<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/NCT02999477</url>
  </required_header>
  <id_info>
    <org_study_id>16-466</org_study_id>
    <nct_id>NCT02999477</nct_id>
  </id_info>
  <brief_title>A Study Of Changes In PD-L1 Expression During Preoperative Treatment With Nab-Paclitaxel And Pembrolizumab In Hormone Receptor-Positive Breast Cancer</brief_title>
  <official_title>A Pilot Study Of Changes In PD-L1 Expression During Preoperative Treatment With Nab-Paclitaxel And Pembrolizumab In Hormone Receptor-Positive Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Adrienne G. Waks</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Dana-Farber Cancer Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research study is exploring chemotherapy in combination with immunotherapy (a therapy&#xD;
      that uses the body's own immune system to control cancer) as a possible treatment for hormone&#xD;
      receptor positive breast cancer.&#xD;
&#xD;
      The interventions involved in this study are:&#xD;
&#xD;
        -  Pembrolizumab (MK-3475; Keytruda™)&#xD;
&#xD;
        -  Nab-Paclitaxel (Abraxane&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This research study is a Pilot Study, which is the first time investigators are examining&#xD;
      this study intervention.&#xD;
&#xD;
      In this research study, the investigators are looking at how the participants body and tumor&#xD;
      respond to the combination of Nab-paclitaxel and Pembrolizumab. Also, the investigators will&#xD;
      be examining the participants tumor tissue to learn more about the disease.&#xD;
&#xD;
      The FDA (the U.S. Food and Drug Administration) has not approved Pembrolizumab for this&#xD;
      specific disease; but it has been approved in the United States for the treatment of other&#xD;
      diseases.&#xD;
&#xD;
      The FDA has not approved Nab-paclitaxel as a treatment option for this type of breast cancer;&#xD;
      but it has been approved in the United States for the treatment of metastatic breast cancer&#xD;
      (breast cancer that has spread to other parts of the body).&#xD;
&#xD;
      Pembrolizumab is a medicine that may treat cancer by working with the participant's immune&#xD;
      system. The immune system is the body's natural defense against disease. The immune system&#xD;
      sends types of cells called &quot;T cells&quot; throughout the body to detect and fight infections and&#xD;
      diseases, including cancer. For some types of cancer, the T cells do not work as they should&#xD;
      and are prevented from attacking the tumors. Pembrolizumab is thought to work by blocking a&#xD;
      protein in the T cells called PD-1 (&quot;programmed death 1&quot;), which then allows these cells and&#xD;
      other parts of the immune system to attack tumors.&#xD;
&#xD;
      Nab-paclitaxel (Abraxane) is part of a class of medications called antimicrotubule agents. It&#xD;
      works by stopping the growth and spread of cancer cells by blocking the action of proteins&#xD;
      called microtubules.&#xD;
&#xD;
      The combination of Pembrolizumab and Nab-paclitaxel is investigational. &quot;Investigational&quot;&#xD;
      means that the combination of study drugs is being studied. The study drugs, when given&#xD;
      separately, work in different ways to stop the cancer cells from growing and spreading.&#xD;
      However, it is not known if giving the two study drugs at the same time will have a better&#xD;
      anti-cancer effect than giving each treatment on its own.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">February 23, 2017</start_date>
  <completion_date type="Anticipated">January 2026</completion_date>
  <primary_completion_date type="Actual">November 20, 2022</primary_completion_date>
  <phase>Phase 1</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>Change in PD-L1 Expression By Immunohistochemistry From Baseline Biopsy to Biopsy After 2-Week Treatment (biopsy 2)</measure>
    <time_frame>2 weeks</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>The Absolute Change in PD-L1 Expression By Immunohistochemistry From Baseline Biopsy to Biopsy After Treatment with Nab-Paclitaxel or Pembrolizumab Monotherapy (biopsy 3)</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The Absolute Change in Expression of Core Immune Biomarkers (stromal TILs; PD-1; PD-L2; CD8) from Baseline Biopsy to Biopsy After 2-Week Treatment (biopsy 2)</measure>
    <time_frame>2 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The Absolute Change in Expression of Core Immune Biomarkers (stromal TILs; PD-1; PD-L2; CD8) from Baseline Biopsy to Biopsy After Treatment with Nab-Paclitaxel or Pembrolizumab Monotherapy (biopsy 3)</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum Grade Of All Treatment-Related Adverse Events</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pathologic Complete Response Rate</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease-Free Survival</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Nab-Paclitaxel</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>2 weeks Nab-Paclitaxel Run in&#xD;
Biopsy will be performed&#xD;
Post mono therapy Nab-Paclitaxel administered weekly&#xD;
Post mono therapy Pembrolizumab administered every 3 weeks&#xD;
Agents administered for a total of 15 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pembrolizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>2 weeks Pembrolizumab Run in&#xD;
Biopsy will be performed&#xD;
Post mono therapy Nab-Paclitaxel administered weekly&#xD;
Post mono therapy Pembrolizumab administered every 3 weeks&#xD;
Agents administered for a total of 14 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>Pembrolizumab will be administered in clinic every three weeks.</description>
    <arm_group_label>Nab-Paclitaxel</arm_group_label>
    <arm_group_label>Pembrolizumab</arm_group_label>
    <other_name>Keytruda</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nab-Paclitaxel</intervention_name>
    <description>Nab-Paclitaxel will be administered in clinic every week.</description>
    <arm_group_label>Nab-Paclitaxel</arm_group_label>
    <arm_group_label>Pembrolizumab</arm_group_label>
    <other_name>Abraxane</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Biopsy</intervention_name>
    <description>Biopsies for research purposes will be performed at three separate timepoints during treatment.</description>
    <arm_group_label>Nab-Paclitaxel</arm_group_label>
    <arm_group_label>Pembrolizumab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Participants must have histologically or cytologically confirmed invasive breast&#xD;
             cancer.&#xD;
&#xD;
          -  Participants must have operable breast cancer, with tumors greater than or equal to 2&#xD;
             cm in size; Participants must not have any evidence of distant metastatic disease.&#xD;
             Inflammatory breast cancer is permitted.&#xD;
&#xD;
          -  All confirmed invasive disease must have been tested for ER, PR, and HER2 and&#xD;
             participants must have hormone receptor-positive, HER2-negative breast cancer (ER&gt;1%&#xD;
             or PR&gt;1%, AND HER2-negative per ASCO CAP guidelines, 2013).&#xD;
&#xD;
          -  Participants with multicentric, multifocal, and/or contralateral cancers are allowed&#xD;
             as long as one lesion meets eligibility and no biopsied tumor is HER2+.&#xD;
&#xD;
          -  Prior systemic therapy: No prior chemotherapy, biologic therapy, hormonal therapy or&#xD;
             investigational therapy for this operable breast cancer.&#xD;
&#xD;
          -  Prior radiation therapy: No prior radiation to the ipsilateral breast.&#xD;
&#xD;
          -  The participant is ≥18 years old&#xD;
&#xD;
          -  The participant has an Eastern Cooperative Oncology Group (ECOG) performance status ≤1&#xD;
             (see Appendix A)&#xD;
&#xD;
          -  Participants must have normal organ and marrow function as defined below:&#xD;
&#xD;
               -  Absolute neutrophil count ≥1500/mm3&#xD;
&#xD;
               -  Platelets ≥100,000/mm3&#xD;
&#xD;
               -  Hemoglobin ≥9 g/dL&#xD;
&#xD;
               -  Total Bilirubin ≤1.5 mg/dL (&lt; 2.0 in participants with known Gilbert's syndrome)&#xD;
&#xD;
               -  Serum creatinine ≤1.5 mg/dL OR calculated GFR ≥60mL/min&#xD;
&#xD;
               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times&#xD;
                  the upper limit of normal.&#xD;
&#xD;
               -  International normalized ratio (INR) or Prothrombin Time (PT) &lt;1.5 times the&#xD;
                  upper limit of normal unless subject is receiving anticoagulant therapy, as long&#xD;
                  as PT or PTT is within therapeutic range of intended use of anticoagulants.&#xD;
&#xD;
               -  Activated Partial Thromboplastin Time (aPTT) &lt;1.5 times the upper limit of normal&#xD;
                  unless subject is receiving anticoagulant therapy, as long as PT or PTT is within&#xD;
                  therapeutic range of intended use of anticoagulants.&#xD;
&#xD;
          -  The participant is capable of understanding and complying with the protocol and has&#xD;
             signed the informed consent document.&#xD;
&#xD;
          -  The participant must be willing to undergo the three required research biopsies over&#xD;
             the course of protocol therapy. Participants who undergo an attempted research biopsy&#xD;
             procedure for the purpose of this protocol, and in whom inadequate tissue is obtained,&#xD;
             are not required to undergo a repeat biopsy in order to continue on protocol.&#xD;
&#xD;
          -  The effects of pembrolizumab on the developing human fetus are unknown. For this&#xD;
             reason, both women and men of child-bearing potential must agree to use adequate&#xD;
             contraception (Section 5.5.2) starting with the first dose of study therapy and for&#xD;
             the duration of study participation, through 120 days after the last dose of study&#xD;
             medication.&#xD;
&#xD;
        Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception&#xD;
        for the subject. Should a woman become pregnant or suspect she is pregnant while she or her&#xD;
        partner is participating in this study, she should inform her treating physician&#xD;
        immediately. While on the study, women may not breast-feed. Women of childbearing potential&#xD;
        are defined as those who have not been surgically sterilized or have not been free from&#xD;
        menses for &gt; 1 year.&#xD;
&#xD;
          -  Female subject of childbearing potential should have a negative urine or serum&#xD;
             pregnancy test within 72 hours prior to receiving the first dose of study medication.&#xD;
             If the urine test is positive or cannot be confirmed as negative, a serum pregnancy&#xD;
             test will be required.&#xD;
&#xD;
          -  Participants on bisphosphonates may continue receiving bisphosphonate therapy during&#xD;
             study treatment.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  The participant has received prior pembrolizumab or any other anti-PD-1, anti-PD-L1,&#xD;
             or anti-PD-L2 therapy, or has participated in any prior studies involving&#xD;
             pembrolizumab&#xD;
&#xD;
          -  Hypersensitivity to pembrolizumab or any of its excipients.&#xD;
&#xD;
          -  The participant has any history or evidence of active, non-infectious pneumonitis or&#xD;
             interstitial lung disease.&#xD;
&#xD;
          -  The participant has an uncontrolled intercurrent illness including, but not limited&#xD;
             to, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac&#xD;
             arrhythmia, congestive heart failure (New York Heart Association Class III or IV; see&#xD;
             Appendix B), active ischemic heart disease, myocardial infarction within the previous&#xD;
             six months, uncontrolled diabetes mellitus, chronic liver or renal disease, or severe&#xD;
             malnutrition.&#xD;
&#xD;
          -  Concurrent use of potent CYP3A4 inhibitors (see Appendix C), such as ketoconazole and&#xD;
             erythromycin, should be avoided during the study treatment with nab-paclitaxel.&#xD;
&#xD;
          -  Pregnant women are excluded from this study because pembrolizumab has the potential&#xD;
             for teratogenic or abortifacient effects. Because there is an unknown but potential&#xD;
             risk for adverse events in nursing infants secondary to treatment of the mother with&#xD;
             pembrolizumab, breastfeeding should be discontinued if the mother is treated with&#xD;
             pembrolizumab.&#xD;
&#xD;
          -  Active infection requiring intravenous antibiotics at week 1 day 1.&#xD;
&#xD;
          -  Individuals with a history of a second malignancy are ineligible except for the&#xD;
             following circumstances. Individuals with a history of other malignancies are eligible&#xD;
             if they have been disease-free for at least 5 years and are deemed by the investigator&#xD;
             to be at low risk for recurrence of that malignancy. Individuals with the following&#xD;
             cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer&#xD;
             in situ, and non-melanoma cancer of the skin. Participants with other cancers&#xD;
             diagnosed within the past 5 years and felt to be at low risk of recurrence should be&#xD;
             discussed with the study sponsor to determine eligibility.&#xD;
&#xD;
          -  The participant has a medical condition that requires chronic systemic steroid therapy&#xD;
             or any other form of immunosuppressive medication including disease modifying agents,&#xD;
             or has required such therapy in the last 2 years. Replacement therapy (eg., thyroxine,&#xD;
             insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary&#xD;
             insufficiency, etc.) is not considered a form of systemic treatment.&#xD;
&#xD;
          -  The participant has an active autoimmune disease or a documented history of autoimmune&#xD;
             disease or syndrome that requires systemic steroids or immunosuppressive agents.&#xD;
&#xD;
          -  The participant is known to be positive for Hepatitis B surface antigen, or Hepatitis&#xD;
             C RNA. Testing for screening is not required.&#xD;
&#xD;
          -  Known HIV-positive participants.HIV-positive patients on combination antiretroviral&#xD;
             therapy are ineligible because of the potential for pharmacokinetic interactions with&#xD;
             pembrolizumab. In addition, these participants are at increased risk of lethal&#xD;
             infections with bone marrow suppressive therapy, i.e. nab-paclitaxel. Appropriate&#xD;
             studies will be undertaken in participants receiving combination antiretroviral&#xD;
             therapy when indicated. Testing for screening is not required.&#xD;
&#xD;
          -  The participant has received a live vaccine within 28 days of planned start of study&#xD;
             therapy.&#xD;
&#xD;
          -  Seasonal influenza vaccines for infection are generally inactivated flu vaccines and&#xD;
             are allowed; however intranasal influenza vaccines (i.e. Flu-Mist ®) are live&#xD;
             attenuated vaccines, and are not allowed.&#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>Adrienne Gropper Waks, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dana-Farber Cancer Institute</affiliation>
  </overall_official>
  <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_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>December 19, 2016</study_first_submitted>
  <study_first_submitted_qc>December 20, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 21, 2016</study_first_posted>
  <last_update_submitted>December 12, 2022</last_update_submitted>
  <last_update_submitted_qc>December 12, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 13, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Dana-Farber Cancer Institute</investigator_affiliation>
    <investigator_full_name>Adrienne G. Waks</investigator_full_name>
    <investigator_title>Sponsor Investigator</investigator_title>
  </responsible_party>
  <keyword>Breast Cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Paclitaxel</mesh_term>
    <mesh_term>Pembrolizumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT02999477
org study id: 16-466
nct id: NCT02999477
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This research study is exploring chemotherapy in combination with immunotherapy (a therapy
      that uses the body's own immune system to control cancer) as a possible treatment for hormone
      receptor positive breast cancer.

      The interventions involved in this study are:

        -  Pembrolizumab (MK-3475; Keytruda™)

        -  Nab-Paclitaxel (Abraxane
This research study is a Pilot Study, which is the first time investigators are examining
      this study intervention.

      In this research study, the investigators are looking at how the participants body and tumor
      respond to the combination of Nab-paclitaxel and Pembrolizumab. Also, the investigators will
      be examining the participants tumor tissue to learn more about the disease.

      The FDA (the U.S. Food and Drug Administration) has not approved Pembrolizumab for this
      specific disease; but it has been approved in the United States for the treatment of other
      diseases.

      The FDA has not approved Nab-paclitaxel as a treatment option for this type of breast cancer;
      but it has been approved in the United States for the treatment of metastatic breast cancer
      (breast cancer that has spread to other parts of the body).

      Pembrolizumab is a medicine that may treat cancer by working with the participant's immune
      system. The immune system is the body's natural defense against disease. The immune system
      sends types of cells called "T cells" throughout the body to detect and fight infections and
      diseases, including cancer. For some types of cancer, the T cells do not work as they should
      and are prevented from attacking the tumors. Pembrolizumab is thought to work by blocking a
      protein in the T cells called PD-1 ("programmed death 1"), which then allows these cells and
      other parts of the immune system to attack tumors.

      Nab-paclitaxel (Abraxane) is part of a class of medications called antimicrotubule agents. It
      works by stopping the growth and spread of cancer cells by blocking the action of proteins
      called microtubules.

      The combination of Pembrolizumab and Nab-paclitaxel is investigational. "Investigational"
      means that the combination of study drugs is being studied. The study drugs, when given
      separately, work in different ways to stop the cancer cells from growing and spreading.
      However, it is not known if giving the two study drugs at the same time will have a better
      anti-cancer effect than giving each treatment on its own.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in PD-L1 Expression By Immunohistochemistry From Baseline Biopsy to Biopsy After 2-Week Treatment (biopsy 2)
time frame: 2 weeks
measure: The Absolute Change in PD-L1 Expression By Immunohistochemistry From Baseline Biopsy to Biopsy After Treatment with Nab-Paclitaxel or Pembrolizumab Monotherapy (biopsy 3)
time frame: 2 years
measure: The Absolute Change in Expression of Core Immune Biomarkers (stromal TILs; PD-1; PD-L2; CD8) from Baseline Biopsy to Biopsy After 2-Week Treatment (biopsy 2)
time frame: 2 weeks
measure: The Absolute Change in Expression of Core Immune Biomarkers (stromal TILs; PD-1; PD-L2; CD8) from Baseline Biopsy to Biopsy After Treatment with Nab-Paclitaxel or Pembrolizumab Monotherapy (biopsy 3)
time frame: 2 years
measure: Maximum Grade Of All Treatment-Related Adverse Events
time frame: 2 years
measure: Pathologic Complete Response Rate
time frame: 2 years
measure: Overall Response Rate
time frame: 2 years
measure: Disease-Free Survival
time frame: 2 years
arm group label: Nab-Paclitaxel
arm group type: Experimental
description: 2 weeks Nab-Paclitaxel Run in
Biopsy will be performed
Post mono therapy Nab-Paclitaxel administered weekly
Post mono therapy Pembrolizumab administered every 3 weeks
Agents administered for a total of 15 weeks
arm group label: Pembrolizumab
arm group type: Experimental
description: 2 weeks Pembrolizumab Run in
Biopsy will be performed
Post mono therapy Nab-Paclitaxel administered weekly
Post mono therapy Pembrolizumab administered every 3 weeks
Agents administered for a total of 14 weeks
intervention type: Drug
intervention name: Pembrolizumab
description: Pembrolizumab will be administered in clinic every three weeks.
arm group label: Nab-Paclitaxel
arm group label: Pembrolizumab
other name: Keytruda
intervention type: Drug
intervention name: Nab-Paclitaxel
description: Nab-Paclitaxel will be administered in clinic every week.
arm group label: Nab-Paclitaxel
arm group label: Pembrolizumab
other name: Abraxane
intervention type: Procedure
intervention name: Biopsy
description: Biopsies for research purposes will be performed at three separate timepoints during treatment.
arm group label: Nab-Paclitaxel
arm group label: Pembrolizumab
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Adrienne Gropper Waks, MD
role: Principal Investigator
affiliation: Dana-Farber Cancer Institute
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Dana-Farber Cancer Institute
investigator full name: Adrienne G. Waks
investigator title: Sponsor Investigator
mesh term: Breast Neoplasms
mesh term: Paclitaxel
mesh term: Pembrolizumab
sharing ipd: No