<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/NCT03281902</url>
  </required_header>
  <id_info>
    <org_study_id>MC1634</org_study_id>
    <secondary_id>NCI-2017-01479</secondary_id>
    <secondary_id>MC1634</secondary_id>
    <nct_id>NCT03281902</nct_id>
  </id_info>
  <brief_title>Genetic Analysis in Blood and Tumor Samples From Patients With Advanced or Metastatic Estrogen Receptor Positive and HER2 Negative Breast Cancer Receiving Palbociclib and Endocrine Therapy</brief_title>
  <official_title>Prospective Study to Evaluate the Role of Tumor Sequencing in Women Receiving Palbociclib for Advanced Hormone Receptor (HR)-Positive, Breast Cancer (PROMISE)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mayo Clinic</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Mayo Clinic</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research trial studies genetic profiles in blood and tumor samples from patients with&#xD;
      estrogen receptor positive and HER2 negative breast cancer that has spread to other places in&#xD;
      the body who are receiving palbociclib and endocrine therapy. Examining the genetic changes&#xD;
      associated with the cancer and comparing the genetic material from the cancer tissue with the&#xD;
      genetic material found in the blood may help doctors to develop customized treatment for&#xD;
      breast cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To identify novel genomic variants and pathways associated with baseline, as well as the&#xD;
      change in serum thymidine kinase (TK1) levels (measured pre-registration, after two cycles,&#xD;
      and at disease progression) among women with advanced hormone receptor (HR) positive breast&#xD;
      cancer treated with palbociclib and endocrine therapy (ET).&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To generate patient derived xenograft (PDX)s and organoids from tumor biopsies obtained at&#xD;
      pre-registration, at 2 months, and at disease progression, to test novel endocrine therapy&#xD;
      combinations. (PDX Aim) II. To test whether PDX engraftment is associated with progression&#xD;
      free survival. (PDX Aim) Sequencing Aims III. to describe changes in the genomic landscape of&#xD;
      HR-positive HER2-negative advanced breast cancer by comparing sequencing data&#xD;
      (deoxyribonucleic acid [DNA] and ribonucleic acid [RNA]) from preregistration archival breast&#xD;
      primary tumors (when available), with tumor biopsies obtained preregistration, after two&#xD;
      months on study, and at disease progression on palbociclib and ET.&#xD;
&#xD;
      IV. To evaluate whether genomic variants and pathways (measured using DNA and RNA sequencing&#xD;
      at pre-registration and after two months of treatment) are associated with 1) PFS; 2)&#xD;
      baseline and changes in serum TK1. (Sequencing Aim) V. To tabulate the number of patients who&#xD;
      have targetable mutations found in the preregistration tumor biopsy and to record their&#xD;
      subsequent treatment regimen following progression on palbociclib and ET. (Sequencing Aim)&#xD;
      VI. To compare and contrast the actionable genomic alterations found in cfDNA or CTC derived&#xD;
      DNA that are not found in tumor tissue. (Sequencing Aim) VII. To assess whether genetic&#xD;
      alterations known to be associated with endocrine monotherapy resistance are seen in&#xD;
      circulating tumor- DNA (ctDNA) and circulating tumor cell (CTC) derived DNA. (Sequencing Aim)&#xD;
      VIII.To determine whether use of a 3D micro cancer model, combined with sequencing data from&#xD;
      tumor biopsies, ctDNA and PDXs collected at the time of disease progression, can be used to&#xD;
      personalize future treatment options for PROMISE participants. (Sequencing Aim) IX. To&#xD;
      compare the changes in Ki67 levels (by immunohistochemistry [IHC]) and serum TK1 levels after&#xD;
      2 months of treatment. (Proliferative biomarker aim) X. To assess whether the change in Ki67&#xD;
      and serum TK1 levels after 2 months of treatment with palbociclib and ET is associated with&#xD;
      progression free survival (PFS) outcomes. (Proliferative biomarker aim) XI. To assess whether&#xD;
      high baseline serum TK1 levels (&gt; 200 Du/L) are associated with PFS outcomes. (Proliferative&#xD;
      biomarker aim) XII. To assess whether an increase in TK1 between 2 months and 12 months is&#xD;
      associated with PFS. (Proliferative biomarker aim) XIII. To assess the change in EMT marker&#xD;
      expression (e.g. Vimentin, SLUG and E-cadherin) and serum TK1 after two months of treatment&#xD;
      with palbociclib and ET. (EMT aim) XIV. To determine the association between the expression&#xD;
      of EMT markers and Ki67 levels after two months of treatment with palbociclib and ET. (EMT&#xD;
      aim) XV. To determine the association between the expression of EMT markers after two months&#xD;
      of treatment with palbociclib and ET, and PFS outcomes. (EMT aim) XVI. To assess whether&#xD;
      there is a change in the level of tumor infiltrating lymphocytes (TILs) observed in archival&#xD;
      tumor, at pre-registration, at 2 months, and at disease progression on palbociclib and ET.&#xD;
      (Immune aim) XVII. To assess the change in TILs (including CD8, PD-L1, and FOXP3) after 2&#xD;
      months of treatment with palbociclib and ET. (Immune aim) XVIII. To assess the association&#xD;
      between TILs and serum TK1 levels at preregistration, at 2 months, and at disease progression&#xD;
      on palbociclib and ET. (Immune aim) XIX. To characterize and evaluate changes in the immune&#xD;
      landscape of HR+ HER2 -MBC using serial biopsies obtained pre-registration, at 2 months, and&#xD;
      at disease progression (as well as archived primary tumor when available) using digital&#xD;
      spatial profiling (DSP) (NanoString GeoMx platform) . (Immune aim) XX. To assess, by use of&#xD;
      mass cytometry (CyTOF), whether i) peripheral blood immune markers obtained pretreatment are&#xD;
      associated with either TK1 or PFS and ii) whether the changes in peripheral blood immune&#xD;
      markers after 2 cycles of treatment are associated with changes in serum TK1 levels. (Immune&#xD;
      aim) XXI. To discover putative mechanistic connections underlying bacteria-drug interactions&#xD;
      in all patients. (Microbiome aim) XXII. To identify the biomolecular features within the gut&#xD;
      (stool) microbiome and its association with the pharmacokinetics and pharmacodynamics of&#xD;
      letrozole and palbociclib. (Microbiome aim) XXIII. To discover novel predictive biomarkers of&#xD;
      resistance to CDK4/6i and ET and/or to find biomarkers that add additional predictive power&#xD;
      to other promising biomarkers such as TK1 by performing the following: (Metabolic, proteomic&#xD;
      and lipidomic aim) XXIV. A metabolomics analysis (&gt;5,000 metabolites sampled through&#xD;
      untargeted mass spectrometry at Metabolon) of paired serum samples obtained pre-registration&#xD;
      and after 2 months on palbociclib and ET.&#xD;
&#xD;
      XXIVa. An Olink-based cytokines panel (Explore panel of 1,536 proteins) of paired serum&#xD;
      samples obtained pre-registration and after 2 months on palbociclib and ET.&#xD;
&#xD;
      XXIVb. A lipidomics analysis (platform TBC) of paired serum samples obtained pre-registration&#xD;
      and after 2 months on palbociclib and ET.&#xD;
&#xD;
      XXV. To correlate the changes in the metabolites, cytokines and lipids to the preregistration&#xD;
      genomic tumor characteristics, serial Ki67 levels and PFS outcomes. (Metabolic, proteomic and&#xD;
      lipidomic aim) XXVI. To assess the change in serum TK1 levels after 2 months, and at disease&#xD;
      progression, on palbociclib and ET, and its association with the preregistration&#xD;
      CD44high/CD24/low/ERlow cancer stem cell-like phenotype, including the following: total and&#xD;
      phosphorylated AURKA, breast cancer stemness biomarkers (CD44, CD24, ALDH1) EMT transcription&#xD;
      factors (SMAD5, SOX2), cyclin E, cyclin A and phosphorylated Retinoblastoma (Rb). (Other aim)&#xD;
      XXVII. To examine shifts in the populations of epithelial like CTCs and stem cell like CTCs&#xD;
      during the course of endocrine therapy with palbociclib. (Other aim) XXVIII. To assess CTC&#xD;
      expression of ER, HER2, and other markers of endocrine resistance. (Other aim)&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patents undergo collection of blood and stool samples at baseline, 7 days after letrozole&#xD;
      monotherapy treatment, and at completion of each cycle, urine samples at baseline and&#xD;
      completion of each cycle, and saliva samples at baseline. Patients also undergo collection of&#xD;
      blood and urine samples at disease progression. Biopsy samples are analyzed for genetic&#xD;
      profile via genome sequencing and ribonucleic acid (RNA) sequencing. Biopsy samples are also&#xD;
      used for the generation of xenograft mice model.&#xD;
&#xD;
      After completion of study, patients are followed up every 6 months for 7 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">November 13, 2017</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Actual">March 12, 2021</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Only</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Bioinformatics analysis</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Next-generation sequencing data will be used to identify variants associated with the progression free survival. Pathology analysis will also be performed.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Ki67 and TK1 changes</measure>
    <time_frame>after 2 months of treatment</time_frame>
    <description>Spearman rank correlation coefficients will be used to assess the relationship between tumor ki67 levels and serum TK1 levels prior to the start of treatment and after 2 months of treatment with palbocic.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in EMT markers (including Vimentin, SLUG and E-cadherin) and tumor infiltrating lymphocytes (TILs) (including CD8, PD-L1, and FOXP3)</measure>
    <time_frame>after 2 months of treatment</time_frame>
    <description>Wilcoxon signed rank tests will be used to assess the fold changes in EMT and TILs after 2 cycles of treatment. Benjamini-Hochberg procedure will be used to control false postive rate.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in serum TK1 levels</measure>
    <time_frame>After 2 months of treatment</time_frame>
    <description>Wilcoxon rank sum tests will be used to assess whether a given element of the CD44high/CD24/low/estrogen receptor (ER) low cancer stem cell-like phenotype differ between those whose TK1 levels fell below 200 after 2 cycles of treatment and those whose TK1 levels remained above 200 after 2 cycles of treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in phenotype of Ki67 and serum TK1 levels</measure>
    <time_frame>After 2 months of treatment</time_frame>
    <description>The parameter estimates from fitting a univariate Cox model to these data will be used to obtain an estimate of the hazard ratio and its corresponding 95% confidence interval.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Differences between those with and without a blood draw taken</measure>
    <time_frame>After 2 months of treatment</time_frame>
    <description>A Wilcoxon rank sum test will be used to assess whether baseline TK1 levels differ among those who discontinue treatment prior to the 2 month blood draw and those who do not.</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">68</enrollment>
  <condition>Advanced Breast Carcinoma</condition>
  <condition>Locally Advanced Breast Carcinoma</condition>
  <condition>Metastatic Breast Carcinoma</condition>
  <condition>Recurrent Breast Carcinoma</condition>
  <condition>Stage III Breast Cancer AJCC v7</condition>
  <condition>Stage IIIA Breast Cancer AJCC v7</condition>
  <condition>Stage IIIB Breast Cancer AJCC v7</condition>
  <condition>Stage IIIC Breast Cancer AJCC v7</condition>
  <condition>Stage IV Breast Cancer AJCC v6 and v7</condition>
  <arm_group>
    <arm_group_label>Ancillary-Correlative (genetic profile analysis)</arm_group_label>
    <description>Patents undergo collection of blood and stool samples at baseline, 7 days after letrozole monotherapy treatment, and at completion of each cycle, urine samples at baseline and completion of each cycle, and saliva samples at baseline. Patients also undergo collection of blood and urine samples at disease progression. Biopsy samples are analyzed for genetic profile via genome sequencing and RNA sequencing. Biopsy samples are also used for the generation of xenograft mice model.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Biopsy</intervention_name>
    <description>Undergo tumor biopsy</description>
    <arm_group_label>Ancillary-Correlative (genetic profile analysis)</arm_group_label>
    <other_name>BIOPSY_TYPE</other_name>
    <other_name>Bx</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Biospecimen Collection</intervention_name>
    <description>Undergo collection of blood, urine, stool, and saliva</description>
    <arm_group_label>Ancillary-Correlative (genetic profile analysis)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Ancillary-Correlative (genetic profile analysis)</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood, tissue, urine, stool, saliva&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Women who have disease that is amenable to biopsy and agree to undergo a standard of care&#xD;
        core biopsy of recurrent or metastatic breast cancer, and to collect additional core&#xD;
        samples for research purposes&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  PRE-REGISTRATION INCLUSION CRITERIA&#xD;
&#xD;
          -  Women who have disease that is amenable to biopsy and agree to undergo a standard of&#xD;
             care and /or research biopsy&#xD;
&#xD;
               -  Note: If a standard of care biopsy was recently obtained =&lt; 2 months of&#xD;
                  pre-registration, eligible patients should agree to a research biopsy of&#xD;
                  recurrent or metastatic breast cancer prior to the start of protocol treatment to&#xD;
                  collect additional core samples for research purposes&#xD;
&#xD;
          -  Patients must satisfy one of the following criteria for prior therapy:&#xD;
&#xD;
               -  First line setting: No prior endocrine therapy in the metastatic setting with no&#xD;
                  more than one prior line of chemotherapy in the advanced/metastatic setting&#xD;
&#xD;
               -  Second line setting: Progression on one prior line of endocrine based therapy&#xD;
                  monotherapy either in the adjuvant or advanced/metastatic setting; either one or&#xD;
                  two prior lines of chemotherapy in the advanced setting are allowed&#xD;
&#xD;
               -  Note: Patients receiving bisphosphonate or denosumab therapy prior to&#xD;
                  registration may continue at the same intervals used prior to study registration&#xD;
&#xD;
          -  First line therapy setting only: The intention to begin palbociclib and letrozole as&#xD;
             treatment for locally advanced or metastatic breast cancer&#xD;
&#xD;
          -  Second line therapy setting only: The intention to begin palbociclib and fulvestrant&#xD;
             as treatment for metastatic breast cancer (after progression on first line endocrine&#xD;
             therapy)&#xD;
&#xD;
               -  Note: Patients who are to receive second line endocrine therapy are allowed to&#xD;
                  remain on their most recent treatment (tamoxifen or an aromatase inhibitor during&#xD;
                  the pre-registration period as well as after registration while awaiting&#xD;
                  insurance approval for the use of palbociclib&#xD;
&#xD;
          -  Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST)&#xD;
             criteria or bone only disease are eligible.&#xD;
&#xD;
               -  Note: Those patients with both non-measurable disease and bone metastases are&#xD;
                  eligible&#xD;
&#xD;
               -  Note: Patients are not allowed to begin a new systemic anti-cancer therapy during&#xD;
                  pre-registration with the exception of bisphosphonate or denosumab; palliative&#xD;
                  radiation to lesions that will not be biopsied or used for assessing disease&#xD;
                  response (target lesions) is allowed during pre-registration&#xD;
&#xD;
          -  No current evidence of visceral crisis&#xD;
&#xD;
          -  History of central nervous system metastasis are allowed provided they have been&#xD;
             treated (i.e., surgery, radiation, and/or radiosurgery) &gt;= 12 weeks prior to&#xD;
             pre-registration and have stable neurologic function, including no requirement for&#xD;
             medication(s) to control symptoms for at least 2 weeks; Note: patients with known&#xD;
             leptomeningeal disease are not eligible&#xD;
&#xD;
          -  Women who are premenopausal must agree to begin or continue an leutinizing hormone&#xD;
             releasing hormone (LHRH) agonist (goserelin preferred)&#xD;
&#xD;
               -  NOTE: A woman is considered premenopausal if menses has occurred in the last 12&#xD;
                  months prior to preregistration and both serum and follicle stimulating hormone&#xD;
                  (FSH) levels are not in the laboratory's reference range for postmenopausal&#xD;
                  females&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status: 0, 1, or 2&#xD;
&#xD;
          -  Able to swallow oral formulation of drugs&#xD;
&#xD;
          -  Signed and dated informed consent document for study participation&#xD;
&#xD;
          -  Willing to submit tissue, blood, stool, and saliva and urine for required correlative&#xD;
             research&#xD;
&#xD;
          -  REGISTRATION INCLUSION CRITERIA&#xD;
&#xD;
          -  Histologic confirmation from the pre-registration biopsy of either locally advanced or&#xD;
             metastatic breast cancer that is ER-positive and HER2 -negative&#xD;
&#xD;
               -  Note: ER-positive disease is defined as &gt;= 10% nuclear staining; HER2-negative&#xD;
                  disease per American Society of Clinical Oncology/College of American&#xD;
                  Pathologists (ASCO/CAP) guidelines, one of the following must apply:&#xD;
&#xD;
                    -  0 or 1+ by immunohistochemistry (IHC) and not amplified by in situ&#xD;
                       hybridization (ISH)&#xD;
&#xD;
                    -  0 or 1+ by IHC and ISH not done&#xD;
&#xD;
                    -  2+ by IHC and not amplified by ISH or&#xD;
&#xD;
                    -  IHC not done and not amplified by ISH&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1500/mm^3 (=&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Platelet count &gt;= 100,000/mm^3 (=&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Hemoglobin &gt;= 9.0 g/dL (=&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 x upper limit of normal (ULN), (=&lt; 3 x ULN if Gilbert's&#xD;
             disease) (=&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Aspartate transaminase (AST) =&lt; 3 x ULN (=&lt; 5 x ULN if liver metastases present) (=&lt;&#xD;
             14 days prior to registration)&#xD;
&#xD;
          -  Creatinine =&lt; 1.5 x ULN (=&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Willing to return to enrolling institution for follow-up (during the active monitoring&#xD;
             phase of the study)&#xD;
&#xD;
          -  Toxicities related to all prior anticancer therapies must have resolved or stabilized,&#xD;
             apart from alopecia and peripheral neuropathy; Note: Peripheral neuropathy which has&#xD;
             resolved to =&lt; grade 2 toxicity is acceptable&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  PRE-REGISTRATION EXCLUSION CRITERIA&#xD;
&#xD;
          -  History of metastatic ER negative or HER2 positive breast cancer&#xD;
&#xD;
          -  Prior treatment in the metastatic setting with everolimus, or any agent whose&#xD;
             mechanism of action is to inhibit the PI3K-mTOR pathway&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to:&#xD;
&#xD;
               -  Ongoing or active infection&#xD;
&#xD;
               -  Symptomatic congestive heart failure&#xD;
&#xD;
               -  Unstable angina pectoris&#xD;
&#xD;
               -  Uncontrolled symptomatic cardiac arrhythmia&#xD;
&#xD;
               -  Uncontrolled hypertension (defined as blood pressure &gt; 160/90)&#xD;
&#xD;
          -  Other active second malignancy other than non-melanoma skin cancers =&lt; 3 years of&#xD;
             pre-registration; Note: a second malignancy is not considered active if all treatment&#xD;
             for that malignancy is completed and the patient has been disease-free for =&lt; 3 years&#xD;
             prior to pre-registration&#xD;
&#xD;
          -  Prior hematopoietic stem cell or bone marrow transplantation =&lt; 3 years of&#xD;
             pre-registration&#xD;
&#xD;
          -  Known hypersensitivity to palbociclib, letrozole, fulvestrant, goserelin (if&#xD;
             applicable) or to any of their excipients&#xD;
&#xD;
          -  Known to be pregnant and planning to continue nursing&#xD;
&#xD;
          -  REGISTRATION EXCLUSION CRITERIA&#xD;
&#xD;
          -  No tumor identified on biopsy or insufficient tumor cells to obtain ER or HER2 status&#xD;
&#xD;
          -  Any of the following therapies prior to registration:&#xD;
&#xD;
               -  Chemotherapy =&lt; 2 weeks&#xD;
&#xD;
               -  Immunotherapy =&lt; 2 weeks&#xD;
&#xD;
               -  Biologic therapy =&lt; 2 weeks&#xD;
&#xD;
               -  Monoclonal antibodies =&lt; 2 weeks&#xD;
&#xD;
                    -  Note: Denosumab is exempt from this requirement and can be started at any&#xD;
                       time prior to initiation of palbociclib and letrozole/fulvestrant without&#xD;
                       the need to delay protocol therapy&#xD;
&#xD;
               -  Radiation therapy =&lt; 2 weeks&#xD;
&#xD;
                    -  Note: Palliative radiation therapy to lesions that will not be biopsied for&#xD;
                       this study or used for assessing disease response (target lesions) is&#xD;
                       permitted during the pre-registration period and does not count towards the&#xD;
                       2 week window&#xD;
&#xD;
               -  Anti HER2 or other &quot;targeted&quot; therapy =&lt; 2 weeks&#xD;
&#xD;
          -  The following patients are not eligible&#xD;
&#xD;
               -  Pregnant women&#xD;
&#xD;
               -  Nursing women&#xD;
&#xD;
               -  Women of childbearing potential who are unwilling to employ adequate&#xD;
                  contraception&#xD;
&#xD;
               -  Women who have already commenced treatment with an aromatase inhibitor (first&#xD;
                  line setting) or fulvestrant (second line setting) prior to screening for this&#xD;
                  study or any prior palbociclib&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ciara C O'Sullivan</last_name>
    <role>Principal Investigator</role>
    <affiliation>Mayo Clinic in Rochester</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Mayo Clinic in Arizona</name>
      <address>
        <city>Scottsdale</city>
        <state>Arizona</state>
        <zip>85259</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic in Florida</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>32224-9980</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic in Rochester</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>September 7, 2017</study_first_submitted>
  <study_first_submitted_qc>September 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 13, 2017</study_first_posted>
  <last_update_submitted>June 16, 2023</last_update_submitted>
  <last_update_submitted_qc>June 16, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <!-- 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/NCT03281902
org study id: MC1634
secondary id: NCI-2017-01479
secondary id: MC1634
nct id: NCT03281902
lead sponsor: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
is us export: No
This research trial studies genetic profiles in blood and tumor samples from patients with
      estrogen receptor positive and HER2 negative breast cancer that has spread to other places in
      the body who are receiving palbociclib and endocrine therapy. Examining the genetic changes
      associated with the cancer and comparing the genetic material from the cancer tissue with the
      genetic material found in the blood may help doctors to develop customized treatment for
      breast cancer.
PRIMARY OBJECTIVES:

      I. To identify novel genomic variants and pathways associated with baseline, as well as the
      change in serum thymidine kinase (TK1) levels (measured pre-registration, after two cycles,
      and at disease progression) among women with advanced hormone receptor (HR) positive breast
      cancer treated with palbociclib and endocrine therapy (ET).

      SECONDARY OBJECTIVES:

      I. To generate patient derived xenograft (PDX)s and organoids from tumor biopsies obtained at
      pre-registration, at 2 months, and at disease progression, to test novel endocrine therapy
      combinations. (PDX Aim) II. To test whether PDX engraftment is associated with progression
      free survival. (PDX Aim) Sequencing Aims III. to describe changes in the genomic landscape of
      HR-positive HER2-negative advanced breast cancer by comparing sequencing data
      (deoxyribonucleic acid [DNA] and ribonucleic acid [RNA]) from preregistration archival breast
      primary tumors (when available), with tumor biopsies obtained preregistration, after two
      months on study, and at disease progression on palbociclib and ET.

      IV. To evaluate whether genomic variants and pathways (measured using DNA and RNA sequencing
      at pre-registration and after two months of treatment) are associated with 1) PFS; 2)
      baseline and changes in serum TK1. (Sequencing Aim) V. To tabulate the number of patients who
      have targetable mutations found in the preregistration tumor biopsy and to record their
      subsequent treatment regimen following progression on palbociclib and ET. (Sequencing Aim)
      VI. To compare and contrast the actionable genomic alterations found in cfDNA or CTC derived
      DNA that are not found in tumor tissue. (Sequencing Aim) VII. To assess whether genetic
      alterations known to be associated with endocrine monotherapy resistance are seen in
      circulating tumor- DNA (ctDNA) and circulating tumor cell (CTC) derived DNA. (Sequencing Aim)
      VIII.To determine whether use of a 3D micro cancer model, combined with sequencing data from
      tumor biopsies, ctDNA and PDXs collected at the time of disease progression, can be used to
      personalize future treatment options for PROMISE participants. (Sequencing Aim) IX. To
      compare the changes in Ki67 levels (by immunohistochemistry [IHC]) and serum TK1 levels after
      2 months of treatment. (Proliferative biomarker aim) X. To assess whether the change in Ki67
      and serum TK1 levels after 2 months of treatment with palbociclib and ET is associated with
      progression free survival (PFS) outcomes. (Proliferative biomarker aim) XI. To assess whether
      high baseline serum TK1 levels (> 200 Du/L) are associated with PFS outcomes. (Proliferative
      biomarker aim) XII. To assess whether an increase in TK1 between 2 months and 12 months is
      associated with PFS. (Proliferative biomarker aim) XIII. To assess the change in EMT marker
      expression (e.g. Vimentin, SLUG and E-cadherin) and serum TK1 after two months of treatment
      with palbociclib and ET. (EMT aim) XIV. To determine the association between the expression
      of EMT markers and Ki67 levels after two months of treatment with palbociclib and ET. (EMT
      aim) XV. To determine the association between the expression of EMT markers after two months
      of treatment with palbociclib and ET, and PFS outcomes. (EMT aim) XVI. To assess whether
      there is a change in the level of tumor infiltrating lymphocytes (TILs) observed in archival
      tumor, at pre-registration, at 2 months, and at disease progression on palbociclib and ET.
      (Immune aim) XVII. To assess the change in TILs (including CD8, PD-L1, and FOXP3) after 2
      months of treatment with palbociclib and ET. (Immune aim) XVIII. To assess the association
      between TILs and serum TK1 levels at preregistration, at 2 months, and at disease progression
      on palbociclib and ET. (Immune aim) XIX. To characterize and evaluate changes in the immune
      landscape of HR+ HER2 -MBC using serial biopsies obtained pre-registration, at 2 months, and
      at disease progression (as well as archived primary tumor when available) using digital
      spatial profiling (DSP) (NanoString GeoMx platform) . (Immune aim) XX. To assess, by use of
      mass cytometry (CyTOF), whether i) peripheral blood immune markers obtained pretreatment are
      associated with either TK1 or PFS and ii) whether the changes in peripheral blood immune
      markers after 2 cycles of treatment are associated with changes in serum TK1 levels. (Immune
      aim) XXI. To discover putative mechanistic connections underlying bacteria-drug interactions
      in all patients. (Microbiome aim) XXII. To identify the biomolecular features within the gut
      (stool) microbiome and its association with the pharmacokinetics and pharmacodynamics of
      letrozole and palbociclib. (Microbiome aim) XXIII. To discover novel predictive biomarkers of
      resistance to CDK4/6i and ET and/or to find biomarkers that add additional predictive power
      to other promising biomarkers such as TK1 by performing the following: (Metabolic, proteomic
      and lipidomic aim) XXIV. A metabolomics analysis (>5,000 metabolites sampled through
      untargeted mass spectrometry at Metabolon) of paired serum samples obtained pre-registration
      and after 2 months on palbociclib and ET.

      XXIVa. An Olink-based cytokines panel (Explore panel of 1,536 proteins) of paired serum
      samples obtained pre-registration and after 2 months on palbociclib and ET.

      XXIVb. A lipidomics analysis (platform TBC) of paired serum samples obtained pre-registration
      and after 2 months on palbociclib and ET.

      XXV. To correlate the changes in the metabolites, cytokines and lipids to the preregistration
      genomic tumor characteristics, serial Ki67 levels and PFS outcomes. (Metabolic, proteomic and
      lipidomic aim) XXVI. To assess the change in serum TK1 levels after 2 months, and at disease
      progression, on palbociclib and ET, and its association with the preregistration
      CD44high/CD24/low/ERlow cancer stem cell-like phenotype, including the following: total and
      phosphorylated AURKA, breast cancer stemness biomarkers (CD44, CD24, ALDH1) EMT transcription
      factors (SMAD5, SOX2), cyclin E, cyclin A and phosphorylated Retinoblastoma (Rb). (Other aim)
      XXVII. To examine shifts in the populations of epithelial like CTCs and stem cell like CTCs
      during the course of endocrine therapy with palbociclib. (Other aim) XXVIII. To assess CTC
      expression of ER, HER2, and other markers of endocrine resistance. (Other aim)

      OUTLINE:

      Patents undergo collection of blood and stool samples at baseline, 7 days after letrozole
      monotherapy treatment, and at completion of each cycle, urine samples at baseline and
      completion of each cycle, and saliva samples at baseline. Patients also undergo collection of
      blood and urine samples at disease progression. Biopsy samples are analyzed for genetic
      profile via genome sequencing and ribonucleic acid (RNA) sequencing. Biopsy samples are also
      used for the generation of xenograft mice model.

      After completion of study, patients are followed up every 6 months for 7 years.
observational model: Case-Only
time perspective: Prospective
measure: Bioinformatics analysis
time frame: Up to 3 years
description: Next-generation sequencing data will be used to identify variants associated with the progression free survival. Pathology analysis will also be performed.
measure: Ki67 and TK1 changes
time frame: after 2 months of treatment
description: Spearman rank correlation coefficients will be used to assess the relationship between tumor ki67 levels and serum TK1 levels prior to the start of treatment and after 2 months of treatment with palbocic.
measure: Changes in EMT markers (including Vimentin, SLUG and E-cadherin) and tumor infiltrating lymphocytes (TILs) (including CD8, PD-L1, and FOXP3)
time frame: after 2 months of treatment
description: Wilcoxon signed rank tests will be used to assess the fold changes in EMT and TILs after 2 cycles of treatment. Benjamini-Hochberg procedure will be used to control false postive rate.
measure: Changes in serum TK1 levels
time frame: After 2 months of treatment
description: Wilcoxon rank sum tests will be used to assess whether a given element of the CD44high/CD24/low/estrogen receptor (ER) low cancer stem cell-like phenotype differ between those whose TK1 levels fell below 200 after 2 cycles of treatment and those whose TK1 levels remained above 200 after 2 cycles of treatment.
measure: Change in phenotype of Ki67 and serum TK1 levels
time frame: After 2 months of treatment
description: The parameter estimates from fitting a univariate Cox model to these data will be used to obtain an estimate of the hazard ratio and its corresponding 95% confidence interval.
measure: Differences between those with and without a blood draw taken
time frame: After 2 months of treatment
description: A Wilcoxon rank sum test will be used to assess whether baseline TK1 levels differ among those who discontinue treatment prior to the 2 month blood draw and those who do not.
arm group label: Ancillary-Correlative (genetic profile analysis)
description: Patents undergo collection of blood and stool samples at baseline, 7 days after letrozole monotherapy treatment, and at completion of each cycle, urine samples at baseline and completion of each cycle, and saliva samples at baseline. Patients also undergo collection of blood and urine samples at disease progression. Biopsy samples are analyzed for genetic profile via genome sequencing and RNA sequencing. Biopsy samples are also used for the generation of xenograft mice model.
intervention type: Procedure
intervention name: Biopsy
description: Undergo tumor biopsy
arm group label: Ancillary-Correlative (genetic profile analysis)
other name: BIOPSY_TYPE
other name: Bx
intervention type: Procedure
intervention name: Biospecimen Collection
description: Undergo collection of blood, urine, stool, and saliva
arm group label: Ancillary-Correlative (genetic profile analysis)
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Ancillary-Correlative (genetic profile analysis)
Blood, tissue, urine, stool, saliva
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ciara C O'Sullivan
role: Principal Investigator
affiliation: Mayo Clinic in Rochester
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Breast Neoplasms