<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/NCT01670500</url>
  </required_header>
  <id_info>
    <org_study_id>12-258</org_study_id>
    <nct_id>NCT01670500</nct_id>
  </id_info>
  <brief_title>Cisplatin vs. Doxorubicin/Cyclophosphamide in BrCa</brief_title>
  <official_title>A Randomized Phase II Trial of Neoadjuvant Cisplatin vs. Doxorubicin/Cyclophosphamide (AC) in Women With Newly Diagnosed Breast Cancer and Germline BrCa Mutations</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Beth Israel Deaconess Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Dana-Farber Cancer Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research study is a Phase II clinical trial. Phase II clinical trials test the&#xD;
      effectiveness of an investigational drug, which is cisplatin in this trial, to learn how well&#xD;
      it works in treating a specific cancer. &quot;Investigational&quot; means that cisplatin is still being&#xD;
      studied for use in this setting and that research doctors are trying to find out more about&#xD;
      it-in this case, how effective cisplatin is for treating breast cancer in BRCA mutation&#xD;
      carriers. It also means that the FDA has not yet approved cisplatin for your type of cancer.&#xD;
      Cisplatin has been approved by the FDA for treatment of other cancers.&#xD;
&#xD;
      The purpose of this study is to evaluate cisplatin, a chemotherapy drug that has been shown&#xD;
      to be active in the treatment of women with breast cancer and a BRCA mutation. In this study,&#xD;
      we are comparing cisplatin to the standard chemotherapy, doxorubicin and cyclophosphamide&#xD;
      (&quot;AC&quot;) that you might receive if you did not participate in this study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      If screening tests show that you are eligible to participate in the research study you will&#xD;
      begin study treatment. You may undergo an optional research biopsy so the study team can&#xD;
      obtain tissue samples. This will be used for biomarker research and will help your doctors to&#xD;
      better understand your disease, how the drug is working in your body, and may help to&#xD;
      identify which people may benefit most from platinum or from adriamycin/cytoxan in the&#xD;
      future.&#xD;
&#xD;
      Because no one knows which of the study options is best, you will be &quot;randomized&quot; to receive&#xD;
      either cisplatin or doxorubicin and cyclophosphamide (&quot;AC&quot;) chemotherapy prior to removal of&#xD;
      your breast cancer. Chemotherapy administered before the removal of the cancer is known as&#xD;
      neoadjuvant chemotherapy. Randomization means that you are put into a group by chance. It is&#xD;
      like flipping a coin. Neither you nor the research doctor will choose what group you will be&#xD;
      in. You will have an equal chance of being placed in either group.&#xD;
&#xD;
      If you are randomized to receive cisplatin you will receive cisplatin once every three weeks&#xD;
      for a total of four doses. You will be given cisplatin by vein (IV) on the first day of each&#xD;
      treatment cycle. The cisplatin infusion can take between 1 to 2 hours. Before and after&#xD;
      receiving cisplatin, you will receive fluid hydration by vein, and you will also be given&#xD;
      medicine to help prevent side effects such as nausea. The total time of the infusion of&#xD;
      cisplatin and the additional fluid and medications will take about 6 hours. After you receive&#xD;
      cisplatin, you will be asked to drink about 12 eight ounce glasses of fluid per day,&#xD;
      especially 2 or 3 days after therapy. The study treatment will stop if you have serious side&#xD;
      effects or if the tumor grows despite receiving cisplatin chemotherapy.&#xD;
&#xD;
      If you are randomized to &quot;AC&quot; chemotherapy you will receive both doxorubicin and&#xD;
      cyclophosphamide once every 2 or 3 weeks for a total of four doses by vein on the first day&#xD;
      of each treatment cycle. The interval between chemotherapy will be decided by your research&#xD;
      doctor. If you receive the chemotherapy every two weeks, you will also receive a subcutaneous&#xD;
      injection the day after chemotherapy. This injection contains a medicine that contains a&#xD;
      growth factor that will boost your immune system in order to allow your body to be ready for&#xD;
      chemotherapy in two weeks. The study treatment will be stopped if you have serious side&#xD;
      effects or if the tumor grows despite the doxorubicin and cyclophosphamide chemotherapy.&#xD;
&#xD;
      At the beginning of each treatment cycle you will have a physical exam (including weight and&#xD;
      vital signs) and you will be asked general questions about your health and any medications&#xD;
      you may be taking, as well as specific questions about any side effects you may be&#xD;
      experiencing while receiving study treatment. Prior to each cycle of chemotherapy, you will&#xD;
      have standard blood tests to check your blood counts. If you are receiving cisplatin your&#xD;
      kidney function and body salts will also be checked prior to each chemotherapy cycle. In&#xD;
      addition, 7-10 days after chemotherapy your blood will be drawn to look at your blood cell&#xD;
      count to determine your risk of infection; if you have received cisplatin, your kidney&#xD;
      function and blood electrolytes will also be evaluated. The blood draw performed 7-10 days&#xD;
      after chemotherapy can be done in the hospital where you received your chemotherapy or closer&#xD;
      to home. About 1 tablespoon of blood will be drawn for these tests.&#xD;
&#xD;
      Surgery to remove your tumor will occur within six weeks after the last dose of chemotherapy.&#xD;
      Your surgery will be performed by your surgeon, as part of the standard care for your&#xD;
      disease.&#xD;
&#xD;
      Your treating physician or nurse practitioner will examine you to assess your tumor each time&#xD;
      you receive chemotherapy. A measurement of your tumor will be performed on the first day of&#xD;
      each treatment cycle as part of your physical exam. After the slides of your initial breast&#xD;
      cancer biopsy have been reviewed at your hospital, these slides and your tumor block will be&#xD;
      sent to the study pathologist at DF/HCC. Likewise, after chemotherapy, your breast cancer&#xD;
      will be removed by lumpectomy or mastectomy. After these slides are reviewed at your&#xD;
      hospital, they will also be sent with the tumor block to the study pathologist so that the&#xD;
      response of your tumor to the study treatment can be assessed. After these slides are&#xD;
      reviewed, they will be returned to the hospital at which the biopsy and surgery were&#xD;
      performed.&#xD;
&#xD;
      Decisions about whether you will receive more chemotherapy after your surgery is up to your&#xD;
      treating physicians. If you receive chemotherapy, the choice of chemotherapy is also up to&#xD;
      your doctors. Decisions about post-operative chemotherapy are not part of this study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Anticipated">April 2023</completion_date>
  <primary_completion_date type="Actual">May 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Rate of Pathologic Complete Response (pCR)</measure>
    <time_frame>3 years</time_frame>
    <description>Pathologic complete response (pCR) rate (determined by the Miller-Payne method) in doxorubicin-cyclophosphamide vs cisplatin arms.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Rate of Residual Cancer Burden (RCB) 0/1</measure>
    <time_frame>2 years</time_frame>
    <description>Residual Cancer Burden (RCB) rate of RCB 0 or 1 in participants receiving Doxorubicin-Cyclophosphamide vs participants receiving Cisplatin.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Response Rate</measure>
    <time_frame>3 years</time_frame>
    <description>Clinical response rate, defined as the number of partial and complete responses, after preoperative therapy with either cisplatin or AC in participants with germline BRCA mutation and breast cancer.&#xD;
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI or ultrasound: Complete Response (CR) = Disappearance of all target lesions; Partial Response (PR) is &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Grade 3 and Grade 4 Adverse Events</measure>
    <time_frame>2 years</time_frame>
    <description>Comparison of toxicities for cisplatin and AC preoperative chemotherapy in BRCA mutation carriers with newly diagnosed breast cancer, reported as number of all Grade 3 and 4 adverse events and number of non-hematologic Grade 3 and 4 adverse events.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Analysis of Pre-chemotherapy Biopsies</measure>
    <time_frame>5 years</time_frame>
    <description>Biopsies collected for future analyses of biomarkers that predict for response to cisplatin or AC chemotherapy in BRCA mutation carriers. Pretreatment tumor biopsies will be analyzed using genome wide SNP profiling to determine number of regions of telomeric allelic imbalance (NtAI) and chromosome 15q26 copy number, and chromosome 8q22 copy number. Tumor sections will be examined for gene amplifications, losses and NtAI in tumors. Gene expression profiling will be performed to determine intrinsic subtype (basal-like, claudin-low, etc.) and to measure biomarker genes including BLM and FANCI associated with cisplatin sensitivity or LAPTM4B and YWHAZ associated with anthracycline resistance. Exploratory analysis will be performed to seek new measures of therapy response using the data from DNA copy number and gene expression profiles. In addition, we will plan to perform whole exome and possibly whole genome sequencing of tumors to identify potential modifiers of response to therapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Miller Payne 4 and 5</measure>
    <time_frame>3 years</time_frame>
    <description>Rates of Miller Payne 4 (near pCR) and 5 (near pCR) combined between those subjects who received neoadjuvant cisplatin and those who received neoadjuvant AC.&#xD;
Definitions:&#xD;
Miller Payne 4: a marked disappearance of tumor cells (more than 90%) such that only small clusters or widely dispersed individual cells remain (almost pCR);&#xD;
Miller Payne 5: no malignant cells identifiable in sections from the site of the tumor (pCR)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Recurrence Free Survival (RFS) After Cisplatin or AC</measure>
    <time_frame>5 years</time_frame>
    <description>Rate of 3-year recurrence free survival in doxorubicin-cyclophosphamide and cisplatin arms for germline BRCA mutation (gBRCAm) carriers with newly diagnosed HER2-negative breast cancer</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Recurrence Free Survival (RFS) With Pathologic Complete Response (pCR) vs. With no pCR</measure>
    <time_frame>5 years</time_frame>
    <description>Rate of 3-year recurrence free survival for gBRCAm carriers who achieved pCR with those who did not.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">118</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Doxorubicin-Cyclophosphamide</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Doxorubicin q 2-3 wk x 4 Cyclophosphamide q 2-3 wk x 4</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cisplatin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Cisplatin q 3 wk x 4</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cisplatin</intervention_name>
    <description>administered intravenously every 3 weeks for 4 doses</description>
    <arm_group_label>Cisplatin</arm_group_label>
    <other_name>cisplatinum, or cis-diamminedichloroplatinum(II) (CDDP)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>administered with doxorubicin intravenously every 2 or 3 weeks for 4 doses</description>
    <arm_group_label>Doxorubicin-Cyclophosphamide</arm_group_label>
    <other_name>Cytoxan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Doxorubicin</intervention_name>
    <description>administered with Cyclophosphamide intravenously every 2 or 3 weeks for 4 doses</description>
    <arm_group_label>Doxorubicin-Cyclophosphamide</arm_group_label>
    <other_name>Adriamycin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Pathologic confirmation of invasive breast cancer&#xD;
&#xD;
          -  Stage: Clinical T1 &gt;/= 1.0 cm, T2 or T3, N0-3, M0&#xD;
&#xD;
          -  HER2 negative&#xD;
&#xD;
          -  ER and PgR status by immunohistochemistry must be known. ER positive patients are&#xD;
             allowed if physicain has determined neoadjuvant chemo is appropriate.&#xD;
&#xD;
          -  Life expectancy greater than six months&#xD;
&#xD;
          -  Use of an effective means of contraception is required&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant or breastfeeding&#xD;
&#xD;
          -  Prior anthracycline or platinum based therapy&#xD;
&#xD;
          -  Prior treatment for the current breast cancer, including chemotherapy, hormonal&#xD;
             therapy, radiation or experimental therapy&#xD;
&#xD;
          -  Ipsilateral breast recurrence, unless prior treatment consisted of excision alone for&#xD;
             DCIS or breast-conserving treatment and hormonal therapy for DCIS or invasive cancer&#xD;
&#xD;
          -  Peripheral neuropathy of any etiology that exceeds grade 1&#xD;
&#xD;
          -  Significant hearing loss&#xD;
&#xD;
          -  Renal dysfunction&#xD;
&#xD;
          -  Use of other investigational or study agents&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to study drugs&#xD;
&#xD;
          -  Uncontrolled intercurrent illness&#xD;
&#xD;
          -  Any condition that would prohibit administration of corticosteroids&#xD;
&#xD;
          -  Uncontrolled diabetes&#xD;
&#xD;
          -  Pre-existing medical condition that would represent toxicity in excess of grade 1 as&#xD;
             measured by CTCAE (unless not considered medically significant by the physician)&#xD;
&#xD;
          -  Known HIV positive individuals on combination antiretroviral therapy&#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>Nadine Tung, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Beth Israel Deaconess Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Colorado Cancer Center</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Smilow Cancer Hospital Care Center at Derby</name>
      <address>
        <city>Derby</city>
        <state>Connecticut</state>
        <zip>06418</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Smilow Cancer Hospital Care Center at Guilford</name>
      <address>
        <city>Guilford</city>
        <state>Connecticut</state>
        <zip>06437</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Francis Hospital and Medical Center</name>
      <address>
        <city>Hartford</city>
        <state>Connecticut</state>
        <zip>06105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Yale School of Medicine</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06520</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Georgetown University Medical Center</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20007</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sibley Memorial Hospital</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20016-2698</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Johns Hopkins</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beth Israel Deaconess Medical Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana-Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rutgers Cancer Institute of New Jersey</name>
      <address>
        <city>New Brunswick</city>
        <state>New Jersey</state>
        <zip>08901</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke University</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27708</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Women and Infants Hospital</name>
      <address>
        <city>Providence</city>
        <state>Rhode Island</state>
        <zip>02905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MD Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>August 16, 2012</study_first_submitted>
  <study_first_submitted_qc>August 20, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 22, 2012</study_first_posted>
  <results_first_submitted>June 12, 2020</results_first_submitted>
  <results_first_submitted_qc>July 16, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">August 3, 2020</results_first_posted>
  <last_update_submitted>May 9, 2022</last_update_submitted>
  <last_update_submitted_qc>May 9, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 25, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Dana-Farber Cancer Institute</investigator_affiliation>
    <investigator_full_name>Nadine Tung, MD</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>germline mutation</keyword>
  <keyword>BRCA1 mutation</keyword>
  <keyword>BRCA2 mutation</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>Cyclophosphamide</mesh_term>
    <mesh_term>Cisplatin</mesh_term>
    <mesh_term>Doxorubicin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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>August 16, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/00/NCT01670500/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>The trial was conducted at 13 academic centers and participants were recruited from these locations. Accrual occurred between January 2012 and January 2019.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Doxorubicin-Cyclophosphamide</title>
          <description>Doxorubicin q 2-3 wk x 4 Cyclophosphamide q 2-3 wk x 4&#xD;
Cyclophosphamide: administered with doxorubicin intravenously every 2 or 3 weeks for 4 doses&#xD;
Doxorubicin: administered with Cyclophosphamide intravenously every 2 or 3 weeks for 4 doses</description>
        </group>
        <group group_id="P2">
          <title>Cisplatin</title>
          <description>Cisplatin q 3 wk x 4&#xD;
Cisplatin: administered intravenously every 3 weeks for 4 doses</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="58"/>
                <participants group_id="P2" count="60"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="57">1 patient withdrew after 3 cycles; 5 patients received additional non-protocol chemo before surgery</participants>
                <participants group_id="P2" count="60">4 pts received &lt;4 cycles of assigned chemo; 2 pts received add'l non-protocol chemo before surgery</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Doxorubicin-Cyclophosphamide</title>
          <description>Doxorubicin q 2-3 wk x 4 Cyclophosphamide q 2-3 wk x 4&#xD;
Cyclophosphamide: administered with doxorubicin intravenously every 2 or 3 weeks for 4 doses&#xD;
Doxorubicin: administered with Cyclophosphamide intravenously every 2 or 3 weeks for 4 doses</description>
        </group>
        <group group_id="B2">
          <title>Cisplatin</title>
          <description>Cisplatin q 3 wk x 4&#xD;
Cisplatin: administered intravenously every 3 weeks for 4 doses</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="58"/>
            <count group_id="B2" value="60"/>
            <count group_id="B3" value="118"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="58"/>
                    <count group_id="B2" value="60"/>
                    <count group_id="B3" value="118"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="44" spread="10"/>
                    <measurement group_id="B2" value="40" spread="9"/>
                    <measurement group_id="B3" value="42" spread="10"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="58"/>
                    <count group_id="B2" value="60"/>
                    <count group_id="B3" value="118"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="58"/>
                    <measurement group_id="B2" value="59"/>
                    <measurement group_id="B3" value="117"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="58"/>
                    <count group_id="B2" value="60"/>
                    <count group_id="B3" value="118"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="49"/>
                    <measurement group_id="B2" value="48"/>
                    <measurement group_id="B3" value="97"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="6"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="58"/>
                    <count group_id="B2" value="60"/>
                    <count group_id="B3" value="118"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="44"/>
                    <measurement group_id="B2" value="43"/>
                    <measurement group_id="B3" value="87"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>BRCA status</title>
          <description>Eligible patients had a germline pathogenic or likely pathogenic variant (i.e. mutation) in BRCA1 or BRCA2; genetic testing was not performed as part of the trial, but known genetic status was required for eligibility</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="58"/>
                    <count group_id="B2" value="60"/>
                    <count group_id="B3" value="118"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>BRCA 1</title>
                  <measurement_list>
                    <measurement group_id="B1" value="37"/>
                    <measurement group_id="B2" value="44"/>
                    <measurement group_id="B3" value="81"/>
                  </measurement_list>
                </category>
                <category>
                  <title>BRCA 2</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="35"/>
                  </measurement_list>
                </category>
                <category>
                  <title>BRCA 1 and BRCA 2</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Tumor size by imaging</title>
          <units>centimeters</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="58"/>
                    <count group_id="B2" value="60"/>
                    <count group_id="B3" value="118"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2" lower_limit="2" upper_limit="4"/>
                    <measurement group_id="B2" value="3" lower_limit="2" upper_limit="4"/>
                    <measurement group_id="B3" value="2" lower_limit="2" upper_limit="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>T Stage (Tumor Size)</title>
          <description>Per National Cancer Institute (NCI) definition, T describes the size of the tumor and any spread of cancer into nearby tissue. The higher the T number, the larger the tumor and/or the more it has grown into nearby tissues.&#xD;
T1: The tumor in the breast is 20 millimeters (mm) or smaller in size at its widest area.&#xD;
T2: The tumor is larger than 20 mm but not larger than 50 mm.&#xD;
T3: The tumor is larger than 50 mm.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="58"/>
                    <count group_id="B2" value="60"/>
                    <count group_id="B3" value="118"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>T1</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="29"/>
                  </measurement_list>
                </category>
                <category>
                  <title>T2</title>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                    <measurement group_id="B2" value="35"/>
                    <measurement group_id="B3" value="66"/>
                  </measurement_list>
                </category>
                <category>
                  <title>T3</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="22"/>
                  </measurement_list>
                </category>
                <category>
                  <title>unknown</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>N stage</title>
          <description>Per the National Cancer Institute Definition: N stage refers to the number of nearby lymph nodes that have cancer.&#xD;
N0: There is no cancer in nearby lymph nodes. N1, N2, N3: Refers to the number and location of lymph nodes that contain cancer. The higher the number after the N, the more lymph nodes that contain cancer.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="58"/>
                    <count group_id="B2" value="60"/>
                    <count group_id="B3" value="118"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>N0</title>
                  <measurement_list>
                    <measurement group_id="B1" value="34"/>
                    <measurement group_id="B2" value="31"/>
                    <measurement group_id="B3" value="65"/>
                  </measurement_list>
                </category>
                <category>
                  <title>N1</title>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                    <measurement group_id="B2" value="24"/>
                    <measurement group_id="B3" value="43"/>
                  </measurement_list>
                </category>
                <category>
                  <title>N2</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>N3</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Node status: biopsy before chemotherapy</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="58"/>
                    <count group_id="B2" value="60"/>
                    <count group_id="B3" value="118"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>positive</title>
                  <measurement_list>
                    <measurement group_id="B1" value="24"/>
                    <measurement group_id="B2" value="29"/>
                    <measurement group_id="B3" value="53"/>
                  </measurement_list>
                </category>
                <category>
                  <title>negative</title>
                  <measurement_list>
                    <measurement group_id="B1" value="34"/>
                    <measurement group_id="B2" value="31"/>
                    <measurement group_id="B3" value="65"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Stage</title>
          <description>Per the National Cancer Institute Definitions:&#xD;
Stage of Cancer.&#xD;
For Stage I, II, III, cancer is present. The higher the number, the larger the cancer tumor and the more it has spread into nearby tissues.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="58"/>
                    <count group_id="B2" value="60"/>
                    <count group_id="B3" value="118"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>I</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
                <category>
                  <title>II</title>
                  <measurement_list>
                    <measurement group_id="B1" value="34"/>
                    <measurement group_id="B2" value="40"/>
                    <measurement group_id="B3" value="74"/>
                  </measurement_list>
                </category>
                <category>
                  <title>III</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Estrogen Receptor (ER)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="58"/>
                    <count group_id="B2" value="60"/>
                    <count group_id="B3" value="118"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Positive (&gt;/= 1%)</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="40"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Negative (&lt; 1%)</title>
                  <measurement_list>
                    <measurement group_id="B1" value="38"/>
                    <measurement group_id="B2" value="40"/>
                    <measurement group_id="B3" value="78"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Hormone receptor 1% cutoff</title>
          <description>ER= estrogen receptor; PR= progesterone receptor</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="58"/>
                    <count group_id="B2" value="60"/>
                    <count group_id="B3" value="118"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Triple Negative Breast Cancer (ER &amp; PR &lt; 1%)</title>
                  <measurement_list>
                    <measurement group_id="B1" value="36"/>
                    <measurement group_id="B2" value="40"/>
                    <measurement group_id="B3" value="76"/>
                  </measurement_list>
                </category>
                <category>
                  <title>ER+ or PR+</title>
                  <measurement_list>
                    <measurement group_id="B1" value="22"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Histology</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="58"/>
                    <count group_id="B2" value="60"/>
                    <count group_id="B3" value="118"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Invasive ductal</title>
                  <measurement_list>
                    <measurement group_id="B1" value="52"/>
                    <measurement group_id="B2" value="57"/>
                    <measurement group_id="B3" value="109"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Invasive lobular</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Mixed</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Other</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Pre-chemotherapy tumor grade</title>
          <description>Per the National Cancer Institute Definition: Tumor grade is description of tumor based on how abnormal the tumor cells and tumor tissue look under a microscope.&#xD;
In general, tumors are graded as 1, 2, 3, or 4, depending on the amount of abnormality. In Grade 1 tumors, the tumor cells and organization of the tumor tissue appear close to normal. These tumors tend to grow and spread slowly. In contrast, the cells and tissue of Grade 3 and Grade 4 tumors do not look like normal cells and tissue. Grade 3 and Grade 4 tumors tend to grow rapidly and spread faster than tumors with a lower grade.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="58"/>
                    <count group_id="B2" value="60"/>
                    <count group_id="B3" value="118"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>1</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>2</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
                <category>
                  <title>3</title>
                  <measurement_list>
                    <measurement group_id="B1" value="45"/>
                    <measurement group_id="B2" value="46"/>
                    <measurement group_id="B3" value="91"/>
                  </measurement_list>
                </category>
                <category>
                  <title>unknown</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Lymphovascular invasion</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="58"/>
                    <count group_id="B2" value="60"/>
                    <count group_id="B3" value="118"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Present</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Absent</title>
                  <measurement_list>
                    <measurement group_id="B1" value="47"/>
                    <measurement group_id="B2" value="48"/>
                    <measurement group_id="B3" value="95"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>lymphocytic infiltrate</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="58"/>
                    <count group_id="B2" value="60"/>
                    <count group_id="B3" value="118"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>moderate/marked</title>
                  <measurement_list>
                    <measurement group_id="B1" value="22"/>
                    <measurement group_id="B2" value="21"/>
                    <measurement group_id="B3" value="43"/>
                  </measurement_list>
                </category>
                <category>
                  <title>absent/scant</title>
                  <measurement_list>
                    <measurement group_id="B1" value="33"/>
                    <measurement group_id="B2" value="36"/>
                    <measurement group_id="B3" value="69"/>
                  </measurement_list>
                </category>
                <category>
                  <title>unknown</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Stromal TILs</title>
          <description>TILs= tumor infiltrating lymphocytes&#xD;
The pre-chemotherapy clinical biopsy was assessed for tumor infiltrating lymphocytes.</description>
          <population>Stromal TILS missing for 5 in Doxorubicin-Cyclophosphamide arm and 4 in the Cisplatin arm</population>
          <units>percentage of stromal TILs</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="53"/>
                    <count group_id="B2" value="56"/>
                    <count group_id="B3" value="109"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10" lower_limit="1" upper_limit="20"/>
                    <measurement group_id="B2" value="10" lower_limit="3" upper_limit="30"/>
                    <measurement group_id="B3" value="10" lower_limit="1" upper_limit="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Rate of Pathologic Complete Response (pCR)</title>
        <description>Pathologic complete response (pCR) rate (determined by the Miller-Payne method) in doxorubicin-cyclophosphamide vs cisplatin arms.</description>
        <time_frame>3 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Doxorubicin-Cyclophosphamide</title>
            <description>Doxorubicin q 2-3 wk x 4 Cyclophosphamide q 2-3 wk x 4&#xD;
Cyclophosphamide: administered with doxorubicin intravenously every 2 or 3 weeks for 4 doses&#xD;
Doxorubicin: administered with Cyclophosphamide intravenously every 2 or 3 weeks for 4 doses</description>
          </group>
          <group group_id="O2">
            <title>Cisplatin</title>
            <description>Cisplatin q 3 wk x 4&#xD;
Cisplatin: administered intravenously every 3 weeks for 4 doses</description>
          </group>
        </group_list>
        <measure>
          <title>Rate of Pathologic Complete Response (pCR)</title>
          <description>Pathologic complete response (pCR) rate (determined by the Miller-Payne method) in doxorubicin-cyclophosphamide vs cisplatin arms.</description>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="57"/>
                <count group_id="O2" value="60"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="26"/>
                    <measurement group_id="O2" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <param_type>Risk Ratio (RR)</param_type>
            <param_value>.70</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.39</ci_lower_limit>
            <ci_upper_limit>1.2</ci_upper_limit>
            <estimate_desc>The risk ratio is comparing cisplatin to doxorubicin-cyclophosphamide (AC)</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of Residual Cancer Burden (RCB) 0/1</title>
        <description>Residual Cancer Burden (RCB) rate of RCB 0 or 1 in participants receiving Doxorubicin-Cyclophosphamide vs participants receiving Cisplatin.</description>
        <time_frame>2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Doxorubicin-Cyclophosphamide</title>
            <description>Doxorubicin q 2-3 wk x 4 Cyclophosphamide q 2-3 wk x 4&#xD;
Cyclophosphamide: administered with doxorubicin intravenously every 2 or 3 weeks for 4 doses&#xD;
Doxorubicin: administered with Cyclophosphamide intravenously every 2 or 3 weeks for 4 doses</description>
          </group>
          <group group_id="O2">
            <title>Cisplatin</title>
            <description>Cisplatin q 3 wk x 4&#xD;
Cisplatin: administered intravenously every 3 weeks for 4 doses</description>
          </group>
        </group_list>
        <measure>
          <title>Rate of Residual Cancer Burden (RCB) 0/1</title>
          <description>Residual Cancer Burden (RCB) rate of RCB 0 or 1 in participants receiving Doxorubicin-Cyclophosphamide vs participants receiving Cisplatin.</description>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="57"/>
                <count group_id="O2" value="60"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="46"/>
                    <measurement group_id="O2" value="33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <param_type>Risk Ratio (RR)</param_type>
            <param_value>.73</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>.5</ci_lower_limit>
            <ci_upper_limit>1.1</ci_upper_limit>
            <estimate_desc>The risk ratio is comparing cisplatin to doxorubicin-cyclophosphamide (AC)</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clinical Response Rate</title>
        <description>Clinical response rate, defined as the number of partial and complete responses, after preoperative therapy with either cisplatin or AC in participants with germline BRCA mutation and breast cancer.&#xD;
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI or ultrasound: Complete Response (CR) = Disappearance of all target lesions; Partial Response (PR) is &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.</description>
        <time_frame>3 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Doxorubicin-Cyclophosphamide</title>
            <description>Doxorubicin q 2-3 wk x 4 Cyclophosphamide q 2-3 wk x 4&#xD;
Cyclophosphamide: administered with doxorubicin intravenously every 2 or 3 weeks for 4 doses&#xD;
Doxorubicin: administered with Cyclophosphamide intravenously every 2 or 3 weeks for 4 doses</description>
          </group>
          <group group_id="O2">
            <title>Cisplatin</title>
            <description>Cisplatin q 3 wk x 4&#xD;
Cisplatin: administered intravenously every 3 weeks for 4 doses</description>
          </group>
        </group_list>
        <measure>
          <title>Clinical Response Rate</title>
          <description>Clinical response rate, defined as the number of partial and complete responses, after preoperative therapy with either cisplatin or AC in participants with germline BRCA mutation and breast cancer.&#xD;
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI or ultrasound: Complete Response (CR) = Disappearance of all target lesions; Partial Response (PR) is &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.</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="58"/>
                <count group_id="O2" value="60"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="43"/>
                    <measurement group_id="O2" value="45"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Grade 3 and Grade 4 Adverse Events</title>
        <description>Comparison of toxicities for cisplatin and AC preoperative chemotherapy in BRCA mutation carriers with newly diagnosed breast cancer, reported as number of all Grade 3 and 4 adverse events and number of non-hematologic Grade 3 and 4 adverse events.</description>
        <time_frame>2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Doxorubicin-Cyclophosphamide</title>
            <description>Doxorubicin q 2-3 wk x 4 Cyclophosphamide q 2-3 wk x 4&#xD;
Cyclophosphamide: administered with doxorubicin intravenously every 2 or 3 weeks for 4 doses&#xD;
Doxorubicin: administered with Cyclophosphamide intravenously every 2 or 3 weeks for 4 doses</description>
          </group>
          <group group_id="O2">
            <title>Cisplatin</title>
            <description>Cisplatin q 3 wk x 4&#xD;
Cisplatin: administered intravenously every 3 weeks for 4 doses</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Grade 3 and Grade 4 Adverse Events</title>
          <description>Comparison of toxicities for cisplatin and AC preoperative chemotherapy in BRCA mutation carriers with newly diagnosed breast cancer, reported as number of all Grade 3 and 4 adverse events and number of non-hematologic Grade 3 and 4 adverse events.</description>
          <units>Adverse Events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="57"/>
                <count group_id="O2" value="60"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>All Grade 3 &amp; 4 Adverse Events</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15"/>
                    <measurement group_id="O2" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Non-hematologic Grade 3 &amp; 4 Adverse Events</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Analysis of Pre-chemotherapy Biopsies</title>
        <description>Biopsies collected for future analyses of biomarkers that predict for response to cisplatin or AC chemotherapy in BRCA mutation carriers. Pretreatment tumor biopsies will be analyzed using genome wide SNP profiling to determine number of regions of telomeric allelic imbalance (NtAI) and chromosome 15q26 copy number, and chromosome 8q22 copy number. Tumor sections will be examined for gene amplifications, losses and NtAI in tumors. Gene expression profiling will be performed to determine intrinsic subtype (basal-like, claudin-low, etc.) and to measure biomarker genes including BLM and FANCI associated with cisplatin sensitivity or LAPTM4B and YWHAZ associated with anthracycline resistance. Exploratory analysis will be performed to seek new measures of therapy response using the data from DNA copy number and gene expression profiles. In addition, we will plan to perform whole exome and possibly whole genome sequencing of tumors to identify potential modifiers of response to therapy.</description>
        <time_frame>5 years</time_frame>
        <posting_date>04/2022</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of Miller Payne 4 and 5</title>
        <description>Rates of Miller Payne 4 (near pCR) and 5 (near pCR) combined between those subjects who received neoadjuvant cisplatin and those who received neoadjuvant AC.&#xD;
Definitions:&#xD;
Miller Payne 4: a marked disappearance of tumor cells (more than 90%) such that only small clusters or widely dispersed individual cells remain (almost pCR);&#xD;
Miller Payne 5: no malignant cells identifiable in sections from the site of the tumor (pCR)</description>
        <time_frame>3 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Doxorubicin-Cyclophosphamide</title>
            <description>Doxorubicin q 2-3 wk x 4 Cyclophosphamide q 2-3 wk x 4&#xD;
Cyclophosphamide: administered with doxorubicin intravenously every 2 or 3 weeks for 4 doses&#xD;
Doxorubicin: administered with Cyclophosphamide intravenously every 2 or 3 weeks for 4 doses</description>
          </group>
          <group group_id="O2">
            <title>Cisplatin</title>
            <description>Cisplatin q 3 wk x 4&#xD;
Cisplatin: administered intravenously every 3 weeks for 4 doses</description>
          </group>
        </group_list>
        <measure>
          <title>Rate of Miller Payne 4 and 5</title>
          <description>Rates of Miller Payne 4 (near pCR) and 5 (near pCR) combined between those subjects who received neoadjuvant cisplatin and those who received neoadjuvant AC.&#xD;
Definitions:&#xD;
Miller Payne 4: a marked disappearance of tumor cells (more than 90%) such that only small clusters or widely dispersed individual cells remain (almost pCR);&#xD;
Miller Payne 5: no malignant cells identifiable in sections from the site of the tumor (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="58"/>
                <count group_id="O2" value="60"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="30"/>
                    <measurement group_id="O2" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of Recurrence Free Survival (RFS) After Cisplatin or AC</title>
        <description>Rate of 3-year recurrence free survival in doxorubicin-cyclophosphamide and cisplatin arms for germline BRCA mutation (gBRCAm) carriers with newly diagnosed HER2-negative breast cancer</description>
        <time_frame>5 years</time_frame>
        <posting_date>04/2022</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of Recurrence Free Survival (RFS) With Pathologic Complete Response (pCR) vs. With no pCR</title>
        <description>Rate of 3-year recurrence free survival for gBRCAm carriers who achieved pCR with those who did not.</description>
        <time_frame>5 years</time_frame>
        <posting_date>04/2022</posting_date>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse event information was collected from time of treatment start, during treatment, and until 30 days after the last dose of treatment, about 3 months on average per participant.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Doxorubicin-Cyclophosphamide</title>
          <description>Doxorubicin q 2-3 wk x 4 Cyclophosphamide q 2-3 wk x 4&#xD;
Cyclophosphamide: administered with doxorubicin intravenously every 2 or 3 weeks for 4 doses&#xD;
Doxorubicin: administered with Cyclophosphamide intravenously every 2 or 3 weeks for 4 doses</description>
        </group>
        <group group_id="E2">
          <title>Cisplatin</title>
          <description>Cisplatin q 3 wk x 4&#xD;
Cisplatin: administered intravenously every 3 weeks for 4 doses</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE v 4</default_vocab>
        <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="57"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Febrile Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Non-Cardiac Chest Pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic Reaction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Breast Infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Neutrophil Count Decreased</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Increased Creatinine</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE v 4</default_vocab>
        <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="55" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="60" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Tinnitus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="32" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="40" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="52" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="20" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Oral Mucositis</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="45" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="48" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Decreased Neutrophil Count</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Decreased White Blood Cell Count</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Decreased lymphocyte count</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <description>Note: Hair loss could not be accurately assessed for patients receiving AC, since hair loss was anticipated in this study before initiation of scalp cooling techniques and many patients shaved their hair in anticipation.</description>
                <counts group_id="E1" subjects_affected="31" subjects_at_risk="57"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="60"/>
              </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>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>Project Manager</name_or_title>
      <organization>DFCI</organization>
      <phone>617-632-2257</phone>
      <email>CTOPM@dfci.harvard.edu</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/NCT01670500
org study id: 12-258
nct id: NCT01670500
lead sponsor: 
has dmc: Yes
This research study is a Phase II clinical trial. Phase II clinical trials test the
      effectiveness of an investigational drug, which is cisplatin in this trial, to learn how well
      it works in treating a specific cancer. "Investigational" means that cisplatin is still being
      studied for use in this setting and that research doctors are trying to find out more about
      it-in this case, how effective cisplatin is for treating breast cancer in BRCA mutation
      carriers. It also means that the FDA has not yet approved cisplatin for your type of cancer.
      Cisplatin has been approved by the FDA for treatment of other cancers.

      The purpose of this study is to evaluate cisplatin, a chemotherapy drug that has been shown
      to be active in the treatment of women with breast cancer and a BRCA mutation. In this study,
      we are comparing cisplatin to the standard chemotherapy, doxorubicin and cyclophosphamide
      ("AC") that you might receive if you did not participate in this study.
If screening tests show that you are eligible to participate in the research study you will
      begin study treatment. You may undergo an optional research biopsy so the study team can
      obtain tissue samples. This will be used for biomarker research and will help your doctors to
      better understand your disease, how the drug is working in your body, and may help to
      identify which people may benefit most from platinum or from adriamycin/cytoxan in the
      future.

      Because no one knows which of the study options is best, you will be "randomized" to receive
      either cisplatin or doxorubicin and cyclophosphamide ("AC") chemotherapy prior to removal of
      your breast cancer. Chemotherapy administered before the removal of the cancer is known as
      neoadjuvant chemotherapy. Randomization means that you are put into a group by chance. It is
      like flipping a coin. Neither you nor the research doctor will choose what group you will be
      in. You will have an equal chance of being placed in either group.

      If you are randomized to receive cisplatin you will receive cisplatin once every three weeks
      for a total of four doses. You will be given cisplatin by vein (IV) on the first day of each
      treatment cycle. The cisplatin infusion can take between 1 to 2 hours. Before and after
      receiving cisplatin, you will receive fluid hydration by vein, and you will also be given
      medicine to help prevent side effects such as nausea. The total time of the infusion of
      cisplatin and the additional fluid and medications will take about 6 hours. After you receive
      cisplatin, you will be asked to drink about 12 eight ounce glasses of fluid per day,
      especially 2 or 3 days after therapy. The study treatment will stop if you have serious side
      effects or if the tumor grows despite receiving cisplatin chemotherapy.

      If you are randomized to "AC" chemotherapy you will receive both doxorubicin and
      cyclophosphamide once every 2 or 3 weeks for a total of four doses by vein on the first day
      of each treatment cycle. The interval between chemotherapy will be decided by your research
      doctor. If you receive the chemotherapy every two weeks, you will also receive a subcutaneous
      injection the day after chemotherapy. This injection contains a medicine that contains a
      growth factor that will boost your immune system in order to allow your body to be ready for
      chemotherapy in two weeks. The study treatment will be stopped if you have serious side
      effects or if the tumor grows despite the doxorubicin and cyclophosphamide chemotherapy.

      At the beginning of each treatment cycle you will have a physical exam (including weight and
      vital signs) and you will be asked general questions about your health and any medications
      you may be taking, as well as specific questions about any side effects you may be
      experiencing while receiving study treatment. Prior to each cycle of chemotherapy, you will
      have standard blood tests to check your blood counts. If you are receiving cisplatin your
      kidney function and body salts will also be checked prior to each chemotherapy cycle. In
      addition, 7-10 days after chemotherapy your blood will be drawn to look at your blood cell
      count to determine your risk of infection; if you have received cisplatin, your kidney
      function and blood electrolytes will also be evaluated. The blood draw performed 7-10 days
      after chemotherapy can be done in the hospital where you received your chemotherapy or closer
      to home. About 1 tablespoon of blood will be drawn for these tests.

      Surgery to remove your tumor will occur within six weeks after the last dose of chemotherapy.
      Your surgery will be performed by your surgeon, as part of the standard care for your
      disease.

      Your treating physician or nurse practitioner will examine you to assess your tumor each time
      you receive chemotherapy. A measurement of your tumor will be performed on the first day of
      each treatment cycle as part of your physical exam. After the slides of your initial breast
      cancer biopsy have been reviewed at your hospital, these slides and your tumor block will be
      sent to the study pathologist at DF/HCC. Likewise, after chemotherapy, your breast cancer
      will be removed by lumpectomy or mastectomy. After these slides are reviewed at your
      hospital, they will also be sent with the tumor block to the study pathologist so that the
      response of your tumor to the study treatment can be assessed. After these slides are
      reviewed, they will be returned to the hospital at which the biopsy and surgery were
      performed.

      Decisions about whether you will receive more chemotherapy after your surgery is up to your
      treating physicians. If you receive chemotherapy, the choice of chemotherapy is also up to
      your doctors. Decisions about post-operative chemotherapy are not part of this study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Rate of Pathologic Complete Response (pCR)
time frame: 3 years
description: Pathologic complete response (pCR) rate (determined by the Miller-Payne method) in doxorubicin-cyclophosphamide vs cisplatin arms.
measure: Rate of Residual Cancer Burden (RCB) 0/1
time frame: 2 years
description: Residual Cancer Burden (RCB) rate of RCB 0 or 1 in participants receiving Doxorubicin-Cyclophosphamide vs participants receiving Cisplatin.
measure: Clinical Response Rate
time frame: 3 years
description: Clinical response rate, defined as the number of partial and complete responses, after preoperative therapy with either cisplatin or AC in participants with germline BRCA mutation and breast cancer.
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI or ultrasound: Complete Response (CR) = Disappearance of all target lesions; Partial Response (PR) is >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
measure: Number of Grade 3 and Grade 4 Adverse Events
time frame: 2 years
description: Comparison of toxicities for cisplatin and AC preoperative chemotherapy in BRCA mutation carriers with newly diagnosed breast cancer, reported as number of all Grade 3 and 4 adverse events and number of non-hematologic Grade 3 and 4 adverse events.
measure: Analysis of Pre-chemotherapy Biopsies
time frame: 5 years
description: Biopsies collected for future analyses of biomarkers that predict for response to cisplatin or AC chemotherapy in BRCA mutation carriers. Pretreatment tumor biopsies will be analyzed using genome wide SNP profiling to determine number of regions of telomeric allelic imbalance (NtAI) and chromosome 15q26 copy number, and chromosome 8q22 copy number. Tumor sections will be examined for gene amplifications, losses and NtAI in tumors. Gene expression profiling will be performed to determine intrinsic subtype (basal-like, claudin-low, etc.) and to measure biomarker genes including BLM and FANCI associated with cisplatin sensitivity or LAPTM4B and YWHAZ associated with anthracycline resistance. Exploratory analysis will be performed to seek new measures of therapy response using the data from DNA copy number and gene expression profiles. In addition, we will plan to perform whole exome and possibly whole genome sequencing of tumors to identify potential modifiers of response to therapy.
measure: Rate of Miller Payne 4 and 5
time frame: 3 years
description: Rates of Miller Payne 4 (near pCR) and 5 (near pCR) combined between those subjects who received neoadjuvant cisplatin and those who received neoadjuvant AC.
Definitions:
Miller Payne 4: a marked disappearance of tumor cells (more than 90%) such that only small clusters or widely dispersed individual cells remain (almost pCR);
Miller Payne 5: no malignant cells identifiable in sections from the site of the tumor (pCR)
measure: Rate of Recurrence Free Survival (RFS) After Cisplatin or AC
time frame: 5 years
description: Rate of 3-year recurrence free survival in doxorubicin-cyclophosphamide and cisplatin arms for germline BRCA mutation (gBRCAm) carriers with newly diagnosed HER2-negative breast cancer
measure: Rate of Recurrence Free Survival (RFS) With Pathologic Complete Response (pCR) vs. With no pCR
time frame: 5 years
description: Rate of 3-year recurrence free survival for gBRCAm carriers who achieved pCR with those who did not.
arm group label: Doxorubicin-Cyclophosphamide
arm group type: Active Comparator
description: Doxorubicin q 2-3 wk x 4 Cyclophosphamide q 2-3 wk x 4
arm group label: Cisplatin
arm group type: Active Comparator
description: Cisplatin q 3 wk x 4
intervention type: Drug
intervention name: Cisplatin
description: administered intravenously every 3 weeks for 4 doses
arm group label: Cisplatin
other name: cisplatinum, or cis-diamminedichloroplatinum(II) (CDDP)
intervention type: Drug
intervention name: Cyclophosphamide
description: administered with doxorubicin intravenously every 2 or 3 weeks for 4 doses
arm group label: Doxorubicin-Cyclophosphamide
other name: Cytoxan
intervention type: Drug
intervention name: Doxorubicin
description: administered with Cyclophosphamide intravenously every 2 or 3 weeks for 4 doses
arm group label: Doxorubicin-Cyclophosphamide
other name: Adriamycin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Nadine Tung, MD
role: Principal Investigator
affiliation: Beth Israel Deaconess Medical Center
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country: United States
responsible party type: Principal Investigator
investigator affiliation: Dana-Farber Cancer Institute
investigator full name: Nadine Tung, MD
investigator title: Principal Investigator
mesh term: Breast Neoplasms
mesh term: Cyclophosphamide
mesh term: Cisplatin
mesh term: Doxorubicin
sharing ipd: No
provided document: 
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