<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/NCT02988986</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00016065</org_study_id>
    <nct_id>NCT02988986</nct_id>
  </id_info>
  <brief_title>TAK-228 Plus Tamoxifen in Patients With ER-Positive, HER2-negative Breast Cancer</brief_title>
  <acronym>ANETT</acronym>
  <official_title>Open Label, Phase II Trial of Neoadjuvant TAK-228 Plus Tamoxifen in Patients With Estrogen Receptor (ER)-Positive, Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Methodist Hospital Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Millennium Pharmaceuticals, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>The Methodist Hospital Research Institute</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is an open label phase II clinical trial to determine the efficacy, toxicity, and safety&#xD;
      of TAK-228 plus tamoxifen in patients with newly diagnosed ER-positive, HER2-negative breast&#xD;
      cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The mTOR pathway is commonly dysregulated in ER-positive breast cancers and represents a key&#xD;
      resistance mechanism to endocrine therapy such as tamoxifen. We plan to target the mTOR&#xD;
      pathway with mTORC1/2 inhibitor TAK-228 to overcome tamoxifen resistance in early-stage&#xD;
      ER-positive breast cancer. An open label phase II clinical trial will be conducted to&#xD;
      determine the efficacy, toxicity, and safety of TAK-228 plus tamoxifen in patients with newly&#xD;
      diagnosed ER-positive, HER2-negative breast cancer. TAK-228 (30 mg weekly) plus tamoxifen (20&#xD;
      mg daily) will be administered for 16 weeks. Patients will undergo tumor biopsy before&#xD;
      starting the study treatment and after 6 weeks of study treatment. Blood samples for&#xD;
      pharmacokinetics analysis will be obtained 1 hour before and after TAK-228 dosing on days 1&#xD;
      and 15 of the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 24, 2017</start_date>
  <completion_date type="Actual">March 30, 2019</completion_date>
  <primary_completion_date type="Actual">February 1, 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Ki67 Expression</measure>
    <time_frame>Baseline to 6 weeks</time_frame>
    <description>Ki67 expression change from baseline to 6 weeks</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants Meeting Certain Preoperative Endocrine Prognostic Index (PEPI)</measure>
    <time_frame>16 weeks</time_frame>
    <description>Evaluate the number of participants meeting certain PEPI score after treatment with TAK-228 plus tamoxifen.&#xD;
PEPI score of 0 indicates low risk of disease recurrence (better outcome) PEPI score of 1-3 indicates intermediate risk of of disease recurrence (worse outcome) PEPI score of &gt;4 indicates high risk of of disease recurrence (worst outcome)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Pathological Complete Response (pCR)</measure>
    <time_frame>16 weeks</time_frame>
    <description>Pathologic complete response was defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypT0 ypN0 or ypTis ypN0 in the current American Joint Committee on Cancer staging system).</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Plasma Concentrations of TAK-228 Plus Tamoxifen</measure>
    <time_frame>16 weeks</time_frame>
    <description>Measure plasma concentrations of TAK-228 plus tamoxifen over time</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlation Between Change in Ki67 Expression and pCR to TAK-228 Plus Tamoxifen</measure>
    <time_frame>16 weeks</time_frame>
    <description>Assess the correlation between change in Ki67 expression and pCR to TAK-228 plus tamoxifen</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlation Between Tumor Mutational Status and Response to TAK-228 Plus Tamoxifen</measure>
    <time_frame>16 weeks</time_frame>
    <description>Assess correlation between tumor mutational status and response to TAK-228 plus tamoxifen</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlation Between Change in mTOR Expression and pCR to TAK-228 Plus Tamoxifen</measure>
    <time_frame>16 weeks</time_frame>
    <description>Assess the correlation between change in mTOR expression and pCR to TAK-228 plus tamoxifen</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">28</enrollment>
  <condition>Estrogen Receptor Positive Breast Cancer</condition>
  <arm_group>
    <arm_group_label>TAK-228 Plus Tamoxifen</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TAK-228 will be orally administered at 30 mg weekly for 16 weeks.&#xD;
Tamoxifen will be orally administered at 20 mg daily for 16 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TAK-228</intervention_name>
    <description>MTORC1/2 inhibitor</description>
    <arm_group_label>TAK-228 Plus Tamoxifen</arm_group_label>
    <other_name>INK128, MLN0128</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tamoxifen</intervention_name>
    <description>Non-steroidal anti-estrogen</description>
    <arm_group_label>TAK-228 Plus Tamoxifen</arm_group_label>
    <other_name>Apo-Tamox, Gen-Tamoxifen, Nolvadex, Novo-Tamoxifen</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Female or male ≥ 18 years of age.&#xD;
&#xD;
          2. Newly diagnosed ER-positive, HER2-negative breast cancer. ER-positive is defined as ≥&#xD;
             1% immunohistochemical (IHC) staining of any intensity. HER2 test result is negative&#xD;
             if a single test (or both tests) performed show:&#xD;
&#xD;
               -  IHC 1+ or 0&#xD;
&#xD;
               -  In situ hybridization negative based on:&#xD;
&#xD;
                    -  Single-probe average HER2 copy number &lt; 4.0 signals/cell&#xD;
&#xD;
                    -  Dual-probe HER2/CEP17 ratio &lt; 2 with an average HER2 copy number &lt; 4.0&#xD;
                       signals/cell.&#xD;
&#xD;
          3. Patients with stage II-III breast cancer are eligible if they are deemed appropriate&#xD;
             for neoadjuvant endocrine therapy by the referring or treating medical oncologist.&#xD;
             Patients with stage I disease are eligible if they are deemed borderline candidates&#xD;
             for breast conservation and the treating surgeon recommends preoperative therapy to&#xD;
             increase the chances of breast conservation.&#xD;
&#xD;
          4. Eastern Cooperative Oncology Group performance status and/or other performance status&#xD;
             of ≤ 1.&#xD;
&#xD;
          5. Female patients who:&#xD;
&#xD;
               -  Are postmenopausal for at least 1 year before the screening visit, OR&#xD;
&#xD;
               -  Are surgically sterile, OR&#xD;
&#xD;
               -  If they are of childbearing potential, agree to practice 1 effective method of&#xD;
                  contraception and 1 additional effective (barrier) method, at the same time, from&#xD;
                  the time of signing the ICF through 90 days (or longer, as mandated by local&#xD;
                  labeling [e.g., United Surgical Partners International, summary of product&#xD;
                  characteristics, etc.] after the last dose of the study drugs, OR&#xD;
&#xD;
               -  Agree to practice true abstinence, when this is in line with the preferred and&#xD;
                  usual lifestyle of the patient (periodic abstinence [e.g., calendar, ovulation,&#xD;
                  symptothermal, postovulation methods] and withdrawal, spermicides only, and&#xD;
                  lactational amenorrhea are not acceptable methods of contraception. Female and&#xD;
                  male condom should not be used together).&#xD;
&#xD;
          6. Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:&#xD;
&#xD;
               -  Agree to practice highly effective barrier contraception during the entire study&#xD;
                  treatment period and through 120 days after the last dose of the study drugs, OR&#xD;
&#xD;
               -  Agree to practice true abstinence, when this is in line with the preferred and&#xD;
                  usual lifestyle of the patient&#xD;
&#xD;
               -  Agree not to donate sperm during the course of this study or within 120 days&#xD;
                  after receiving their last dose of the study drugs.&#xD;
&#xD;
          7. Screening clinical laboratory values as specified below:&#xD;
&#xD;
               1. Bone marrow reserve consistent with: absolute neutrophil count ≥ 1.5 x 109/L,&#xD;
                  platelet count ≥ 100 x 109/L, and hemoglobin ≥ 9 g/dL (without transfusion)&#xD;
                  within 1 week preceding the administration of the study drugs;&#xD;
&#xD;
               2. Hepatic status: Serum total bilirubin ≤ 1 x upper limit of normal (ULN; in the&#xD;
                  case of known Gilbert's syndrome, a higher serum total bilirubin [&lt; 1.5 x ULN] is&#xD;
                  allowed), aspartate aminotransferase and alanine aminotransferase ≤ 1.5 x ULN,&#xD;
                  and alkaline phosphatase ≤ 1.5 x ULN;&#xD;
&#xD;
               3. Renal status: Creatinine clearance ≥50 mL/min based on Cockcroft-Gault estimate&#xD;
                  or based on urine collection (12 or 24 hour);&#xD;
&#xD;
               4. Metabolic status: HbA1c &lt; 7.0%, fasting serum glucose ≤ 130 mg/dL, and fasting&#xD;
                  triglycerides ≤ 300 mg/dL.&#xD;
&#xD;
          8. Ability to swallow oral medications.&#xD;
&#xD;
          9. Voluntary written consent must be given before performance of any study-related&#xD;
             procedure not part of standard medical care, with the understanding that consent may&#xD;
             be withdrawn by the patient at any time without prejudice to future medical care.&#xD;
&#xD;
         10. Negative serum pregnancy test within 7 days prior to the administration of the study&#xD;
             drugs for female patients of childbearing potential.&#xD;
&#xD;
         11. Patient must be accessible for treatment and follow-up.&#xD;
&#xD;
         12. Patient must be willing to undergo breast biopsies as required by the study protocol.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any patient with metastatic disease.&#xD;
&#xD;
          2. Other clinically significant comorbidities, such as uncontrolled pulmonary disease,&#xD;
             active central nervous system disease, active infection, or any other condition that&#xD;
             could compromise the patient's participation in the study.&#xD;
&#xD;
          3. Known human immunodeficiency virus infection.&#xD;
&#xD;
          4. Known hepatitis B surface antigen-positive or known or suspected active hepatitis C&#xD;
             infection.&#xD;
&#xD;
          5. Any serious medical or psychiatric illness that could, in the investigator's opinion,&#xD;
             potentially interfere with the completion of the protocol-specified treatment.&#xD;
&#xD;
          6. Diagnosed or treated for another malignancy within 2 years before administration of&#xD;
             the first dose of the study drugs or previously diagnosed with another malignancy and&#xD;
             have any evidence of residual disease. Patients with non-melanoma skin cancer or&#xD;
             carcinoma in situ of any type are not excluded if they have undergone complete&#xD;
             resection.&#xD;
&#xD;
          7. Breastfeeding or pregnant.&#xD;
&#xD;
          8. Manifestations of malabsorption due to prior gastrointestinal surgery,&#xD;
             gastrointestinal disease, or an unknown reason that may alter the absorption of&#xD;
             TAK-228. Patients with enteric stomata are also excluded.&#xD;
&#xD;
          9. Treatment with any investigational products within 2 weeks before administration of&#xD;
             the first dose of the study drugs.&#xD;
&#xD;
         10. Poorly controlled diabetes mellitus (defined as HbA1c &gt; 7%). Patients with a history&#xD;
             of transient glucose intolerance due to corticosteroid administration may be enrolled&#xD;
             in the study if all other inclusion criteria and none of the other exclusion criteria&#xD;
             are met.&#xD;
&#xD;
         11. History of any of the following within the last 6 months before administration of the&#xD;
             first dose of the study drugs:&#xD;
&#xD;
               -  Ischemic myocardial event, including angina requiring therapy and artery&#xD;
                  revascularization procedures&#xD;
&#xD;
               -  Ischemic cerebrovascular event, including transient ischemic attack and artery&#xD;
                  revascularization procedures&#xD;
&#xD;
               -  Requirement for inotropic support (excluding digoxin) or serious (uncontrolled)&#xD;
                  cardiac arrhythmia (including atrial flutter/fibrillation, ventricular&#xD;
                  fibrillation, and ventricular tachycardia)&#xD;
&#xD;
               -  Placement of a pacemaker for control of rhythm&#xD;
&#xD;
               -  New York Heart Association Class III or IV heart failure&#xD;
&#xD;
               -  Pulmonary embolism&#xD;
&#xD;
         12. Significant active cardiovascular or pulmonary disease including:&#xD;
&#xD;
               -  Uncontrolled hypertension (i.e., systolic blood pressure &gt; 180 mm Hg, diastolic&#xD;
                  blood pressure &gt; 95 mm Hg). Use of antihypertensive agents to control&#xD;
                  hypertension before week 1, day 1 is allowed.&#xD;
&#xD;
               -  Pulmonary hypertension&#xD;
&#xD;
               -  Uncontrolled asthma or O2 saturation &lt; 90% by arterial blood gas analysis or&#xD;
                  pulse oximetry on room air&#xD;
&#xD;
               -  Significant valvular disease, severe regurgitation, or stenosis by imaging&#xD;
                  independent of symptom control with medical intervention or history of valve&#xD;
                  replacement&#xD;
&#xD;
               -  Medically significant (symptomatic) bradycardia&#xD;
&#xD;
               -  History of arrhythmia requiring an implantable cardiac defibrillator&#xD;
&#xD;
               -  Baseline QTc prolongation (e.g., repeated demonstration of QTc interval &gt; 480&#xD;
                  milliseconds or history of congenital long QT syndrome or torsades de pointes)&#xD;
&#xD;
         13. Treatment with strong inhibitors and/or inducers of CYP3A4, CYP2C9, or CYP2C19 within&#xD;
             7 days preceding the first dose of the study drugs.&#xD;
&#xD;
         14. Patients receiving systemic corticosteroids (either IV or oral steroids, excluding&#xD;
             inhalers or low-dose hormone replacement therapy) within 1 week before administration&#xD;
             of the first dose of the study drugs.&#xD;
&#xD;
         15. Daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI within&#xD;
             7 days before receiving the first dose of the study drugs.&#xD;
&#xD;
         16. Patients unwilling or unable to comply with the study protocol.&#xD;
&#xD;
         17. Patients previously treated with hormonal therapy (tamoxifen, AI) or PI3K, AKT, dual&#xD;
             PI3K/mTOR, TORC1/2, or mTORC1 inhibitors.&#xD;
&#xD;
         18. Patients who are currently being treated with cancer therapy (chemotherapy, radiation&#xD;
             therapy, immunotherapy, or biologic therapy) other than the trial therapy.&#xD;
&#xD;
         19. Patients with hypersensitivity to mTOR inhibitors or tamoxifen.&#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>Jenny C Chang, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Houston Methodist Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Houston Methodist Hospital</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Houston Methodist Hospital Willowbrook</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77070</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Houston Methodist Hospital Sugar Land</name>
      <address>
        <city>Sugar Land</city>
        <state>Texas</state>
        <zip>77479</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>November 30, 2016</study_first_submitted>
  <study_first_submitted_qc>December 7, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 12, 2016</study_first_posted>
  <results_first_submitted>December 3, 2020</results_first_submitted>
  <results_first_submitted_qc>July 5, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">July 27, 2021</results_first_posted>
  <last_update_submitted>August 27, 2021</last_update_submitted>
  <last_update_submitted_qc>August 27, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 22, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The Methodist Hospital Research Institute</investigator_affiliation>
    <investigator_full_name>Jenny C. Chang, MD</investigator_full_name>
    <investigator_title>Houston Methodist Cancer Center Director</investigator_title>
  </responsible_party>
  <keyword>mTOR</keyword>
  <keyword>Tamoxifen</keyword>
  <keyword>Breast Cancer</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>Tamoxifen</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Data and materials on human subjects will be shared with other eligible investigators through appropriate means in accordance with the NIH policy on Sharing Research Data (NIH Guide, February 26, 2003). Data will be also shared with the funding agency and regulatory agencies as required. Data will be shared with other investigators within the limits of HIPAA and other patient confidentiality requirements. This will generally require removal of all patient identifiers for all source documents and the use of arbitrarily assigned one-way identifiers. In some cases, requestors will be asked to sign a formal data sharing agreement that will provide for a commitment to use data only for research purposes and not to identify individuals, keep the data secure, and destroy or return data after analyses are complete. Prior approval will be obtained from collaborating investigators, research sponsors, and/or other stake-holders before sharing if proprietary information or products are involved.</ipd_description>
    <ipd_time_frame>From study end (3/30/2019) for 5 years.</ipd_time_frame>
    <ipd_access_criteria>Data and materials on human subjects will be shared with other eligible investigators through appropriate means in accordance with the NIH policy on Sharing Research Data (NIH Guide, February 26, 2003). Data will be also shared with the funding agency and regulatory agencies as required. Data will be shared with other investigators within the limits of HIPAA and other patient confidentiality requirements. This will generally require removal of all patient identifiers for all source documents and the use of arbitrarily assigned one-way identifiers. In some cases, requestors will be asked to sign a formal data sharing agreement that will provide for a commitment to use data only for research purposes and not to identify individuals, keep the data secure, and destroy or return data after analyses are complete. Prior approval will be obtained from collaborating investigators, research sponsors, and/or other stake-holders before sharing if proprietary information or products are involved.</ipd_access_criteria>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>June 25, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/86/NCT02988986/Prot_SAP_002.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>TAK-228 Plus Tamoxifen</title>
          <description>TAK-228 will be orally administered at 30 mg weekly for 16 weeks.&#xD;
Tamoxifen will be orally administered at 20 mg daily for 16 weeks.&#xD;
TAK-228: MTORC1/2 inhibitor&#xD;
Tamoxifen: Non-steroidal anti-estrogen</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="28"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="25"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>TAK-228 Plus Tamoxifen</title>
          <description>TAK-228 will be orally administered at 30 mg weekly for 16 weeks.&#xD;
Tamoxifen will be orally administered at 20 mg daily for 16 weeks.&#xD;
TAK-228: MTORC1/2 inhibitor&#xD;
Tamoxifen: Non-steroidal anti-estrogen</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="28"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="28"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <description>Twenty-eight women were enrolled on the trial, and 25 completed the entire study course.</description>
          <population>28 patients were enrolled in the study. 25 completed the entire study. 23 were evaluable for the primary endpoint. All 28 patients were evaluated for safety and toxicity.</population>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="52" spread="11.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="28"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Stage I-III ER-positive, HER-2 negative breast cancer</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Ki67 Expression</title>
        <description>Ki67 expression change from baseline to 6 weeks</description>
        <time_frame>Baseline to 6 weeks</time_frame>
        <population>Change in baseline Ki67 expression at 6 weeks</population>
        <group_list>
          <group group_id="O1">
            <title>TAK-228 Plus Tamoxifen</title>
            <description>TAK-228 will be orally administered at 30 mg weekly for 16 weeks.&#xD;
Tamoxifen will be orally administered at 20 mg daily for 16 weeks.&#xD;
TAK-228: MTORC1/2 inhibitor&#xD;
Tamoxifen: Non-steroidal anti-estrogen</description>
          </group>
        </group_list>
        <measure>
          <title>Ki67 Expression</title>
          <description>Ki67 expression change from baseline to 6 weeks</description>
          <population>Change in baseline Ki67 expression at 6 weeks</population>
          <units>Percentage of cells with Ki67 expression</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Ki67 expression at baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15" lower_limit="10" upper_limit="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ki67 expression at 6 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10" lower_limit="2" upper_limit="38"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>The primary endpoint was the change in Ki67 after 6 weeks of treatment.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>Based on prior data for Ki67 changes in the tamoxifen arm alone, we will assume null hypothesis and alternative hypotheses of 60% and 80% reduction in Ki67, respectively. A sample of 25 patients will provide 86% power to detect the hypothesized reduction in Ki67 with 5% alpha based on a two-sided, one sample t-test of mean percent change in Ki67 level.</non_inferiority_desc>
            <p_value>=0.0023</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants Meeting Certain Preoperative Endocrine Prognostic Index (PEPI)</title>
        <description>Evaluate the number of participants meeting certain PEPI score after treatment with TAK-228 plus tamoxifen.&#xD;
PEPI score of 0 indicates low risk of disease recurrence (better outcome) PEPI score of 1-3 indicates intermediate risk of of disease recurrence (worse outcome) PEPI score of &gt;4 indicates high risk of of disease recurrence (worst outcome)</description>
        <time_frame>16 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Tamoxifen</title>
            <description>20 mg p.o QW x16 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Meeting Certain Preoperative Endocrine Prognostic Index (PEPI)</title>
          <description>Evaluate the number of participants meeting certain PEPI score after treatment with TAK-228 plus tamoxifen.&#xD;
PEPI score of 0 indicates low risk of disease recurrence (better outcome) PEPI score of 1-3 indicates intermediate risk of of disease recurrence (worse outcome) PEPI score of &gt;4 indicates high risk of of disease recurrence (worst outcome)</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>PEPI score of 0</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PEPI score of 1-3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PEPI score of &gt;4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Pathological Complete Response (pCR)</title>
        <description>Pathologic complete response was defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypT0 ypN0 or ypTis ypN0 in the current American Joint Committee on Cancer staging system).</description>
        <time_frame>16 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>TAK-228 Plus Tamoxifen</title>
            <description>TAK-228 will be orally administered at 30 mg weekly for 16 weeks.&#xD;
Tamoxifen will be orally administered at 20 mg daily for 16 weeks.&#xD;
TAK-228: MTORC1/2 inhibitor&#xD;
Tamoxifen: Non-steroidal anti-estrogen</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Pathological Complete Response (pCR)</title>
          <description>Pathologic complete response was defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypT0 ypN0 or ypTis ypN0 in the current American Joint Committee on Cancer staging system).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Plasma Concentrations of TAK-228 Plus Tamoxifen</title>
        <description>Measure plasma concentrations of TAK-228 plus tamoxifen over time</description>
        <time_frame>16 weeks</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Correlation Between Change in Ki67 Expression and pCR to TAK-228 Plus Tamoxifen</title>
        <description>Assess the correlation between change in Ki67 expression and pCR to TAK-228 plus tamoxifen</description>
        <time_frame>16 weeks</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Correlation Between Tumor Mutational Status and Response to TAK-228 Plus Tamoxifen</title>
        <description>Assess correlation between tumor mutational status and response to TAK-228 plus tamoxifen</description>
        <time_frame>16 weeks</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Correlation Between Change in mTOR Expression and pCR to TAK-228 Plus Tamoxifen</title>
        <description>Assess the correlation between change in mTOR expression and pCR to TAK-228 plus tamoxifen</description>
        <time_frame>16 weeks</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Up to 16 weeks</time_frame>
      <group_list>
        <group group_id="E1">
          <title>TAK-228 and Tamoxifen</title>
          <description>20 mg p.o QW x16 weeks</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>hyperglycemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>3</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="28" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="28" subjects_affected="28" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Jenny Chang, Director of Houston Methodist Cancer Center</name_or_title>
      <organization>Houston Methodist Hospital</organization>
      <phone>713-441-0681</phone>
      <email>jcchang@houstonmethodist.org</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02988986
org study id: Pro00016065
nct id: NCT02988986
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This is an open label phase II clinical trial to determine the efficacy, toxicity, and safety
      of TAK-228 plus tamoxifen in patients with newly diagnosed ER-positive, HER2-negative breast
      cancer.
The mTOR pathway is commonly dysregulated in ER-positive breast cancers and represents a key
      resistance mechanism to endocrine therapy such as tamoxifen. We plan to target the mTOR
      pathway with mTORC1/2 inhibitor TAK-228 to overcome tamoxifen resistance in early-stage
      ER-positive breast cancer. An open label phase II clinical trial will be conducted to
      determine the efficacy, toxicity, and safety of TAK-228 plus tamoxifen in patients with newly
      diagnosed ER-positive, HER2-negative breast cancer. TAK-228 (30 mg weekly) plus tamoxifen (20
      mg daily) will be administered for 16 weeks. Patients will undergo tumor biopsy before
      starting the study treatment and after 6 weeks of study treatment. Blood samples for
      pharmacokinetics analysis will be obtained 1 hour before and after TAK-228 dosing on days 1
      and 15 of the study.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Ki67 Expression
time frame: Baseline to 6 weeks
description: Ki67 expression change from baseline to 6 weeks
measure: Number of Participants Meeting Certain Preoperative Endocrine Prognostic Index (PEPI)
time frame: 16 weeks
description: Evaluate the number of participants meeting certain PEPI score after treatment with TAK-228 plus tamoxifen.
PEPI score of 0 indicates low risk of disease recurrence (better outcome) PEPI score of 1-3 indicates intermediate risk of of disease recurrence (worse outcome) PEPI score of >4 indicates high risk of of disease recurrence (worst outcome)
measure: Number of Participants With Pathological Complete Response (pCR)
time frame: 16 weeks
description: Pathologic complete response was defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypT0 ypN0 or ypTis ypN0 in the current American Joint Committee on Cancer staging system).
measure: Plasma Concentrations of TAK-228 Plus Tamoxifen
time frame: 16 weeks
description: Measure plasma concentrations of TAK-228 plus tamoxifen over time
measure: Correlation Between Change in Ki67 Expression and pCR to TAK-228 Plus Tamoxifen
time frame: 16 weeks
description: Assess the correlation between change in Ki67 expression and pCR to TAK-228 plus tamoxifen
measure: Correlation Between Tumor Mutational Status and Response to TAK-228 Plus Tamoxifen
time frame: 16 weeks
description: Assess correlation between tumor mutational status and response to TAK-228 plus tamoxifen
measure: Correlation Between Change in mTOR Expression and pCR to TAK-228 Plus Tamoxifen
time frame: 16 weeks
description: Assess the correlation between change in mTOR expression and pCR to TAK-228 plus tamoxifen
arm group label: TAK-228 Plus Tamoxifen
arm group type: Experimental
description: TAK-228 will be orally administered at 30 mg weekly for 16 weeks.
Tamoxifen will be orally administered at 20 mg daily for 16 weeks.
intervention type: Drug
intervention name: TAK-228
description: MTORC1/2 inhibitor
arm group label: TAK-228 Plus Tamoxifen
other name: INK128, MLN0128
intervention type: Drug
intervention name: Tamoxifen
description: Non-steroidal anti-estrogen
arm group label: TAK-228 Plus Tamoxifen
other name: Apo-Tamox, Gen-Tamoxifen, Nolvadex, Novo-Tamoxifen
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jenny C Chang, M.D.
role: Principal Investigator
affiliation: Houston Methodist Cancer Center
facility: 
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: The Methodist Hospital Research Institute
investigator full name: Jenny C. Chang, MD
investigator title: Houston Methodist Cancer Center Director
mesh term: Breast Neoplasms
mesh term: Tamoxifen
sharing ipd: Yes
ipd description: Data and materials on human subjects will be shared with other eligible investigators through appropriate means in accordance with the NIH policy on Sharing Research Data (NIH Guide, February 26, 2003). Data will be also shared with the funding agency and regulatory agencies as required. Data will be shared with other investigators within the limits of HIPAA and other patient confidentiality requirements. This will generally require removal of all patient identifiers for all source documents and the use of arbitrarily assigned one-way identifiers. In some cases, requestors will be asked to sign a formal data sharing agreement that will provide for a commitment to use data only for research purposes and not to identify individuals, keep the data secure, and destroy or return data after analyses are complete. Prior approval will be obtained from collaborating investigators, research sponsors, and/or other stake-holders before sharing if proprietary information or products are involved.
ipd time frame: From study end (3/30/2019) for 5 years.
ipd access criteria: Data and materials on human subjects will be shared with other eligible investigators through appropriate means in accordance with the NIH policy on Sharing Research Data (NIH Guide, February 26, 2003). Data will be also shared with the funding agency and regulatory agencies as required. Data will be shared with other investigators within the limits of HIPAA and other patient confidentiality requirements. This will generally require removal of all patient identifiers for all source documents and the use of arbitrarily assigned one-way identifiers. In some cases, requestors will be asked to sign a formal data sharing agreement that will provide for a commitment to use data only for research purposes and not to identify individuals, keep the data secure, and destroy or return data after analyses are complete. Prior approval will be obtained from collaborating investigators, research sponsors, and/or other stake-holders before sharing if proprietary information or products are involved.
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 