<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/NCT01688609</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2012-01970</org_study_id>
    <secondary_id>NCI-2012-01970</secondary_id>
    <secondary_id>CDR0000734375</secondary_id>
    <secondary_id>ACE-001</secondary_id>
    <secondary_id>9020</secondary_id>
    <nct_id>NCT01688609</nct_id>
  </id_info>
  <brief_title>Lapatinib Ditosylate, Trastuzumab, Paclitaxel, and Surgery in Treating Patients With Breast Cancer</brief_title>
  <official_title>Phase II Study of Lapatinib and Trastuzumab Followed by Concurrent Lapatinib, Trastuzumab, and Paclitaxel Followed by Surgery for Primary HER2-positive (HER2+) Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute (NCI)</source>
  <brief_summary>
    <textblock>
      This phase II trial studies how well giving lapatinib ditosylate together with trastuzumab,&#xD;
      paclitaxel, and surgery works in treating patients with breast cancer. Lapatinib ditosylate&#xD;
      may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.&#xD;
      Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some&#xD;
      block the ability of tumor to grow and spread. Others find tumor cells and help kill them or&#xD;
      carry cancer-killing substances to them. Drugs used in chemotherapy, such as paclitaxel, work&#xD;
      in different ways to stop the growth of tumor cells, either by killing the cells or by&#xD;
      stopping them from dividing.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To evaluate the changes in cancer stem cell (CSC) markers; % CD44 variant (CD44v)-positive&#xD;
      tumor cells and aldehyde dehydrogenase-1 (ALDH1) positivity before and after study drug&#xD;
      exposure and after concurrent preoperative chemotherapy.&#xD;
&#xD;
      II. To determine the pathological complete response (pCR) rate produced by lapatinib&#xD;
      (lapatinib ditosylate) + trastuzumab followed by concurrent preoperative lapatinib,&#xD;
      trastuzumab, and paclitaxel chemotherapy for operable human epidermal growth factor receptor&#xD;
      2-positive (HER2+) breast cancer.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the cellular response rate produced by study drug exposure and/or concurrent&#xD;
      preoperative chemotherapy.&#xD;
&#xD;
      II. To determine cutoff values of baseline ratios of phosphorylated HER2 (pHER2)/HER2,&#xD;
      phosphorylated epidermal growth factor receptor (EGFR) (pEGFR)/EGFR, phosphorylated ERK&#xD;
      (pERK)/ERK and phosphorylated protein kinase B (pAkt)/Akt that are associated with pCR.&#xD;
&#xD;
      III. To assess the safety and tolerability of study therapy in Japanese women.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Drug exposure: Patients receive lapatinib ditosylate orally (PO) once daily (QD) and&#xD;
      trastuzumab intravenously (IV) over 30-90 minutes once weekly for 6 weeks in the absence of&#xD;
      disease progression or unacceptable toxicity.&#xD;
&#xD;
      Preoperative therapy: Patients receive lapatinib ditosylate PO QD, trastuzumab IV over 30&#xD;
      minutes once weekly, and paclitaxel IV over 90 minutes once weekly for 12 weeks in the&#xD;
      absence of disease progression or unacceptable toxicity. Patients then undergo lumpectomy* or&#xD;
      mastectomy*.&#xD;
&#xD;
      After completion of study treatment, patients are followed up for 12 weeks.&#xD;
&#xD;
      NOTE: * Patients considered to be candidates for breast-conservation therapy (BCT) are&#xD;
      offered lumpectomy. Patients who are not considered to be candidates for BCT or who do not&#xD;
      desire BCT undergo total mastectomy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>July 2012</start_date>
  <completion_date type="Actual">August 15, 2016</completion_date>
  <primary_completion_date type="Actual">December 2013</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>Expression of ALDH1 and CD44v Change in the Binary Biomarkers From Baseline to 6 Weeks and 18 Weeks</measure>
    <time_frame>From baseline to 18 weeks</time_frame>
    <description>For biomarkers ALDH1 and CD44v, the change in the proportions of CD44v-positive (CD44v+) tumor cells and ALDH1-positive (ALDH1+) tumor cells in tumor tissue from baseline to 6 weeks and 18 weeks time points were determined for each patient. For biomarker change, changes in the binary biomarkers between time points were assessed using McNemar's test in all patients and separately in patients with and without pCR.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants With Pathological Complete Response (pCR)</measure>
    <time_frame>Up to 12 weeks</time_frame>
    <description>The point estimate of the pCR rate will be calculated for all patients. pCR is defined as the abscence of invasive cancer in the breast and regional lymph nodes following neoadjuvant chemotherapy.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cellular Response Rate, Defined as Patients With an Epithelial Phenotype Having Eradication of CTCs; Patients With a Mesenchymal Phenotype Having Eradication of Tumor Cells; Patients With a Mesenchymal Phenotype Converting to an Epithelial Phenotype</measure>
    <time_frame>Up to 18 weeks</time_frame>
    <description>Cellular response will be documented and calculated for rate in all patients.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EGFR-mutation Status of Tumors and Changes in the Ratio of Phosphorylated to Nonphosphorylated HER2, EGFR, ERK, Akt, and the Ki67 and TUNEL Indices Before and After Treatment</measure>
    <time_frame>From baseline to 24 weeks</time_frame>
    <description>The EGFR mutation status will be a binary variable (yes vs. no), and the phosphorylation status of HER2 and EGFR will be a ratio variable (0-100%). The CART method to identify cut-off points for the phosphorylation ratio of molecules of interest will be used, such that ratios above the cut-off point will be considered &quot;high phosphorylation&quot; and ratios below the cut-off point will be considered &quot;low phosphorylation.&quot;</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Treatment-Related Toxicities</measure>
    <time_frame>Up to 12 weeks after completion of study treatment</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>HER2-positive Breast Cancer</condition>
  <condition>Stage II Breast Cancer</condition>
  <condition>Stage IIIA Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Treatment (lapatinib, trastuzumab, paclitaxel, surgery)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Drug exposure: Patients receive lapatinib ditosylate PO QD and trastuzumab IV over 30-90 minutes once weekly for 6 weeks in the absence of disease progression or unacceptable toxicity.&#xD;
Preoperative therapy: Patients receive lapatinib ditosylate PO QD, trastuzumab IV over 30 minutes once weekly, and paclitaxel IV over 90 minutes once weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo lumpectomy or mastectomy.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>lapatinib ditosylate</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (lapatinib, trastuzumab, paclitaxel, surgery)</arm_group_label>
    <other_name>GSK572016</other_name>
    <other_name>GW-572016</other_name>
    <other_name>GW2016</other_name>
    <other_name>Lapatinib</other_name>
    <other_name>Tykerb</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>paclitaxel</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (lapatinib, trastuzumab, paclitaxel, surgery)</arm_group_label>
    <other_name>Anzatax</other_name>
    <other_name>Asotax</other_name>
    <other_name>TAX</other_name>
    <other_name>Taxol</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>trastuzumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (lapatinib, trastuzumab, paclitaxel, surgery)</arm_group_label>
    <other_name>anti-c-erB-2</other_name>
    <other_name>Herceptin</other_name>
    <other_name>MOAB HER2</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>therapeutic conventional surgery</intervention_name>
    <description>Undergo lumpectomy or mastectomy</description>
    <arm_group_label>Treatment (lapatinib, trastuzumab, paclitaxel, surgery)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>pharmacological study</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (lapatinib, trastuzumab, paclitaxel, surgery)</arm_group_label>
    <other_name>pharmacological studies</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>laboratory biomarker analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (lapatinib, trastuzumab, paclitaxel, surgery)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have histologically or cytologically confirmed primary invasive breast&#xD;
             cancer&#xD;
&#xD;
          -  Primary tumor is larger than 2 cm in diameter (T2) as measured by caliper or&#xD;
             ultrasound&#xD;
&#xD;
          -  Overexpression and/or amplification of HER2 is confirmed by immunohistochemistry (IHC)&#xD;
             3+ or fluorescence in situ hybridization (FISH) + when IHC 2+&#xD;
&#xD;
          -  Patients have not received prior therapies for breast cancer&#xD;
&#xD;
          -  Patients have Karnofsky &gt;= 70%&#xD;
&#xD;
          -  Leukocytes &gt;= 3,000/mcL&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 1,500/mcL&#xD;
&#xD;
          -  Hemoglobin &gt;= 9.0 g/dL&#xD;
&#xD;
          -  Platelets &gt;= 75,000/mcL&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 times institutional upper limit of normal&#xD;
&#xD;
          -  Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase&#xD;
             [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvate transaminase[SGPT]) =&lt;&#xD;
             2.5 times institutional ULN&#xD;
&#xD;
          -  Creatinine =&lt; 1.5 times institutional upper limit of normal (ULN)&#xD;
&#xD;
          -  Patients must have left ventricular ejection fraction (LVEF) &gt;= 50% by multi-gated&#xD;
             acquisition (MUGA) or echocardiography&#xD;
&#xD;
          -  Patients must be able to take oral medications (i.e., no uncontrolled vomiting,&#xD;
             inability to swallow, or diagnosis of chronic malabsorption)&#xD;
&#xD;
          -  Women of childbearing potential must agree to use adequate contraception (hormonal or&#xD;
             barrier method of birth control; abstinence) prior to study entry and for the duration&#xD;
             of study participation as well as for at least 6 months after the last dose of&#xD;
             trastuzumab&#xD;
&#xD;
          -  Ability to understand and willingness not only for treatment but also for undergoing&#xD;
             serial biopsies and sign a written informed consent document&#xD;
&#xD;
          -  Only Japanese women are eligible for the trial&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who have had chemotherapy or radiotherapy&#xD;
&#xD;
          -  Patients who are receiving any other investigational agents&#xD;
&#xD;
          -  Patients have distal metastasis (stage IV disease)&#xD;
&#xD;
          -  Patients with previous (within 10 years) or current history of malignant neoplasm&#xD;
             except for curatively treated basal and squamous cell carcinoma of the skin or&#xD;
             carcinoma in situ of the cervix&#xD;
&#xD;
          -  Patients with a history of allergic reactions attributed to compounds of similar&#xD;
             chemical or biologic composition to lapatinib or other agents used in study&#xD;
&#xD;
          -  Patients receiving any medications or substances that are inhibitors or inducers of&#xD;
             cytochrome P450 3A4 (CYP3A4) are ineligible&#xD;
&#xD;
          -  Patients who have uncontrolled intercurrent illness including, but not limited to,&#xD;
             ongoing or active infection, symptomatic congestive heart failure, unstable angina&#xD;
             pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would&#xD;
             limit compliance with study requirements&#xD;
&#xD;
          -  Pregnant women&#xD;
&#xD;
          -  Patients who have family or personal history of congenital long or short QT syndrome,&#xD;
             Brugada syndrome, QT/QTc prolongation, or torsade de pointes&#xD;
&#xD;
          -  Patients who have chronic gastrointestinal disease presenting with diarrhea&#xD;
             (inflammatory bowel disease, malabsorption, or &gt;= grade 2 diarrhea of any etiology at&#xD;
             baseline)&#xD;
&#xD;
          -  Patients who have neuropathy &gt;= grade 2 of any cause&#xD;
&#xD;
          -  Patients are diagnosed with inflammatory breast cancer or bilateral breast cancer&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Teruo Yamauchi</last_name>
    <role>Principal Investigator</role>
    <affiliation>Saint Luke's International Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>M D Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Keio University</name>
      <address>
        <city>Shinjuku-ku</city>
        <state>Tokyo</state>
        <zip>160-8582</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Luke's International Hospital</name>
      <address>
        <city>Chuo-ku</city>
        <state>Toyko</state>
        <zip>104-8560</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Japan</country>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>September 16, 2012</study_first_submitted>
  <study_first_submitted_qc>September 16, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 20, 2012</study_first_posted>
  <results_first_submitted>June 8, 2017</results_first_submitted>
  <results_first_submitted_qc>August 9, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">September 11, 2017</results_first_posted>
  <last_update_submitted>August 9, 2017</last_update_submitted>
  <last_update_submitted_qc>August 9, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 11, 2017</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>Paclitaxel</mesh_term>
    <mesh_term>Trastuzumab</mesh_term>
    <mesh_term>Lapatinib</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Treatment (Lapatinib, Trastuzumab, Paclitaxel, Surgery)</title>
          <description>Drug exposure: Patients receive lapatinib ditosylate PO QD and trastuzumab IV over 30-90 minutes once weekly for 6 weeks in the absence of disease progression or unacceptable toxicity.&#xD;
Preoperative therapy: Patients receive lapatinib ditosylate PO QD, trastuzumab IV over 30 minutes once weekly, and paclitaxel IV over 90 minutes once weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo lumpectomy or mastectomy.&#xD;
lapatinib ditosylate: Given PO&#xD;
paclitaxel: Given IV&#xD;
trastuzumab: Given IV&#xD;
therapeutic conventional surgery: Undergo lumpectomy or mastectomy&#xD;
pharmacological study: Correlative studies&#xD;
laboratory biomarker analysis: Correlative studies</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Treatment (Lapatinib, Trastuzumab, Paclitaxel, Surgery)</title>
          <description>Drug exposure: Patients receive lapatinib ditosylate PO QD and trastuzumab IV over 30-90 minutes once weekly for 6 weeks in the absence of disease progression or unacceptable toxicity.&#xD;
Preoperative therapy: Patients receive lapatinib ditosylate PO QD, trastuzumab IV over 30 minutes once weekly, and paclitaxel IV over 90 minutes once weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo lumpectomy or mastectomy.&#xD;
lapatinib ditosylate: Given PO&#xD;
paclitaxel: Given IV&#xD;
trastuzumab: Given IV&#xD;
therapeutic conventional surgery: Undergo lumpectomy or mastectomy&#xD;
pharmacological study: Correlative studies&#xD;
laboratory biomarker analysis: Correlative studies</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="18"/>
          </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="18"/>
                  </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>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="18"/>
                  </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>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Japan</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Expression of ALDH1 and CD44v Change in the Binary Biomarkers From Baseline to 6 Weeks and 18 Weeks</title>
        <description>For biomarkers ALDH1 and CD44v, the change in the proportions of CD44v-positive (CD44v+) tumor cells and ALDH1-positive (ALDH1+) tumor cells in tumor tissue from baseline to 6 weeks and 18 weeks time points were determined for each patient. For biomarker change, changes in the binary biomarkers between time points were assessed using McNemar's test in all patients and separately in patients with and without pCR.</description>
        <time_frame>From baseline to 18 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Lapatinib, Trastuzumab, Paclitaxel, Surgery)</title>
            <description>Drug exposure: Patients receive lapatinib ditosylate PO QD and trastuzumab IV over 30-90 minutes once weekly for 6 weeks in the absence of disease progression or unacceptable toxicity.&#xD;
Preoperative therapy: Patients receive lapatinib ditosylate PO QD, trastuzumab IV over 30 minutes once weekly, and paclitaxel IV over 90 minutes once weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo lumpectomy or mastectomy.&#xD;
lapatinib ditosylate: Given PO&#xD;
paclitaxel: Given IV&#xD;
trastuzumab: Given IV&#xD;
therapeutic conventional surgery: Undergo lumpectomy or mastectomy&#xD;
pharmacological study: Correlative studies&#xD;
laboratory biomarker analysis: Correlative studies</description>
          </group>
        </group_list>
        <measure>
          <title>Expression of ALDH1 and CD44v Change in the Binary Biomarkers From Baseline to 6 Weeks and 18 Weeks</title>
          <description>For biomarkers ALDH1 and CD44v, the change in the proportions of CD44v-positive (CD44v+) tumor cells and ALDH1-positive (ALDH1+) tumor cells in tumor tissue from baseline to 6 weeks and 18 weeks time points were determined for each patient. For biomarker change, changes in the binary biomarkers between time points were assessed using McNemar's test in all patients and separately in patients with and without pCR.</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="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>baseline CD44v expression : pCR</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>baseline CD44v expression : non-pCR</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CD44v expression at 6 weeks : pCR</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CD44v expression at 6 weeks : non-pCR</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CD44v expression at 18 weeks : pCR</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CD44v expression at 18 weeks : non-pCR</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>baseline ALDH1 expression : pCR</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>baseline ALDH1 expression : non-pCR</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ALDH1 expression at 6 weeks : pCR</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ALDH1 expression at 6 weeks : non-pCR</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ALDH1 expression at 18 weeks : pCR</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ALDH1 expression at 18 weeks : non-pCR</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Pathological Complete Response (pCR)</title>
        <description>The point estimate of the pCR rate will be calculated for all patients. pCR is defined as the abscence of invasive cancer in the breast and regional lymph nodes following neoadjuvant chemotherapy.</description>
        <time_frame>Up to 12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Lapatinib, Trastuzumab, Paclitaxel, Surgery)</title>
            <description>Drug exposure: Patients receive lapatinib ditosylate PO QD and trastuzumab IV over 30-90 minutes once weekly for 6 weeks in the absence of disease progression or unacceptable toxicity.&#xD;
Preoperative therapy: Patients receive lapatinib ditosylate PO QD, trastuzumab IV over 30 minutes once weekly, and paclitaxel IV over 90 minutes once weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo lumpectomy or mastectomy.&#xD;
lapatinib ditosylate: Given PO&#xD;
paclitaxel: Given IV&#xD;
trastuzumab: Given IV&#xD;
therapeutic conventional surgery: Undergo lumpectomy or mastectomy&#xD;
pharmacological study: Correlative studies&#xD;
laboratory biomarker analysis: Correlative studies</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Pathological Complete Response (pCR)</title>
          <description>The point estimate of the pCR rate will be calculated for all patients. pCR is defined as the abscence of invasive cancer in the breast and regional lymph nodes following neoadjuvant chemotherapy.</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="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Cellular Response Rate, Defined as Patients With an Epithelial Phenotype Having Eradication of CTCs; Patients With a Mesenchymal Phenotype Having Eradication of Tumor Cells; Patients With a Mesenchymal Phenotype Converting to an Epithelial Phenotype</title>
        <description>Cellular response will be documented and calculated for rate in all patients.</description>
        <time_frame>Up to 18 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Lapatinib, Trastuzumab, Paclitaxel, Surgery)</title>
            <description>Drug exposure: Patients receive lapatinib ditosylate PO QD and trastuzumab IV over 30-90 minutes once weekly for 6 weeks in the absence of disease progression or unacceptable toxicity.&#xD;
Preoperative therapy: Patients receive lapatinib ditosylate PO QD, trastuzumab IV over 30 minutes once weekly, and paclitaxel IV over 90 minutes once weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo lumpectomy or mastectomy.&#xD;
lapatinib ditosylate: Given PO&#xD;
paclitaxel: Given IV&#xD;
trastuzumab: Given IV&#xD;
therapeutic conventional surgery: Undergo lumpectomy or mastectomy&#xD;
pharmacological study: Correlative studies&#xD;
laboratory biomarker analysis: Correlative studies</description>
          </group>
        </group_list>
        <measure>
          <title>Cellular Response Rate, Defined as Patients With an Epithelial Phenotype Having Eradication of CTCs; Patients With a Mesenchymal Phenotype Having Eradication of Tumor Cells; Patients With a Mesenchymal Phenotype Converting to an Epithelial Phenotype</title>
          <description>Cellular response will be documented and calculated for rate in all patients.</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>positive cellular response at 6 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>positive cellular response at 18 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>EGFR-mutation Status of Tumors and Changes in the Ratio of Phosphorylated to Nonphosphorylated HER2, EGFR, ERK, Akt, and the Ki67 and TUNEL Indices Before and After Treatment</title>
        <description>The EGFR mutation status will be a binary variable (yes vs. no), and the phosphorylation status of HER2 and EGFR will be a ratio variable (0-100%). The CART method to identify cut-off points for the phosphorylation ratio of molecules of interest will be used, such that ratios above the cut-off point will be considered &quot;high phosphorylation&quot; and ratios below the cut-off point will be considered &quot;low phosphorylation.&quot;</description>
        <time_frame>From baseline to 24 weeks</time_frame>
        <population>The study was not able to determine the cut off value of total and phorylated RTK ratio. Assays were not reliable. Data of EGFR mutations were not collected.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Lapatinib, Trastuzumab, Paclitaxel, Surgery)</title>
            <description>Drug exposure: Patients receive lapatinib ditosylate PO QD and trastuzumab IV over 30-90 minutes once weekly for 6 weeks in the absence of disease progression or unacceptable toxicity.&#xD;
Preoperative therapy: Patients receive lapatinib ditosylate PO QD, trastuzumab IV over 30 minutes once weekly, and paclitaxel IV over 90 minutes once weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo lumpectomy or mastectomy.&#xD;
lapatinib ditosylate: Given PO&#xD;
paclitaxel: Given IV&#xD;
trastuzumab: Given IV&#xD;
therapeutic conventional surgery: Undergo lumpectomy or mastectomy&#xD;
pharmacological study: Correlative studies&#xD;
laboratory biomarker analysis: Correlative studies</description>
          </group>
        </group_list>
        <measure>
          <title>EGFR-mutation Status of Tumors and Changes in the Ratio of Phosphorylated to Nonphosphorylated HER2, EGFR, ERK, Akt, and the Ki67 and TUNEL Indices Before and After Treatment</title>
          <description>The EGFR mutation status will be a binary variable (yes vs. no), and the phosphorylation status of HER2 and EGFR will be a ratio variable (0-100%). The CART method to identify cut-off points for the phosphorylation ratio of molecules of interest will be used, such that ratios above the cut-off point will be considered &quot;high phosphorylation&quot; and ratios below the cut-off point will be considered &quot;low phosphorylation.&quot;</description>
          <population>The study was not able to determine the cut off value of total and phorylated RTK ratio. Assays were not reliable. Data of EGFR mutations were not collected.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Treatment-Related Toxicities</title>
        <time_frame>Up to 12 weeks after completion of study treatment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Lapatinib, Trastuzumab, Paclitaxel, Surgery)</title>
            <description>Drug exposure: Patients receive lapatinib ditosylate PO QD and trastuzumab IV over 30-90 minutes once weekly for 6 weeks in the absence of disease progression or unacceptable toxicity.&#xD;
Preoperative therapy: Patients receive lapatinib ditosylate PO QD, trastuzumab IV over 30 minutes once weekly, and paclitaxel IV over 90 minutes once weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo lumpectomy or mastectomy.&#xD;
lapatinib ditosylate: Given PO&#xD;
paclitaxel: Given IV&#xD;
trastuzumab: Given IV&#xD;
therapeutic conventional surgery: Undergo lumpectomy or mastectomy&#xD;
pharmacological study: Correlative studies&#xD;
laboratory biomarker analysis: Correlative studies</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Treatment-Related Toxicities</title>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Grade 3 ALT increase</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 3 GGT increase</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 3 leukopenia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 3 neutropenia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Treatment (Lapatinib, Trastuzumab, Paclitaxel, Surgery)</title>
          <description>Drug exposure: Patients receive lapatinib ditosylate PO QD and trastuzumab IV over 30-90 minutes once weekly for 6 weeks in the absence of disease progression or unacceptable toxicity.&#xD;
Preoperative therapy: Patients receive lapatinib ditosylate PO QD, trastuzumab IV over 30 minutes once weekly, and paclitaxel IV over 90 minutes once weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo lumpectomy or mastectomy.&#xD;
lapatinib ditosylate: Given PO&#xD;
paclitaxel: Given IV&#xD;
trastuzumab: Given IV&#xD;
therapeutic conventional surgery: Undergo lumpectomy or mastectomy&#xD;
pharmacological study: Correlative studies&#xD;
laboratory biomarker analysis: Correlative studies</description>
        </group>
      </group_list>
      <serious_events>
        <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="18"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</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="17" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>oral mucositis</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>increased alanine aminotransferase level</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>increased aspartate aminotransferase</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>hand-foot syndrome</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>rash</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Teruo Yamauchi</name_or_title>
      <organization>St. Luke's International Hospital</organization>
      <phone>+81-3-3541-5151</phone>
      <email>tryhi@luke.ac.jp</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/NCT01688609
org study id: NCI-2012-01970
secondary id: NCI-2012-01970
secondary id: CDR0000734375
secondary id: ACE-001
secondary id: 9020
nct id: NCT01688609
lead sponsor: 
This phase II trial studies how well giving lapatinib ditosylate together with trastuzumab,
      paclitaxel, and surgery works in treating patients with breast cancer. Lapatinib ditosylate
      may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
      Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some
      block the ability of tumor to grow and spread. Others find tumor cells and help kill them or
      carry cancer-killing substances to them. Drugs used in chemotherapy, such as paclitaxel, work
      in different ways to stop the growth of tumor cells, either by killing the cells or by
      stopping them from dividing.
PRIMARY OBJECTIVES:

      I. To evaluate the changes in cancer stem cell (CSC) markers; % CD44 variant (CD44v)-positive
      tumor cells and aldehyde dehydrogenase-1 (ALDH1) positivity before and after study drug
      exposure and after concurrent preoperative chemotherapy.

      II. To determine the pathological complete response (pCR) rate produced by lapatinib
      (lapatinib ditosylate) + trastuzumab followed by concurrent preoperative lapatinib,
      trastuzumab, and paclitaxel chemotherapy for operable human epidermal growth factor receptor
      2-positive (HER2+) breast cancer.

      SECONDARY OBJECTIVES:

      I. To determine the cellular response rate produced by study drug exposure and/or concurrent
      preoperative chemotherapy.

      II. To determine cutoff values of baseline ratios of phosphorylated HER2 (pHER2)/HER2,
      phosphorylated epidermal growth factor receptor (EGFR) (pEGFR)/EGFR, phosphorylated ERK
      (pERK)/ERK and phosphorylated protein kinase B (pAkt)/Akt that are associated with pCR.

      III. To assess the safety and tolerability of study therapy in Japanese women.

      OUTLINE:

      Drug exposure: Patients receive lapatinib ditosylate orally (PO) once daily (QD) and
      trastuzumab intravenously (IV) over 30-90 minutes once weekly for 6 weeks in the absence of
      disease progression or unacceptable toxicity.

      Preoperative therapy: Patients receive lapatinib ditosylate PO QD, trastuzumab IV over 30
      minutes once weekly, and paclitaxel IV over 90 minutes once weekly for 12 weeks in the
      absence of disease progression or unacceptable toxicity. Patients then undergo lumpectomy* or
      mastectomy*.

      After completion of study treatment, patients are followed up for 12 weeks.

      NOTE: * Patients considered to be candidates for breast-conservation therapy (BCT) are
      offered lumpectomy. Patients who are not considered to be candidates for BCT or who do not
      desire BCT undergo total mastectomy.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Expression of ALDH1 and CD44v Change in the Binary Biomarkers From Baseline to 6 Weeks and 18 Weeks
time frame: From baseline to 18 weeks
description: For biomarkers ALDH1 and CD44v, the change in the proportions of CD44v-positive (CD44v+) tumor cells and ALDH1-positive (ALDH1+) tumor cells in tumor tissue from baseline to 6 weeks and 18 weeks time points were determined for each patient. For biomarker change, changes in the binary biomarkers between time points were assessed using McNemar's test in all patients and separately in patients with and without pCR.
measure: Number of Participants With Pathological Complete Response (pCR)
time frame: Up to 12 weeks
description: The point estimate of the pCR rate will be calculated for all patients. pCR is defined as the abscence of invasive cancer in the breast and regional lymph nodes following neoadjuvant chemotherapy.
measure: Cellular Response Rate, Defined as Patients With an Epithelial Phenotype Having Eradication of CTCs; Patients With a Mesenchymal Phenotype Having Eradication of Tumor Cells; Patients With a Mesenchymal Phenotype Converting to an Epithelial Phenotype
time frame: Up to 18 weeks
description: Cellular response will be documented and calculated for rate in all patients.
measure: EGFR-mutation Status of Tumors and Changes in the Ratio of Phosphorylated to Nonphosphorylated HER2, EGFR, ERK, Akt, and the Ki67 and TUNEL Indices Before and After Treatment
time frame: From baseline to 24 weeks
description: The EGFR mutation status will be a binary variable (yes vs. no), and the phosphorylation status of HER2 and EGFR will be a ratio variable (0-100%). The CART method to identify cut-off points for the phosphorylation ratio of molecules of interest will be used, such that ratios above the cut-off point will be considered "high phosphorylation" and ratios below the cut-off point will be considered "low phosphorylation."
measure: Number of Participants With Treatment-Related Toxicities
time frame: Up to 12 weeks after completion of study treatment
arm group label: Treatment (lapatinib, trastuzumab, paclitaxel, surgery)
arm group type: Experimental
description: Drug exposure: Patients receive lapatinib ditosylate PO QD and trastuzumab IV over 30-90 minutes once weekly for 6 weeks in the absence of disease progression or unacceptable toxicity.
Preoperative therapy: Patients receive lapatinib ditosylate PO QD, trastuzumab IV over 30 minutes once weekly, and paclitaxel IV over 90 minutes once weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo lumpectomy or mastectomy.
intervention type: Drug
intervention name: lapatinib ditosylate
description: Given PO
arm group label: Treatment (lapatinib, trastuzumab, paclitaxel, surgery)
other name: GSK572016
other name: GW-572016
other name: GW2016
other name: Lapatinib
other name: Tykerb
intervention type: Drug
intervention name: paclitaxel
description: Given IV
arm group label: Treatment (lapatinib, trastuzumab, paclitaxel, surgery)
other name: Anzatax
other name: Asotax
other name: TAX
other name: Taxol
intervention type: Biological
intervention name: trastuzumab
description: Given IV
arm group label: Treatment (lapatinib, trastuzumab, paclitaxel, surgery)
other name: anti-c-erB-2
other name: Herceptin
other name: MOAB HER2
intervention type: Procedure
intervention name: therapeutic conventional surgery
description: Undergo lumpectomy or mastectomy
arm group label: Treatment (lapatinib, trastuzumab, paclitaxel, surgery)
intervention type: Other
intervention name: pharmacological study
description: Correlative studies
arm group label: Treatment (lapatinib, trastuzumab, paclitaxel, surgery)
other name: pharmacological studies
intervention type: Other
intervention name: laboratory biomarker analysis
description: Correlative studies
arm group label: Treatment (lapatinib, trastuzumab, paclitaxel, surgery)
criteria: 
gender: Female
minimum age: 20 Years
maximum age: N/A
healthy volunteers: No
last name: Teruo Yamauchi
role: Principal Investigator
affiliation: Saint Luke's International Hospital
facility: 
facility: 
facility: 
country: Japan
country: United States
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Paclitaxel
mesh term: Trastuzumab
mesh term: Lapatinib
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 