<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/NCT04443348</url>
  </required_header>
  <id_info>
    <org_study_id>20-157</org_study_id>
    <nct_id>NCT04443348</nct_id>
  </id_info>
  <brief_title>Pre-op Pembro + Radiation Therapy in Breast Cancer (P-RAD)</brief_title>
  <official_title>P-RAD: A Randomized Study of Preoperative Chemotherapy, Pembrolizumab and No, Low or High Dose RADiation in Node-Positive, HER2-Negative Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Laura M. Spring, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Breast Cancer Research Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Translational Breast Cancer Research Consortium</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Massachusetts General Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research trial is studying a combination of neoadjuvant radiotherapy (RT), immunotherapy&#xD;
      (pembrolizumab) and chemotherapy for lymph node-positive, triple negative (TN) or hormone&#xD;
      receptor positive/HER2-negative breast cancer.&#xD;
&#xD;
      The names of the study interventions involved in this study are:&#xD;
&#xD;
        -  Radiation Therapy (RT)&#xD;
&#xD;
        -  Immunotherapy: Pembrolizumab (MK-3475)&#xD;
&#xD;
        -  Chemotherapies:&#xD;
&#xD;
             -  Paclitaxel&#xD;
&#xD;
             -  Doxorubicin (also called Adriamycin)&#xD;
&#xD;
             -  Cyclophosphamide&#xD;
&#xD;
             -  Carboplatin (optional, and in TN only)&#xD;
&#xD;
             -  Capecitabine (optional, and in TN only)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The main purpose of this study is to find out what is the best dose of preoperative RT when&#xD;
      combined with pembrolizumab and chemotherapy. The study will assess if combining the RT with&#xD;
      the immunotherapy agent, pembrolizumab, will increase the ability of the immune system to&#xD;
      destroy cancer cells.&#xD;
&#xD;
      The research study procedures include: screening for eligibility and study treatment,&#xD;
      including evaluations and follow-up visits.&#xD;
&#xD;
      The study aims to assess the effectiveness of pembrolizumab (study drug) with or without RT&#xD;
      directed to the breast tumor. Participants will then undergo neoadjuvant chemotherapy with&#xD;
      pembrolizumab, followed by treatment that can consist of one or more of the following:&#xD;
&#xD;
        -  Pembrolizumab (optional, per MD discretion)&#xD;
&#xD;
        -  Standard of Care Treatment&#xD;
&#xD;
             -  Breast surgery (lumpectomy or mastectomy) and axillary surgery&#xD;
&#xD;
             -  Adjuvant radiation to the entire breast or chest wall, plus or minus the lymph&#xD;
                nodes after surgery&#xD;
&#xD;
             -  Adjuvant chemotherapy (optional Capecitabine for TNBC patients)&#xD;
&#xD;
             -  Hormone therapy&#xD;
&#xD;
      Participants will be randomized to 1 of 3 groups. Neither the participant not the research&#xD;
      doctor will choose the group that the participant is assigned to. However, the participant&#xD;
      will be notified of the group prior to the start of study treatment. Participants will&#xD;
      receive study treatment for up to 13 months. Participants will be followed for 2 years after&#xD;
      the end of the study treatment.&#xD;
&#xD;
      It is expected that a total of 120 people will be participating in total.&#xD;
&#xD;
      This research study is a randomized, phase II study. The U.S. Food and Drug Administration&#xD;
      (FDA) has not approved pembrolizumab for your specific disease, but it has been approved for&#xD;
      other uses. The U.S. Food and Drug Administration (FDA) has approved the chemotherapies being&#xD;
      used in this study (Paclitaxel, Doxorubicin, Cyclophosphamide, Carboplatin, Capecitabine).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 16, 2020</start_date>
  <completion_date type="Anticipated">December 1, 2023</completion_date>
  <primary_completion_date type="Anticipated">June 1, 2023</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>Tumor Infiltrating Lymphocytes (TILs; CD3+/CD8+ T-cell Breast Immunoscore)</measure>
    <time_frame>14 through 21 Days</time_frame>
    <description>Quantitative immunofluorescence in post-treatment tumor biopsy samples collected on day 14-21 of C1 of Pembrolizumab.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Rate of pathologic response in the lymph node</measure>
    <time_frame>7 Months</time_frame>
    <description>Defined as the percentage of patients no evidence of residual cancer cells in all sampled regional lymph nodes following completion of neoadjuvant systemic therapy assessed by the study pathologist at the time of definitive surgery.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Residual Cancer Burden (RCB) score</measure>
    <time_frame>24 Weeks</time_frame>
    <description>RCB is a measure of residual cancer burden in the breast and regional lymph nodes at the time of definitive surgery following completion of neoadjuvant systemic therapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pathologic response rate</measure>
    <time_frame>24 Weeks</time_frame>
    <description>Pathologic response rate is measured by the presence or absence of residual cancer cells in all sampled regional lymph nodes. RCB measures residual disease in the breast and lymph nodes at the time of definitive surgery. CD3+/CD8+ T cell Breast Immunoscore greater than 75% versus patients with Post-treatment CD3+/CD8+ T cell Breast Immunoscore less than or equal to 75%.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent change in pre- versus post-treatment intra-tumoral TILs</measure>
    <time_frame>24 Weeks</time_frame>
    <description>Intra-tumoral, peri-tumoral and stromal CD3+, CD8+, and CD3+CD8+ T cell densities will be measured using pan-cytokeratin staining and multiplexed QIF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent changes in pre- versus post-treatment peri-tumoral</measure>
    <time_frame>24 Weeks</time_frame>
    <description>Intra-tumoral, peri-tumoral and stromal CD3+, CD8+, and CD3+CD8+ T cell densities will be measured using pan-cytokeratin staining and multiplexed QIF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent changes in pre- versus post-treatment stromal CD3+ or CD8+ T cell</measure>
    <time_frame>24 Weeks</time_frame>
    <description>Intra-tumoral, peri-tumoral and stromal CD3+, CD8+, and CD3+CD8+ T cell densities will be measured using pan-cytokeratin staining and multiplexed QIF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in TIL counts by H&amp;E in pre-treatment versus post-RT boost tumor biopsy</measure>
    <time_frame>24 Weeks</time_frame>
    <description>TIL counts by H&amp;E in pre-treatment versus post-RT boost tumor biopsy specimens in each RT dose and breast cancer subtype cohort.&#xD;
H&amp;E will be performed according to Salgado Criteria [1].</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in PD-L1 expression</measure>
    <time_frame>24 Weeks</time_frame>
    <description>To quantify changes in PD-L1 expression levels after treatment with Pembro + no, low or high RT boost (at the time of the time of interval biopsy).&#xD;
QIF for PD-L1 will be performed in pre- and post-treatment FFPE tumor biopsy samples.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in intratumoral, per-tumoral, and stromal CD4+Foxp3+ T regulatory cell densities</measure>
    <time_frame>24 Weeks</time_frame>
    <description>To quantify changes in intratumoral, per-tumoral, and stromal CD4+Foxp3+ T regulatory cell densities in response to treatment with preoperative Pembro + no, low, or high dose RT boost (at the time of interval biopsy).&#xD;
QIF for CD4 and Foxp3 will be performed in pre- and post-treatment FFPE tumor biopsy samples. Pan-cytokeratin staining will be used to identify tumor regions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants with Treatment Related Adverse Events as Assessed NCI CTCAE version 5.0</measure>
    <time_frame>Baseline up 6 months post surgery up to 13 months</time_frame>
    <description>NCI CTCAE version 5.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Invasive disease-free survival</measure>
    <time_frame>time from completion of surgery to the first occurrence of the following events: invasive ipsilateral, local, regional, or distant recurrence, or death due to breast cancer up to 31 months</time_frame>
    <description>iDFS is defined as time from completion of surgery to the first occurrence of the following events: invasive ipsilateral, local, regional, or distant recurrence, or death due to breast cancer.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Event-free survival (EFS)</measure>
    <time_frame>time from completion of surgery to the first occurrence of the following events: progression of disease (precluding surgery), recurrence (local or distant), or death due to any cause up to 31 months.</time_frame>
    <description>EFS is defined as the time from the initiation of the study treatment to any of the following events: progression of disease (precluding surgery), recurrence (local or distant), or death due to any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Symptomatic Improvement</measure>
    <time_frame>baseline to 21 Weeks</time_frame>
    <description>PROMIS Global Health Measure Quality of life (e.g., global, physical, mental, and social health) outcomes will be measured by two PROMIS (Patient-Reported Outcomes Measurement Information System) short forms consisting of 4 questions total. This instrument has demonstrated content-validity, cross-sectional validity, and responsiveness to change in numerous publications[93].</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Symptoms and Satisfaction with Treatment</measure>
    <time_frame>baseline to Week 3</time_frame>
    <description>(Breast-Q), four domains will be evaluated both before and after surgery: satisfaction with breasts, psychosocial, sexual, and physical well-being. Scores for each domain range from 0-100, with higher scores indicative of better quality of life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Symptoms and Satisfaction with Treatment</measure>
    <time_frame>baseline to week 21</time_frame>
    <description>(Breast-Q), four domains will be evaluated both before and after surgery: satisfaction with breasts, psychosocial, sexual, and physical well-being. Scores for each domain range from 0-100, with higher scores indicative of better quality of life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change Patient Reported Outcomes</measure>
    <time_frame>3 years</time_frame>
    <description>PRO-CTCAE will evaluate symptom burden in the previous week using a Likert scale to assess presence/absence, frequency, severity and/or interference for different symptoms. Each symptom will be presented descriptively, using summary statistics and graphical representations across time points.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Financial Burden</measure>
    <time_frame>3 to 6 wks after last dose in the Neoadjuvant Period up to 8 Months</time_frame>
    <description>Recently coined term used to describe the potential financial burden patients experience while receiving medical care. Two questions were adapted from the National Health Interview Survey[95] and a survey administered to caregivers of participants of the Cancer Car Outcomes Research and Surveillance (CanCORS) study[96] to assess financial burden and impact on employment-related metrics (e.g., sick leave, unpaid time off work). Financial burden will be assessed at the post-surgery visit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trial Satisfaction</measure>
    <time_frame>3 to 6 wks after last dose in the Neoadjuvant Period up to 8 Months</time_frame>
    <description>The Was It Worth It (WIWI) instrument, also called the &quot;Trial Satisfaction&quot; survey, was developed to investigate the patient experience on clinical trials. Multiple cooperative group studies have utilized this instrument at the completion of treatment to measure patient satisfaction relating to clinical trial enrollment, although formal validity and reliability data is not yet available[</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">120</enrollment>
  <condition>Triple Negative Breast Cancer</condition>
  <condition>Hormone Receptor Positive (HR+), HER2-negative Breast Cancer</condition>
  <condition>Biopsy-proven, Positive Lymph Node(s)</condition>
  <arm_group>
    <arm_group_label>Group A (No RT Boost)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>No RT boost plus pembrolizumab, followed by pembrolizumab plus paclitaxel, doxorubicin and cyclophosphamide chemotherapy.There will be up to a total of 8 cycles of pembrolizumab (4 cycle before surgery and 4 cycles after surgery at the discretion of the study doctor).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group B (Low Dose RT Boost)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Low-dose RT boost plus pembrolizumab, followed by pembrolizumab plus paclitaxel, doxorubicin and cyclophosphamide chemotherapy. There will be up to a total of 8 cycles of pembrolizumab (4 cycle before surgery and 4 cycles after surgery at the discretion of the study doctor).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group C (High Dose RT Boost)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>High-dose RT boost plus pembrolizumab followed by pembrolizumab plus paclitaxel, doxorubicin and cyclophosphamide chemotherapy. There will be up to a total of 8 cycles of pembrolizumab (4 cycle before surgery and 4 cycles after surgery at the discretion of the study doctor).</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Radiation Therapy Boost</intervention_name>
    <description>Participants randomized to the low-dose or high-dose RT boost group will be receiving treatment on Day 1-3 of Cycle 1 of pembrolizumab. Proton therapy may be used in the high dose RT group.</description>
    <arm_group_label>Group B (Low Dose RT Boost)</arm_group_label>
    <arm_group_label>Group C (High Dose RT Boost)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>Neoadjuvant Phase: Day 1 (once every 6 weeks) of Cycles 1-4 (by intravenous infusion) over about 30 minutes.&#xD;
Adjuvant Phase: Pembrolizumab may be given post-surgery for up to 4 cycles (once every 6 weeks) by intravenous infusion over about 30 minutes. Pembrolizumab after surgery is optional and should be discussed with the study doctor.</description>
    <arm_group_label>Group A (No RT Boost)</arm_group_label>
    <arm_group_label>Group B (Low Dose RT Boost)</arm_group_label>
    <arm_group_label>Group C (High Dose RT Boost)</arm_group_label>
    <other_name>Keytruda®.</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Paclitaxel</intervention_name>
    <description>Starting Week 3 and administered once per week for 12 weeks (up to 12 doses) by intravenous infusion over about 30 minutes.</description>
    <arm_group_label>Group A (No RT Boost)</arm_group_label>
    <arm_group_label>Group B (Low Dose RT Boost)</arm_group_label>
    <arm_group_label>Group C (High Dose RT Boost)</arm_group_label>
    <other_name>Taxol</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carboplatin</intervention_name>
    <description>Carboplatin is optional for TNBC patients and should be discussed with the study doctor.&#xD;
Starting Week 3 and administered once per week for 12 weeks (up to 12 doses) by intravenous infusion over about 30 minutes.</description>
    <arm_group_label>Group A (No RT Boost)</arm_group_label>
    <arm_group_label>Group B (Low Dose RT Boost)</arm_group_label>
    <arm_group_label>Group C (High Dose RT Boost)</arm_group_label>
    <other_name>Paraplatin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>Starting Week 15 and administered every 2 weeks for 4 cycles (up to 4 doses) into your vein (by intravenous infusion).</description>
    <arm_group_label>Group A (No RT Boost)</arm_group_label>
    <arm_group_label>Group B (Low Dose RT Boost)</arm_group_label>
    <arm_group_label>Group C (High Dose RT Boost)</arm_group_label>
    <other_name>Cytophosphane</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Doxorubicin</intervention_name>
    <description>Starting Week 15 and administered every 2 weeks for 4 cycles (up to 4 doses) into your vein (by intravenous infusion). Doxorubicin will be administered after pembrolizumab.</description>
    <arm_group_label>Group A (No RT Boost)</arm_group_label>
    <arm_group_label>Group B (Low Dose RT Boost)</arm_group_label>
    <arm_group_label>Group C (High Dose RT Boost)</arm_group_label>
    <other_name>Adriamycin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Capecitabine</intervention_name>
    <description>Capecitabine after surgery is optional for TNBC patients and should be discussed with the study doctor.&#xD;
Starting 3-6 weeks after surgery, administered orally twice daily for 6 courses, each 3 weeks long (for a total of 18 weeks).</description>
    <arm_group_label>Group A (No RT Boost)</arm_group_label>
    <arm_group_label>Group B (Low Dose RT Boost)</arm_group_label>
    <arm_group_label>Group C (High Dose RT Boost)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥18 years old&#xD;
&#xD;
          -  Participant has non-metastatic, T1*-T2 and N1-3 and one of the following&#xD;
             histologically confirmed disease subtypes:&#xD;
&#xD;
             -- Triple negative breast cancer is defined as ER-negative (&lt;1% cells), PR-negative&#xD;
             (&lt;1% cells) and HER2-negative (&lt;2+ HER2 IHC or &lt;2.2 HER2/CEP17 ratio by FISH), as per&#xD;
             testing at local institution&#xD;
&#xD;
               -  High-risk HR+/HER2-negative breast cancer is defined as ER≥1%, HER2-negative (&lt;2+&#xD;
                  Her2 IHC or &lt;2.2 HER2/CEP17 ratio by FISH) and either histologic grade II-III or&#xD;
                  a high-risk genomic assay score (Oncotype RS&gt;25, high risk Mammaprint, PAM-50,&#xD;
                  EndoPredict or ProSigna score).&#xD;
&#xD;
               -  Note: Eligibility requires primary tumor size ≥1.0 cm in maximum diameter and&#xD;
                  axillary node-positive breast cancer&#xD;
&#xD;
          -  Primary breast tumor measuring ≥1.5 cm in maximal diameter as measured by any&#xD;
             available standard of care imaging (mammogram, breast ultrasound, breast MRI).&#xD;
&#xD;
          -  Biopsy-proven, axillary lymph node-positive breast cancer at diagnosis. Note:&#xD;
             Clinically node-positive disease is classified as cN1-3. cN1: without matted nodes,&#xD;
             even if several/multiple appear matted on ultrasound or MRI; cN2: clinically fixed or&#xD;
             matted nodes on examination or clinically or imaging-detected internal mammary node&#xD;
             involvement.&#xD;
&#xD;
          -  Clips or fiducial placement within the biopsy-proven axillary lymph node and breast&#xD;
             primary tumor are required.&#xD;
&#xD;
          -  Multifocal and multicentric disease is permitted; however only one breast tumor may be&#xD;
             preoperatively boosted.&#xD;
&#xD;
             --Note: For patients with multifocal disease and are randomized to receive a&#xD;
             preoperative RT boost, all sites of multifocal disease should be contained within the&#xD;
             pre-operative boost volume. Subsequently, these patients will not need a post-op&#xD;
             boost.&#xD;
&#xD;
          -  Synchronous bilateral invasive breast cancer is permitted; however only one breast&#xD;
             tumor may be preoperatively boosted.&#xD;
&#xD;
          -  No indication of distant metastases. Staging scans are not required and are per the&#xD;
             discretion of the treating physician.&#xD;
&#xD;
          -  Neoadjuvant chemotherapy (NAC) with paclitaxel, dose-dense doxorubicin and&#xD;
             cyclophosphamide (dd AC) is planned. Note: For TNBC patients, administration of&#xD;
             carboplatin is optional, as per MD choice. For HR+ patients, carboplatin will not be&#xD;
             administered.&#xD;
&#xD;
          -  The boost volume is determined to be able to meet study dose constraints by the&#xD;
             treating radiation oncologist.&#xD;
&#xD;
          -  Breast-conserving surgery or mastectomy +/- reconstruction is planned following NAC.&#xD;
&#xD;
          -  ECOG performance status score of 0 or 1.&#xD;
&#xD;
          -  Have adequate organ function as defined in the following table. Bloodwork must be&#xD;
             collected within 10 days prior to the start of study treatment.&#xD;
&#xD;
               -  Hematological --- Absolute neutrophil count (ANC) ≥1500/µL&#xD;
&#xD;
                    -  Platelets ≥100 000/µL&#xD;
&#xD;
                    -  Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La&#xD;
&#xD;
               -  Renal&#xD;
&#xD;
                  --- Creatinine ≤1.5 × ULN OR Measured or calculated b creatinine clearance (GFR&#xD;
                  can also be used in place of creatinine or CrCl) OR ≥30 mL/min for participant&#xD;
                  with creatinine levels &gt;1.5 × institutional ULN&#xD;
&#xD;
               -  Hepatic&#xD;
&#xD;
                    -  Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with&#xD;
                       total bilirubin levels &gt;1.5 × ULN&#xD;
&#xD;
                    -  AST (SGOT) and ALT (SGPT) ≤2.5 × ULN&#xD;
&#xD;
               -  Coagulation&#xD;
&#xD;
                    -  International normalized ratio (INR) OR prothrombin time (PT) Activated&#xD;
                       partial thromboplastin time (aPTT)&#xD;
&#xD;
                    -  ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as&#xD;
                       PT or aPTT is within therapeutic range of intended use of anticoagulants&#xD;
&#xD;
                    -  ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase);&#xD;
                       AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic&#xD;
                       transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.&#xD;
&#xD;
                    -  Criteria must be met without erythropoietin dependency and without packed&#xD;
                       red blood cell (pRBC) transfusion within last 2 weeks.&#xD;
&#xD;
                    -  Creatinine clearance (CrCl) should be calculated per institutional standard.&#xD;
&#xD;
               -  Note: This table includes eligibility-defining laboratory value requirements for&#xD;
                  treatment; laboratory value requirements should be adapted according to local&#xD;
                  regulations and guidelines for the administration of specific chemotherapies.&#xD;
&#xD;
          -  A female participant is eligible to participate if she is not pregnant, not&#xD;
             breastfeeding, and at least one of the following conditions applies:&#xD;
&#xD;
             -- a) Not a woman of childbearing potential (WOCBP) OR b) A WOCBP who agrees to follow&#xD;
             the contraceptive guidance throughout the study and for at least 4 months after the&#xD;
             last dose of pembrolizumab in such a manner that the risk of pregnancy is minimized.&#xD;
&#xD;
          -  A male participant must agree to use a contraception as detailed in Appendix A of this&#xD;
             protocol during the treatment period and for at least 4 months after the last dose of&#xD;
             after the last dose of study treatment and refrain from donating sperm during this&#xD;
             period.&#xD;
&#xD;
          -  Willingness to adhere to the study visit schedule and the prohibitions and&#xD;
             restrictions specified in this protocol.&#xD;
&#xD;
          -  Willingness to undergo mandatory research biopsy of the breast tumor between weeks 2-3&#xD;
             of Cycle 1.&#xD;
&#xD;
          -  Written informed consent obtained from participant and ability for participant to&#xD;
             comply with the requirements of the study.&#xD;
&#xD;
          -  Patients unable to read/write English are eligible to participate in the overall&#xD;
             study, but will not be required to participate in the Patient-Reported Outcome&#xD;
             questionnaires.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  HER2-positive breast cancer by ASCO/CAP guidelines (HER2 IHC 3+ or ≥ 2.2 HER2/CEP17&#xD;
             ratio by FISH)&#xD;
&#xD;
          -  Inflammatory (cT4d) breast cancer&#xD;
&#xD;
          -  Metastatic breast cancer (M1)&#xD;
&#xD;
          -  Contraindication(s) to breast-conserving therapy or mastectomy&#xD;
&#xD;
          -  Contraindication to radiation therapy including: prior ipsilateral breast or mantle&#xD;
             RT, active scleroderma, systemic lupus erythematosis and pregnancy.&#xD;
&#xD;
             --Note: All cardiac implantable electronic devices are permitted, provided that&#xD;
             methods to assess radiation doses and minimize damage to the devices during RT is&#xD;
             planned, per institutional guidelines.&#xD;
&#xD;
          -  Prior ipsilateral breast, chest wall or thoracic radiotherapy&#xD;
&#xD;
          -  Prior ipsilateral invasive breast cancer, contralateral breast cancer or a known&#xD;
             additional, invasive malignancy that is progressing or required active treatment in&#xD;
             the last 5 years.&#xD;
&#xD;
             --Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of&#xD;
             the skin or cervical carcinoma in situ that has undergone potentially curative therapy&#xD;
             and a previous diagnosis of ductal carcinoma in situ are not excluded.&#xD;
&#xD;
          -  Has a known history of active tuberculosis (Bacillus tuberculosis&#xD;
&#xD;
          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with&#xD;
             an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4,&#xD;
             OX 40, CD137).&#xD;
&#xD;
          -  Has received prior systemic anti-cancer therapy including investigational agents&#xD;
             within 4 weeks prior to randomization.&#xD;
&#xD;
             --Note: Participants must have recovered from all AEs due to previous therapies to ≤&#xD;
             Grade 1 or baseline. Participants with ≤ Grade 2 neuropathy may be eligible. If&#xD;
             participant received major surgery, she/he must have recovered adequately from the&#xD;
             toxicity and/or complications from the intervention prior to starting study treatment.&#xD;
&#xD;
          -  Has a history of (non-infectious) pneumonitis that required steroids or has current&#xD;
             pneumonitis.&#xD;
&#xD;
          -  Has known severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its&#xD;
             excipients.&#xD;
&#xD;
          -  Participants with active, known or suspected autoimmune disease. Participants with&#xD;
             vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune&#xD;
             condition only requiring hormone replacement, psoriasis not requiring systemic&#xD;
             treatment, or conditions not expected to recur in the absence of an external trigger&#xD;
             are permitted to enroll.&#xD;
&#xD;
          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality&#xD;
             that might confound the results of the study, interfere with the subject's&#xD;
             participation for the full duration of the study, or is not in the best interest of&#xD;
             the subject to participate, in the opinion of the treating investigator.&#xD;
&#xD;
          -  Known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required&#xD;
             unless mandated by local health authorities.&#xD;
&#xD;
          -  Known active Hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or&#xD;
             known active hepatitis C virus (defined as HCV RNA [qualitative] is detected). Note:&#xD;
             Testing for hepatitis B or hepatitis C is not required, unless mandated by local&#xD;
             health authorities or institutional guidelines.&#xD;
&#xD;
          -  Has received a live vaccine within 30 days prior to the first dose of study drug.&#xD;
             Examples of live vaccines include, but are not limited to, the following: measles,&#xD;
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus&#xD;
             Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection&#xD;
             are generally killed virus vaccines and are allowed; however, intranasal influenza&#xD;
             vaccines (e.g. FluMist®) are live attenuated vaccines and are not allowed.&#xD;
&#xD;
          -  Has had an allogenic tissue/solid organ transplant&#xD;
&#xD;
          -  A WOCBP who has a positive urine pregnancy test within 72 hours before the first dose&#xD;
             of study treatment (see Appendix A). If the urine test cannot be confirmed as&#xD;
             negative, a serum pregnancy test is required. In such cases, the participant must be&#xD;
             excluded from participation if the serum pregnancy result is positive.&#xD;
&#xD;
          -  Prohibited Treatments and/or Therapies:Use of immunosuppressants and/or systemic&#xD;
             corticosteroids is exclusionary, except the following in the absence of active&#xD;
             autoimmune disease:&#xD;
&#xD;
               -  As premedication for chemotherapy&#xD;
&#xD;
               -  For the prevention of nausea in the three days following chemotherapy&#xD;
&#xD;
               -  Participants are permitted the use of corticosteroids with minimal systemic&#xD;
                  absorption (e.g. topical, ocular, intra-articular, intranasal and inhaled)&#xD;
&#xD;
               -  Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or&#xD;
                  equivalent permitted&#xD;
&#xD;
               -  Adrenal replacement steroid doses including doses &gt;10 mg daily prednisone is&#xD;
                  permitted&#xD;
&#xD;
               -  A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g. CT&#xD;
                  scan premedication against contrast dye allergy) or for treatment of&#xD;
                  non-autoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by&#xD;
                  a contact allergen is permitted (used in the management of cancer or&#xD;
                  non-cancer-related illnesses). However, use of corticosteroids is allowed for the&#xD;
                  treatment of immune-related Adverse Events (irAEs), or adrenal insufficiency.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <gender_based>Yes</gender_based>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Laura M Spring, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Laura M Spring, MD</last_name>
    <phone>617-726-6500</phone>
    <email>LSPRING2@PARTNERS.ORG</email>
  </overall_contact>
  <location>
    <facility>
      <name>Sibley Memorial Hospital</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20016</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Cesar Santa-Maria, MD</last_name>
      <phone>202-660-6500</phone>
    </contact>
    <investigator>
      <last_name>Cesar Santa-Maria, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Indiana University</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Kathy Miller, MD</last_name>
      <phone>317-944-0920</phone>
    </contact>
    <investigator>
      <last_name>Kathy Miller, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Johns Hopkins</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21231</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Cesar Santa-Maria, MD</last_name>
      <phone>410-955-8893</phone>
    </contact>
    <investigator>
      <last_name>Cesar Santa-Maria, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Laura M Spring, MD</last_name>
      <phone>617-726-6500</phone>
      <email>LSPRING2@partners.org</email>
    </contact>
    <investigator>
      <last_name>Laura M Spring, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </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>
    <status>Recruiting</status>
    <contact>
      <last_name>Laura Warren, MD</last_name>
      <phone>617-632-4739</phone>
      <email>LEWARREN@PARTNERS.HARVARD.EDU</email>
    </contact>
    <investigator>
      <last_name>Laura Warren, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic - Rochester</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Robert Mutter, MD</last_name>
      <phone>507-284-2511</phone>
    </contact>
    <investigator>
      <last_name>Robert Mutter, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Montefiore Medical Center</name>
      <address>
        <city>Bronx</city>
        <state>New York</state>
        <zip>10467</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jana Fox, MD</last_name>
      <phone>718-920-7750</phone>
    </contact>
    <investigator>
      <last_name>Jana Fox, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Atif Khan, MD</last_name>
      <phone>848-225-6334</phone>
    </contact>
    <investigator>
      <last_name>Atif Khan, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of North Carolina Medical Center</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27514</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Gaorav Gupta, MD, PhD</last_name>
      <email>gaorav_gupta@med.unc.edu</email>
    </contact>
    <investigator>
      <last_name>Gaorav Gupta, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Duke University Medical Center</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Rachel Blitzblau, MD</last_name>
      <phone>919-660-2100</phone>
    </contact>
    <contact_backup>
      <last_name>Shelley Hwang, MD, MPH</last_name>
      <phone>919-668-6688</phone>
    </contact_backup>
    <investigator>
      <last_name>Rachel Blitzblau, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </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>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Haven Garber, MD, PhD</last_name>
      <phone>877-632-6789</phone>
    </contact>
    <investigator>
      <last_name>Haven Garber, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>June 19, 2020</study_first_submitted>
  <study_first_submitted_qc>June 19, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 23, 2020</study_first_posted>
  <last_update_submitted>February 24, 2023</last_update_submitted>
  <last_update_submitted_qc>February 24, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 27, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Laura M. Spring, MD</investigator_full_name>
    <investigator_title>Medical Oncologist</investigator_title>
  </responsible_party>
  <keyword>Triple Negative Breast Cancer</keyword>
  <keyword>Hormone Receptor Positive breast cancer</keyword>
  <keyword>Estrogen Receptor Positive breast cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Triple Negative Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Paclitaxel</mesh_term>
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Carboplatin</mesh_term>
    <mesh_term>Doxorubicin</mesh_term>
    <mesh_term>Pembrolizumab</mesh_term>
    <mesh_term>Capecitabine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Sponsor Investigator or designee. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>Data can be shared no earlier than 1 year following the date of publication</ipd_time_frame>
    <ipd_access_criteria>Contact the Partners Innovations team at http://www.partners.org/innovation</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04443348
org study id: 20-157
nct id: NCT04443348
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: Yes
This research trial is studying a combination of neoadjuvant radiotherapy (RT), immunotherapy
      (pembrolizumab) and chemotherapy for lymph node-positive, triple negative (TN) or hormone
      receptor positive/HER2-negative breast cancer.

      The names of the study interventions involved in this study are:

        -  Radiation Therapy (RT)

        -  Immunotherapy: Pembrolizumab (MK-3475)

        -  Chemotherapies:

             -  Paclitaxel

             -  Doxorubicin (also called Adriamycin)

             -  Cyclophosphamide

             -  Carboplatin (optional, and in TN only)

             -  Capecitabine (optional, and in TN only)
The main purpose of this study is to find out what is the best dose of preoperative RT when
      combined with pembrolizumab and chemotherapy. The study will assess if combining the RT with
      the immunotherapy agent, pembrolizumab, will increase the ability of the immune system to
      destroy cancer cells.

      The research study procedures include: screening for eligibility and study treatment,
      including evaluations and follow-up visits.

      The study aims to assess the effectiveness of pembrolizumab (study drug) with or without RT
      directed to the breast tumor. Participants will then undergo neoadjuvant chemotherapy with
      pembrolizumab, followed by treatment that can consist of one or more of the following:

        -  Pembrolizumab (optional, per MD discretion)

        -  Standard of Care Treatment

             -  Breast surgery (lumpectomy or mastectomy) and axillary surgery

             -  Adjuvant radiation to the entire breast or chest wall, plus or minus the lymph
                nodes after surgery

             -  Adjuvant chemotherapy (optional Capecitabine for TNBC patients)

             -  Hormone therapy

      Participants will be randomized to 1 of 3 groups. Neither the participant not the research
      doctor will choose the group that the participant is assigned to. However, the participant
      will be notified of the group prior to the start of study treatment. Participants will
      receive study treatment for up to 13 months. Participants will be followed for 2 years after
      the end of the study treatment.

      It is expected that a total of 120 people will be participating in total.

      This research study is a randomized, phase II study. The U.S. Food and Drug Administration
      (FDA) has not approved pembrolizumab for your specific disease, but it has been approved for
      other uses. The U.S. Food and Drug Administration (FDA) has approved the chemotherapies being
      used in this study (Paclitaxel, Doxorubicin, Cyclophosphamide, Carboplatin, Capecitabine).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Tumor Infiltrating Lymphocytes (TILs; CD3+/CD8+ T-cell Breast Immunoscore)
time frame: 14 through 21 Days
description: Quantitative immunofluorescence in post-treatment tumor biopsy samples collected on day 14-21 of C1 of Pembrolizumab.
measure: Rate of pathologic response in the lymph node
time frame: 7 Months
description: Defined as the percentage of patients no evidence of residual cancer cells in all sampled regional lymph nodes following completion of neoadjuvant systemic therapy assessed by the study pathologist at the time of definitive surgery.
measure: Residual Cancer Burden (RCB) score
time frame: 24 Weeks
description: RCB is a measure of residual cancer burden in the breast and regional lymph nodes at the time of definitive surgery following completion of neoadjuvant systemic therapy.
measure: Pathologic response rate
time frame: 24 Weeks
description: Pathologic response rate is measured by the presence or absence of residual cancer cells in all sampled regional lymph nodes. RCB measures residual disease in the breast and lymph nodes at the time of definitive surgery. CD3+/CD8+ T cell Breast Immunoscore greater than 75% versus patients with Post-treatment CD3+/CD8+ T cell Breast Immunoscore less than or equal to 75%.
measure: Percent change in pre- versus post-treatment intra-tumoral TILs
time frame: 24 Weeks
description: Intra-tumoral, peri-tumoral and stromal CD3+, CD8+, and CD3+CD8+ T cell densities will be measured using pan-cytokeratin staining and multiplexed QIF
measure: Percent changes in pre- versus post-treatment peri-tumoral
time frame: 24 Weeks
description: Intra-tumoral, peri-tumoral and stromal CD3+, CD8+, and CD3+CD8+ T cell densities will be measured using pan-cytokeratin staining and multiplexed QIF
measure: Percent changes in pre- versus post-treatment stromal CD3+ or CD8+ T cell
time frame: 24 Weeks
description: Intra-tumoral, peri-tumoral and stromal CD3+, CD8+, and CD3+CD8+ T cell densities will be measured using pan-cytokeratin staining and multiplexed QIF
measure: Change in TIL counts by H&E in pre-treatment versus post-RT boost tumor biopsy
time frame: 24 Weeks
description: TIL counts by H&E in pre-treatment versus post-RT boost tumor biopsy specimens in each RT dose and breast cancer subtype cohort.
H&E will be performed according to Salgado Criteria [1].
measure: Changes in PD-L1 expression
time frame: 24 Weeks
description: To quantify changes in PD-L1 expression levels after treatment with Pembro + no, low or high RT boost (at the time of the time of interval biopsy).
QIF for PD-L1 will be performed in pre- and post-treatment FFPE tumor biopsy samples.
measure: Changes in intratumoral, per-tumoral, and stromal CD4+Foxp3+ T regulatory cell densities
time frame: 24 Weeks
description: To quantify changes in intratumoral, per-tumoral, and stromal CD4+Foxp3+ T regulatory cell densities in response to treatment with preoperative Pembro + no, low, or high dose RT boost (at the time of interval biopsy).
QIF for CD4 and Foxp3 will be performed in pre- and post-treatment FFPE tumor biopsy samples. Pan-cytokeratin staining will be used to identify tumor regions
measure: Number of Participants with Treatment Related Adverse Events as Assessed NCI CTCAE version 5.0
time frame: Baseline up 6 months post surgery up to 13 months
description: NCI CTCAE version 5.0
measure: Invasive disease-free survival
time frame: time from completion of surgery to the first occurrence of the following events: invasive ipsilateral, local, regional, or distant recurrence, or death due to breast cancer up to 31 months
description: iDFS is defined as time from completion of surgery to the first occurrence of the following events: invasive ipsilateral, local, regional, or distant recurrence, or death due to breast cancer.
measure: Event-free survival (EFS)
time frame: time from completion of surgery to the first occurrence of the following events: progression of disease (precluding surgery), recurrence (local or distant), or death due to any cause up to 31 months.
description: EFS is defined as the time from the initiation of the study treatment to any of the following events: progression of disease (precluding surgery), recurrence (local or distant), or death due to any cause.
measure: Symptomatic Improvement
time frame: baseline to 21 Weeks
description: PROMIS Global Health Measure Quality of life (e.g., global, physical, mental, and social health) outcomes will be measured by two PROMIS (Patient-Reported Outcomes Measurement Information System) short forms consisting of 4 questions total. This instrument has demonstrated content-validity, cross-sectional validity, and responsiveness to change in numerous publications[93].
measure: Change in Symptoms and Satisfaction with Treatment
time frame: baseline to Week 3
description: (Breast-Q), four domains will be evaluated both before and after surgery: satisfaction with breasts, psychosocial, sexual, and physical well-being. Scores for each domain range from 0-100, with higher scores indicative of better quality of life
measure: Change in Symptoms and Satisfaction with Treatment
time frame: baseline to week 21
description: (Breast-Q), four domains will be evaluated both before and after surgery: satisfaction with breasts, psychosocial, sexual, and physical well-being. Scores for each domain range from 0-100, with higher scores indicative of better quality of life
measure: Change Patient Reported Outcomes
time frame: 3 years
description: PRO-CTCAE will evaluate symptom burden in the previous week using a Likert scale to assess presence/absence, frequency, severity and/or interference for different symptoms. Each symptom will be presented descriptively, using summary statistics and graphical representations across time points.
measure: Financial Burden
time frame: 3 to 6 wks after last dose in the Neoadjuvant Period up to 8 Months
description: Recently coined term used to describe the potential financial burden patients experience while receiving medical care. Two questions were adapted from the National Health Interview Survey[95] and a survey administered to caregivers of participants of the Cancer Car Outcomes Research and Surveillance (CanCORS) study[96] to assess financial burden and impact on employment-related metrics (e.g., sick leave, unpaid time off work). Financial burden will be assessed at the post-surgery visit.
measure: Trial Satisfaction
time frame: 3 to 6 wks after last dose in the Neoadjuvant Period up to 8 Months
description: The Was It Worth It (WIWI) instrument, also called the "Trial Satisfaction" survey, was developed to investigate the patient experience on clinical trials. Multiple cooperative group studies have utilized this instrument at the completion of treatment to measure patient satisfaction relating to clinical trial enrollment, although formal validity and reliability data is not yet available[
arm group label: Group A (No RT Boost)
arm group type: Experimental
description: No RT boost plus pembrolizumab, followed by pembrolizumab plus paclitaxel, doxorubicin and cyclophosphamide chemotherapy.There will be up to a total of 8 cycles of pembrolizumab (4 cycle before surgery and 4 cycles after surgery at the discretion of the study doctor).
arm group label: Group B (Low Dose RT Boost)
arm group type: Experimental
description: Low-dose RT boost plus pembrolizumab, followed by pembrolizumab plus paclitaxel, doxorubicin and cyclophosphamide chemotherapy. There will be up to a total of 8 cycles of pembrolizumab (4 cycle before surgery and 4 cycles after surgery at the discretion of the study doctor).
arm group label: Group C (High Dose RT Boost)
arm group type: Experimental
description: High-dose RT boost plus pembrolizumab followed by pembrolizumab plus paclitaxel, doxorubicin and cyclophosphamide chemotherapy. There will be up to a total of 8 cycles of pembrolizumab (4 cycle before surgery and 4 cycles after surgery at the discretion of the study doctor).
intervention type: Radiation
intervention name: Radiation Therapy Boost
description: Participants randomized to the low-dose or high-dose RT boost group will be receiving treatment on Day 1-3 of Cycle 1 of pembrolizumab. Proton therapy may be used in the high dose RT group.
arm group label: Group B (Low Dose RT Boost)
arm group label: Group C (High Dose RT Boost)
intervention type: Drug
intervention name: Pembrolizumab
description: Neoadjuvant Phase: Day 1 (once every 6 weeks) of Cycles 1-4 (by intravenous infusion) over about 30 minutes.
Adjuvant Phase: Pembrolizumab may be given post-surgery for up to 4 cycles (once every 6 weeks) by intravenous infusion over about 30 minutes. Pembrolizumab after surgery is optional and should be discussed with the study doctor.
arm group label: Group A (No RT Boost)
arm group label: Group B (Low Dose RT Boost)
arm group label: Group C (High Dose RT Boost)
other name: Keytruda®.
intervention type: Drug
intervention name: Paclitaxel
description: Starting Week 3 and administered once per week for 12 weeks (up to 12 doses) by intravenous infusion over about 30 minutes.
arm group label: Group A (No RT Boost)
arm group label: Group B (Low Dose RT Boost)
arm group label: Group C (High Dose RT Boost)
other name: Taxol
intervention type: Drug
intervention name: Carboplatin
description: Carboplatin is optional for TNBC patients and should be discussed with the study doctor.
Starting Week 3 and administered once per week for 12 weeks (up to 12 doses) by intravenous infusion over about 30 minutes.
arm group label: Group A (No RT Boost)
arm group label: Group B (Low Dose RT Boost)
arm group label: Group C (High Dose RT Boost)
other name: Paraplatin
intervention type: Drug
intervention name: Cyclophosphamide
description: Starting Week 15 and administered every 2 weeks for 4 cycles (up to 4 doses) into your vein (by intravenous infusion).
arm group label: Group A (No RT Boost)
arm group label: Group B (Low Dose RT Boost)
arm group label: Group C (High Dose RT Boost)
other name: Cytophosphane
intervention type: Drug
intervention name: Doxorubicin
description: Starting Week 15 and administered every 2 weeks for 4 cycles (up to 4 doses) into your vein (by intravenous infusion). Doxorubicin will be administered after pembrolizumab.
arm group label: Group A (No RT Boost)
arm group label: Group B (Low Dose RT Boost)
arm group label: Group C (High Dose RT Boost)
other name: Adriamycin
intervention type: Drug
intervention name: Capecitabine
description: Capecitabine after surgery is optional for TNBC patients and should be discussed with the study doctor.
Starting 3-6 weeks after surgery, administered orally twice daily for 6 courses, each 3 weeks long (for a total of 18 weeks).
arm group label: Group A (No RT Boost)
arm group label: Group B (Low Dose RT Boost)
arm group label: Group C (High Dose RT Boost)
criteria: 
gender: All
gender based: Yes
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Laura M Spring, MD
role: Principal Investigator
affiliation: Massachusetts General Hospital
last name: Laura M Spring, MD
phone: 617-726-6500
email: LSPRING2@PARTNERS.ORG
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Not yet recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Not yet recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Not yet recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Laura M. Spring, MD
investigator title: Medical Oncologist
mesh term: Breast Neoplasms
mesh term: Triple Negative Breast Neoplasms
mesh term: Paclitaxel
mesh term: Cyclophosphamide
mesh term: Carboplatin
mesh term: Doxorubicin
mesh term: Pembrolizumab
mesh term: Capecitabine
sharing ipd: Yes
ipd description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Sponsor Investigator or designee. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: Data can be shared no earlier than 1 year following the date of publication
ipd access criteria: Contact the Partners Innovations team at http://www.partners.org/innovation