<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/NCT03772353</url>
  </required_header>
  <id_info>
    <org_study_id>PLEASURABLE</org_study_id>
    <nct_id>NCT03772353</nct_id>
  </id_info>
  <brief_title>Pyrotinib, Dalpiciclib(SHR6390) and Endocrine Therapy in Subjects With Dual-receptor Positive(ER+/HER2+) Advanced Breast Cancer</brief_title>
  <acronym>PLEASURABLE</acronym>
  <official_title>Pyrotinib, Dalpiciclib(SHR6390) and Endocrine Therapy in Subjects With Dual-receptor Positive(ER+/HER2+) Advanced Breast Cancer: a Multi-center Phase Ib/II Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fudan University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Jiangsu HengRui Medicine Co., Ltd.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Fudan University</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a single-center Ib / II study of triple targeted drug combination (endocrine&#xD;
      therapy，novel HER2-targeted small molecule inhibitor pyrotinib and CDK4/6 inhibitor&#xD;
      dalpiciclib(SHR6390) ) as a first or second line of therapy in patients with&#xD;
      relapsed/metastatic hormone receptor positive and HER2-positive breast cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a single-center, single arm, open-label, run-in phase Ib / roll-over phase II study&#xD;
      of endocrine therapy in combination with novel human epidermal growth factor&#xD;
      receptor-2(HER2)-targeted tyrosine kinase Inhibitor pyrotinib and cyclin-dependent kinase&#xD;
      4/6(CDK4/6) Inhibitor dalpiciclib(SHR6390) in subjects with hormone receptor(HR)+/HER2+&#xD;
      relapsed or metastatic breast cancer. The study will enroll natural postmenopausal women, or&#xD;
      women who have undergone bilateral oophorectomy.The phase Ib part of the study will determine&#xD;
      safety and tolerability of the combination of endocrine therapy, pyrotinib and dalpiciclib to&#xD;
      define that appropriate dose of dalpiciclib for phase II.Data from phase Ib showed the&#xD;
      triplet of pyrotinib, dalpiciclib, andendocrine therapy had an acceptable safety profile and&#xD;
      encouraging efficacy, potentially offering a chemotherapy-sparing treatment option for&#xD;
      patients with HER2-positive/HR-positive MBC.Once the recommended regimen has been identified,&#xD;
      subjects with the selected tumor type will be enrolled into expansion cohorts for the purpose&#xD;
      of assessing efficacy and safety of the combination treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">May 12, 2019</start_date>
  <completion_date type="Anticipated">December 10, 2025</completion_date>
  <primary_completion_date type="Anticipated">June 10, 2023</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The number of patients in the Phase 1b part of the study with any adverse events (AE).</measure>
    <time_frame>2 years</time_frame>
    <description>To measure safety and tolerability of SHR6390 used in combination with and letrozole and pyrotinib (phase Ib part) we will assess the incidence, nature and severity of all adverse events (AE) that occur on or after C1D1 of therapy, AE severities will be classified using the CTCAE criteria.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Objective response rate (ORR)</measure>
    <time_frame>12 months</time_frame>
    <description>According to recist1.1 standard, the proportion of patients whose best remission was CR or PR accounted for the total number of evaluable patients.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">59</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Dalpiciclib combined with Pyrotinib and Endocrine therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Data from phase Ib showed the triplet of pyrotinib, SHR6390, and letrozole had an acceptable safety profile and encouraging efficacy, potentially offering a chemotherapy-sparing treatment option for patients with HER2-positive/HR-positive MBC. Based on DLTs and clinical efficacy, pyrotinib 320mg/d, SHR6390 125mg/d, and letrozole 2.5mg/d was declared as RP2D. The pharmacokinetic analysis had not yielded conclusive results and would involve more samples in phase II trial.&#xD;
Dalpiciclib combined with Pyrotinib and Endocrine therapy (treatment of physician's choice: letrozole or fulvestrant) ER+/HER2+ metastatic breast cancer patients eligible for first- or second-line treatment were enrolled to receive dalpiciclib combined with pyrotinib and endocrine therapy (treatment of physician's choice: letrozole or fulvestrant)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dalpiciclib</intervention_name>
    <description>Dalpiciclib (SHR6390) is a novel small molecule inhibitor specifically targeting the CDK4/6 pathway.</description>
    <arm_group_label>Dalpiciclib combined with Pyrotinib and Endocrine therapy</arm_group_label>
    <other_name>SHR6390</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pyrotinib</intervention_name>
    <description>Pyrotinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor, showed promising anti-tumour activity and acceptable tolerability in patients with HER2+ metastatic breast cancer (MBC)</description>
    <arm_group_label>Dalpiciclib combined with Pyrotinib and Endocrine therapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Letrozole</intervention_name>
    <description>Letrozole, a third-generation aromatase inhibitor, is the principal drug used in the treatment of postmenopausal patients with both early- and advanced-stage endocrine-responsive breast cancer (BC).</description>
    <arm_group_label>Dalpiciclib combined with Pyrotinib and Endocrine therapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fulvestrant</intervention_name>
    <description>Fulvestrant is a selective oestrogen receptor (ER) degrader used in postmenopausal women with hormone receptor-positive advanced breast cancer</description>
    <arm_group_label>Dalpiciclib combined with Pyrotinib and Endocrine therapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Subjects voluntarily joined the study, signed informed consent, and had good&#xD;
             compliance.&#xD;
&#xD;
          2. Postmenopausal or premenopausal perimenopausal female patients aged ≥ 18 years and ≤&#xD;
             75 years old,Meet one of the following:&#xD;
&#xD;
               -  Previous bilateral oophorectomy, or age ≥ 60 years; or Age &lt;60, natural&#xD;
                  postmenopausal state (defined as regular months for at least 12 consecutive&#xD;
                  months After spontaneous cessation and no other pathological or physiological&#xD;
                  reasons),E2 and FSH in menopause Post-level; or&#xD;
&#xD;
               -  Pre-menopausal or perimenopausal female patients can also be included, but must&#xD;
                  be willing to receive treatment with LHRH agonists;&#xD;
&#xD;
          3. Patients with HR+/HER2+ recurrent or metastatic breast cancer confirmed by&#xD;
             histopathology&#xD;
&#xD;
               -  HER2 positivity is defined by standard of 3+ staining by immunohistochemical&#xD;
                  staining (IHC) or positive for in situ hybridization (ISH)&#xD;
&#xD;
               -  Estrogen receptor(ER) or Progesterone receptor(PR) positive is defined as the&#xD;
                  percentage of cells positive for ER or PR expression ≥ 1%&#xD;
&#xD;
               -  Local recurrence needs to be confirmed by the physician that is unresectable&#xD;
&#xD;
          4. At least one extracranial measurable lesion according to Response Evaluation Criteria&#xD;
             in Solid Tumors (RECIST) criteria version 1.1.&#xD;
&#xD;
          5. Prior treatment:&#xD;
&#xD;
               -  Previously received no more than 1 prior lines of systemic treatment with&#xD;
                  trastuzumab regimen for repetitive metastatic diabetes [including anti-HER2 ADC,&#xD;
                  subsequent meaning is the same]&#xD;
&#xD;
                    1. The early stage includes trastuzumab-containing regimen treatment， or&#xD;
                       trastuzumab-containing regimen that relapses more than 1 year after the end&#xD;
                       of adjuvant treatment, and subsequent treatment is included as the&#xD;
                       first-line anti-HER2 treatment;&#xD;
&#xD;
                    2. The first-line treatment fails with the trastuzumab-containing regimen, or&#xD;
                       the trastuzumab-containing regimen recurs during the adjuvant treatment or&#xD;
                       relapses within 1 year after the adjuvant treatment ends, the follow-up&#xD;
                       treatment will be included as the second-line anti-HER2 treatment;&#xD;
&#xD;
               -  Have not received anti-HER2 TKI treatment before or received but did not prove&#xD;
                  that the treatment failed;&#xD;
&#xD;
               -  Past endocrine therapy has not proven resistance to aromatase inhibitors&#xD;
                  (definition of resistance: recurrence during or within 1 year after treatment&#xD;
                  with adjuvant aromatase inhibitors, received aromatase inhibitors in the&#xD;
                  recurrence and metastasis stage and disease progression), follow-up Letrozole is&#xD;
                  selected for endocrine therapy. Past endocrine therapy has aromatase inhibitor&#xD;
                  resistance, and follow-up endocrine therapy is fulvestrant.&#xD;
&#xD;
          6. Eastern Cooperative Oncology Group Performance Status of 0-1.&#xD;
&#xD;
          7. Life expectancy ≥ 12 weeks.&#xD;
&#xD;
          8. Adequate function of major organs meets the following requirements (no blood&#xD;
             components and cell growth factors have been used within 14 days before&#xD;
             randomization):&#xD;
&#xD;
               -  Neutrophils ≥ 1.5×10^9/L&#xD;
&#xD;
               -  Platelets ≥ 90×10^9/L&#xD;
&#xD;
               -  Hemoglobin ≥ 90g/L&#xD;
&#xD;
               -  Total bilirubin≤ 1.5 × the upper limit of normal (ULN)&#xD;
&#xD;
               -  ALT and AST ≤ 2.5 × ULN&#xD;
&#xD;
               -  BUN and Cr ≤ 1.5 × ULN&#xD;
&#xD;
               -  Left ventricular ejection fraction (LVEF) ≥ 50%&#xD;
&#xD;
               -  QTcF(Fridericia correction) ≤ 470 ms&#xD;
&#xD;
               -  International normalized ratio(INR)≤1.5 × ULN，activated partial thromboplastin&#xD;
                  time(APTT) ≤ 1.5 × ULN&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Meningeal metastasis or active brain parenchymal metastasis. Patients with clinically&#xD;
             stable brain parenchymal metastases can be included, including asymptomatic brain&#xD;
             metastases that have not received local treatment; or patients who have previously&#xD;
             received central nervous system metastasis therapy (radiotherapy or surgery), if&#xD;
             imaging confirms that stability has been maintained for at least 4 weeks , and have&#xD;
             stopped symptomatic treatment (including hormones and mannitol, etc.) for more than 2&#xD;
             weeks&#xD;
&#xD;
          2. Previously received any CDK4/6 inhibitor treatment.&#xD;
&#xD;
          3. There are ascites, pleural effusion, pericardial effusion with clinical symptoms at&#xD;
             baseline, those who need drainage, or those who have undergone drainage of serous&#xD;
             effusion within 4 weeks before the first dose.&#xD;
&#xD;
          4. Inability to swallow, intestinal obstruction or other factors affecting the&#xD;
             administration and absorption of the drug.&#xD;
&#xD;
          5. Received systemic therapy such as chemotherapy, molecular targeted therapy or other&#xD;
             clinical trial drugs within 4 weeks before enrollment; received endocrine therapy&#xD;
             within 2 weeks before enrollment.&#xD;
&#xD;
          6. Patients with other malignant tumors within 5 years or at the same time( except for&#xD;
             cured skin basal cell carcinoma and cervical carcinoma in situ).&#xD;
&#xD;
          7. Have undergone major surgical procedures or significant trauma within 4 weeks prior to&#xD;
             randomization, or are expected to undergo major surgery.&#xD;
&#xD;
          8. Pregnant women, lactating female, or women of childbearing age who are unwilling to&#xD;
             take effective contraceptive measures.&#xD;
&#xD;
          9. Have a history of allergies to the drug components of this regimen.&#xD;
&#xD;
         10. Patients with active HBV and HCV infection; stable hepatitis B after drug treatment&#xD;
             (HBV virus copy number is higher than the upper limit of reference value) and cured&#xD;
             hepatitis C patients (HCV virus copy number exceeds the lower limit of detection&#xD;
             method).&#xD;
&#xD;
         11. History of immunodeficiency, including HIV positive, or other acquired or congenital&#xD;
             immunodeficiency disease, history of organ transplantation.&#xD;
&#xD;
         12. History of cardiac dysfunction, include(1)angina (2)clinical significant arrythmia or&#xD;
             require drug intervention (3)myocardial infarction (4)heart failure (5) other cardiac&#xD;
             dysfunction (judged by the physician); any cardiac or nephric abnormal ≥ grade 2 found&#xD;
             in screening.&#xD;
&#xD;
         13. Female patients who are pregnancy, lactation or women who are of childbearing&#xD;
             potential tested positive in baseline pregnancy test.&#xD;
&#xD;
         14. Childbearing female who refuse to accept any contraception practice.&#xD;
&#xD;
         15. Determined by the physician, any serious coexisting disease might be harmful to the&#xD;
             patient's safety or avoid the patients from accomplishing the treatment(e.g serious&#xD;
             hypertension, diabetes, thyroid dysfunction,active infection etc.).&#xD;
&#xD;
         16. History of neurological or psychiatric disorders, including epilepsy or dementia.&#xD;
&#xD;
         17. Severe infections within 4 weeks prior to first dose (eg, intravenous infusion of&#xD;
             antibiotics, antifungal or antiviral drugs according to clinical protocols), or&#xD;
             unexplained fever (T &gt; 38.3 °C ) during screening or prior to first administration.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Fudan University Shanghai Cancer Center</name>
      <address>
        <city>Shanghai</city>
        <zip>200032</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>December 10, 2018</study_first_submitted>
  <study_first_submitted_qc>December 10, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 11, 2018</study_first_posted>
  <last_update_submitted>March 5, 2023</last_update_submitted>
  <last_update_submitted_qc>March 5, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 7, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Fudan University</investigator_affiliation>
    <investigator_full_name>Xichun Hu</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>hormone receptor</keyword>
  <keyword>HER2</keyword>
  <keyword>pyrotinib</keyword>
  <keyword>CDK4/6 inhibitor</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>Letrozole</mesh_term>
    <mesh_term>Fulvestrant</mesh_term>
  </intervention_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/NCT03772353
org study id: PLEASURABLE
nct id: NCT03772353
lead sponsor: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
This is a single-center Ib / II study of triple targeted drug combination (endocrine
      therapy，novel HER2-targeted small molecule inhibitor pyrotinib and CDK4/6 inhibitor
      dalpiciclib(SHR6390) ) as a first or second line of therapy in patients with
      relapsed/metastatic hormone receptor positive and HER2-positive breast cancer.
This is a single-center, single arm, open-label, run-in phase Ib / roll-over phase II study
      of endocrine therapy in combination with novel human epidermal growth factor
      receptor-2(HER2)-targeted tyrosine kinase Inhibitor pyrotinib and cyclin-dependent kinase
      4/6(CDK4/6) Inhibitor dalpiciclib(SHR6390) in subjects with hormone receptor(HR)+/HER2+
      relapsed or metastatic breast cancer. The study will enroll natural postmenopausal women, or
      women who have undergone bilateral oophorectomy.The phase Ib part of the study will determine
      safety and tolerability of the combination of endocrine therapy, pyrotinib and dalpiciclib to
      define that appropriate dose of dalpiciclib for phase II.Data from phase Ib showed the
      triplet of pyrotinib, dalpiciclib, andendocrine therapy had an acceptable safety profile and
      encouraging efficacy, potentially offering a chemotherapy-sparing treatment option for
      patients with HER2-positive/HR-positive MBC.Once the recommended regimen has been identified,
      subjects with the selected tumor type will be enrolled into expansion cohorts for the purpose
      of assessing efficacy and safety of the combination treatment.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The number of patients in the Phase 1b part of the study with any adverse events (AE).
time frame: 2 years
description: To measure safety and tolerability of SHR6390 used in combination with and letrozole and pyrotinib (phase Ib part) we will assess the incidence, nature and severity of all adverse events (AE) that occur on or after C1D1 of therapy, AE severities will be classified using the CTCAE criteria.
measure: Objective response rate (ORR)
time frame: 12 months
description: According to recist1.1 standard, the proportion of patients whose best remission was CR or PR accounted for the total number of evaluable patients.
arm group label: Dalpiciclib combined with Pyrotinib and Endocrine therapy
arm group type: Experimental
description: Data from phase Ib showed the triplet of pyrotinib, SHR6390, and letrozole had an acceptable safety profile and encouraging efficacy, potentially offering a chemotherapy-sparing treatment option for patients with HER2-positive/HR-positive MBC. Based on DLTs and clinical efficacy, pyrotinib 320mg/d, SHR6390 125mg/d, and letrozole 2.5mg/d was declared as RP2D. The pharmacokinetic analysis had not yielded conclusive results and would involve more samples in phase II trial.
Dalpiciclib combined with Pyrotinib and Endocrine therapy (treatment of physician's choice: letrozole or fulvestrant) ER+/HER2+ metastatic breast cancer patients eligible for first- or second-line treatment were enrolled to receive dalpiciclib combined with pyrotinib and endocrine therapy (treatment of physician's choice: letrozole or fulvestrant)
intervention type: Drug
intervention name: Dalpiciclib
description: Dalpiciclib (SHR6390) is a novel small molecule inhibitor specifically targeting the CDK4/6 pathway.
arm group label: Dalpiciclib combined with Pyrotinib and Endocrine therapy
other name: SHR6390
intervention type: Drug
intervention name: Pyrotinib
description: Pyrotinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor, showed promising anti-tumour activity and acceptable tolerability in patients with HER2+ metastatic breast cancer (MBC)
arm group label: Dalpiciclib combined with Pyrotinib and Endocrine therapy
intervention type: Drug
intervention name: Letrozole
description: Letrozole, a third-generation aromatase inhibitor, is the principal drug used in the treatment of postmenopausal patients with both early- and advanced-stage endocrine-responsive breast cancer (BC).
arm group label: Dalpiciclib combined with Pyrotinib and Endocrine therapy
intervention type: Drug
intervention name: Fulvestrant
description: Fulvestrant is a selective oestrogen receptor (ER) degrader used in postmenopausal women with hormone receptor-positive advanced breast cancer
arm group label: Dalpiciclib combined with Pyrotinib and Endocrine therapy
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
facility: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Fudan University
investigator full name: Xichun Hu
investigator title: Professor
mesh term: Breast Neoplasms
mesh term: Letrozole
mesh term: Fulvestrant