ≥24 weeks, based on investigator and IRF assessment using RECIST 1.1.
arm group label: Fulvestrant and AZD2014 (continuous)
arm group type: Experimental
description: Experimental arm
arm group label: Everolimus and Fulvestrant
arm group type: Active Comparator
description: Comparator arm
arm group label: Fulvestrant
arm group type: Active Comparator
description: Control 1
arm group label: Fulvestrant +AZD2014 (intermittent)
arm group type: Experimental
description: Experimental arm
intervention type: Drug
intervention name: AZD2014
description: Oral tablet
arm group label: Fulvestrant +AZD2014 (intermittent)
arm group label: Fulvestrant and AZD2014 (continuous)
intervention type: Drug
intervention name: Everolimus
description: Oral tablet
arm group label: Everolimus and Fulvestrant
other name: Afinitor
intervention type: Drug
intervention name: Fulvestrant
description: Im injection
arm group label: Everolimus and Fulvestrant
arm group label: Fulvestrant
arm group label: Fulvestrant +AZD2014 (intermittent)
arm group label: Fulvestrant and AZD2014 (continuous)
other name: Faslodex
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Peter Schmid, Prof
role: Principal Investigator
affiliation: Queen Mary's University of London
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country: France
country: Georgia
country: Germany
country: Hungary
country: Korea, Republic of
country: Portugal
country: Romania
country: Spain
country: United Kingdom
citation: Schmid P, Zaiss M, Harper-Wynne C, Ferreira M, Dubey S, Chan S, Makris A, Nemsadze G, Brunt AM, Kuemmel S, Ruiz I, Perello A, Kendall A, Brown J, Kristeleit H, Conibear J, Saura C, Grenier J, Mahr K, Schenker M, Sohn J, Lee KS, Shepherd CJ, Oelmann E, Sarker SJ, Prendergast A, Marosics P, Moosa A, Lawrence C, Coetzee C, Mousa K, Cortes J. Fulvestrant Plus Vistusertib vs Fulvestrant Plus Everolimus vs Fulvestrant Alone for Women With Hormone Receptor-Positive Metastatic Breast Cancer: The MANTA Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019 Nov 1;5(11):1556-1564. doi: 10.1001/jamaoncol.2019.2526. Erratum In: JAMA Oncol. 2021 Feb 1;7(2):312.
PMID: 31465093
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Everolimus
mesh term: Fulvestrant