<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/NCT04486911</url>
  </required_header>
  <id_info>
    <org_study_id>MUKDEN01</org_study_id>
    <nct_id>NCT04486911</nct_id>
  </id_info>
  <brief_title>Pyrotinib Maleate, CDK4/6 Inhibitor and Letrozole in Combination for Stage II-III TPBC: a Phase II Trial</brief_title>
  <official_title>Pyrotinib Maleate, CDK4/6 Inhibitor and Letrozole in Combination for Treatment of Stage II-III Triple-positive Breast Cancer: a Phase II Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Shengjing Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Shengjing Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The emergence of CDK4/6 inhibitors has brought hope to breast cancer patients resistant to&#xD;
      endocrine therapy. In the mouse model, pyrotinib maleate combined with CDK4/6 inhibitor&#xD;
      exhibits higher anti-tumor activity than any anti-tumor drug alone. Moreover, the toxicity of&#xD;
      the combined therapy does not increase compared with monotherapy. This provides a good&#xD;
      preclinical model for the treatment of breast cancer by pyrotinib maleate combined with&#xD;
      CDK4/6 inhibitor. Based on above, it is hypothesized that pyrotinib maleate, CDK4/6 inhibitor&#xD;
      SHR6390 and aromatase inhibitor letrozole in combination can provide a better neoadjuvant&#xD;
      strategy for stage II-III triple-positive breast cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This single-center, single-arm, open-label trial will include 89 patients with stage II-III&#xD;
      triple-positive breast cancer (Simon's two-stage design). After providing written informed&#xD;
      consent, the participants will undergo combined treatment of pyrotinib maleate, CDK4/6&#xD;
      inhibitor SHR6390, and letrozole. The effectiveness of the combined treatment will be&#xD;
      evaluated by MRI every two treatment cycles. If the disease progresses, the participant will&#xD;
      withdraw from the trial. If the combined treatment has identified effectiveness, the&#xD;
      participant will undergo surgical treatment within 4 weeks (over 2 weeks) after termination&#xD;
      of the neoadjuvant treatment. The patients will be followed up for 5 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 27, 2020</start_date>
  <completion_date type="Anticipated">December 30, 2026</completion_date>
  <primary_completion_date type="Anticipated">December 1, 2026</primary_completion_date>
  <phase>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>
    <intervention_model_description>single arm study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Total pathological complete response (tpCR)</measure>
    <time_frame>1 month to 5 years after surgery</time_frame>
    <description>tpCR is defined as the absence of residual invasive cancer on resected breast specimen and the sampled regional lymph nodes as shown by hematoxylin-eosin staining after completion of the neoadjuvant treatment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Best overall response rate (BORR)</measure>
    <time_frame>During neoadjuvant treatment (1-5 months of treatment)</time_frame>
    <description>The proportion of patients who respond to the treatment at any study time point</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Residual cancer burden (RCB)</measure>
    <time_frame>1 month to 5 years after surgery</time_frame>
    <description>RCB score is obtained according to pathological evaluation after completion of neoadjuvant treatment and surgery</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline of Functional Scales, Symptom Scales and Single Items in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30)</measure>
    <time_frame>Baseline, the end of cycle 2, cycle 4, and before the surgery</time_frame>
    <description>The EORTC QLQ-C30 included global health status, functional scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea/vomiting, and pain) and single items (dyspnoea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Most questions used a 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale [1 'very poor' to 7 'Excellent']). Scores were averaged and transformed to 0 - 100 scale, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 - 10 points considered to be a minimally important difference to participants. A positive value means an increase, while a negative value means a decrease, in score at the indicated time-point(the end of cycle 2, cycle 4, and before the surgery) relative to the score at baseline .</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline of Four Functioning Scales and Four Symptom Scales in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Breast Cancer (QLQ-BR23)</measure>
    <time_frame>Baseline, the end of cycle 2, cycle 4, and before the surgery</time_frame>
    <description>EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual enjoyment, sexual functioning, future perspective [FP]) and four symptom scales (systemic side effects [SE], upset by hair loss, arm symptoms, breast symptoms). Questions used 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Scores averaged and transformed to 0-100 scale. High score for functional scale indicated high/better level of functioning/healthy functioning. Higher scores for symptom scales represent higher levels of symptoms/problems. For functional scales, positive change from baseline indicated deterioration in quality of life (QOL) and negative change from baseline indicated an improvement in QOL. For symptom scales, positive change from baseline indicated an improvement in quality of life (QOL) and negative change from baseline indicated a deterioration in QOL.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Within 5 years after surgery</time_frame>
    <description>It refers to the length of time from the start of treatment to the death of the patient.</description>
  </other_outcome>
  <other_outcome>
    <measure>Disease-free survival (DFS)</measure>
    <time_frame>Within 5 years after surgery</time_frame>
    <description>It refers to the length of time from the start of medication after enrollment to the death of the patient because of the recurrence, distant metastasis of the disease, invasive contralateral breast cancer, or any other cause.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">89</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Pyrotinib maleate, SHR6390, letrozole</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>After providing written informed consent, the participants will undergo combined treatment of pyrotinib maleate, CDK4/6 inhibitor SHR6390, and letrozole. The effectiveness of the combined treatment will be evaluated by MRI every two treatment cycles. If the disease progresses, the participant will withdraw from the trial. If the combined treatment has identified effectiveness, the participant will undergo surgical treatment within 4 weeks (over 2 weeks) after termination of the neoadjuvant treatment. The patients will be followed up for 5 years.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pyrotinib maleate, SHR6390, letrozole</intervention_name>
    <description>After providing written informed consent, the participants will undergo combined treatment of pyrotinib maleate, CDK4/6 inhibitor SHR6390, and letrozole. The effectiveness of the combined treatment will be evaluated by MRI every two treatment cycles. If the disease progresses, the participant will withdraw from the trial. If the combined treatment has identified effectiveness, the participant will undergo surgical treatment within 4 weeks (over 2 weeks) after termination of the neoadjuvant treatment. The patients will be followed up for 5 years.</description>
    <arm_group_label>Pyrotinib maleate, SHR6390, letrozole</arm_group_label>
    <other_name>combined treatment</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  (1)Women aged &gt; 18 years and ≤ 80 years meeting one of the following conditions;&#xD;
&#xD;
               1. Those previously receiving ovariectomy, or aged ≥ 60 years&#xD;
&#xD;
               2. Those aged &lt; 60 years who have had 12 consecutive months of amenorrhoea without&#xD;
                  any pathological or physical causes, and have postmenopausal E2 and follicle&#xD;
                  stimulating hormone (FSH) levels&#xD;
&#xD;
               3. Premenopausal or perimenopausal women who are willing to receive LHRH agonist&#xD;
                  treatment during the study period&#xD;
&#xD;
          -  (2) Women who have breast cancer histopathologically confirmed by positive estrogen&#xD;
             receptor (ER; ≥ 10%), positive progesterone receptor (PR; ≥ 1%), and positive human&#xD;
             epidermal growth factor receptor 2 (HER2) according to the 2018 American Society of&#xD;
             Clinical Oncology/College of American Pathologists (ASCO/CAP) human epidermal growth&#xD;
             factor receptor 2 (HER2) guideline. ER, PR and HER2 will be assessed by&#xD;
             immunohistochemistry (IHC) on harvested tissue. ER, PR and HER2 will be considered&#xD;
             positive if the IHC result is positive (score 3+), or the IHC result is positive (2+)&#xD;
             and in situ hybridization (ISH) amplification rate (≥ 2.0);&#xD;
&#xD;
          -  (3) Women having stage II-III breast cancer diagnosed based on AJCC cancer staging&#xD;
             system (8th edition) who will be admitted because of breast cancer for the first time;&#xD;
&#xD;
          -  (4) Karnofsky Performance Status (KPS) Scale score ≥ 70;&#xD;
&#xD;
          -  (5) The functional level of organs must meet the following requirements:&#xD;
&#xD;
             a) Bone marrow function i) Absolute neutrophil count ≥ 1.5 × 109/L (no use of growth&#xD;
             factor within 14 days) ii) Platelet count ≥ 100 × 109/L (no corrective treatment&#xD;
             within 7 days) iii) Hemoglobin level ≥ 100 g/L (no corrective treatment within 7 days)&#xD;
             b) Liver and kidney function i) Total bilirubin ≤1 upper limit of normal value (ULN)&#xD;
             ii) Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 3 × ULN (ALT and AST&#xD;
             ≤ 5 × ULN in patients with liver metastasis) iii) Blood urea nitrogen (BUN) and&#xD;
             creatinine ≤ 1.5 × ULN and creatinine clearance ≥ 50 mL/min (Cockcroft-Gault formula);&#xD;
             c) Color Doppler echocardiography: Left ventricular ejection fraction ≥ 50% d) 12-lead&#xD;
             electrocardiography: QTc interval ≤ 480 ms&#xD;
&#xD;
          -  (6) Women who can undergo a biopsy;&#xD;
&#xD;
          -  (7) Volunteers to participate in the study, provision of signed informed consent, good&#xD;
             compliance and willingness to cooperate with follow-ups&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  (1) Women who have received any form of anti-tumor treatment - (chemotherapy,&#xD;
             radiotherapy, molecular targeted therapy, or endocrine therapy);&#xD;
&#xD;
          -  (2) Those who have received other anti-tumor drug treatments concurrently;&#xD;
&#xD;
          -  (3) Those who have bilateral breast cancer, inflammatory breast cancer or occult&#xD;
             breast cancer;&#xD;
&#xD;
          -  (4) Those who have stage IV breast cancer;&#xD;
&#xD;
          -  (5) Those who have breast cancer not histopathologically confirmed;&#xD;
&#xD;
          -  (6) Those who have other malignant tumors (with the exception of healed cervical&#xD;
             carcinoma in situ) occurring in the past 5 years;&#xD;
&#xD;
          -  (7) Those who have severe dysfunction of the heart, liver, kidney, and other major&#xD;
             organs;&#xD;
&#xD;
          -  (8) There are multiple factors that affect drug administration and absorption, such as&#xD;
             inability to swallow, chronic diarrhea, and intestinal obstruction;&#xD;
&#xD;
          -  (9) Those who have participated in other clinical drug trials in the past 4 weeks;&#xD;
&#xD;
          -  (10) Those who are known to have a history of allergy to the component of study drugs;&#xD;
             those who have a history of immunodeficiency, including positive detection of human&#xD;
             immunodeficiency virus, hepatitis C virus, active hepatitis B or other acquired,&#xD;
             congenital immunodeficiency diseases, or organ transplantation;&#xD;
&#xD;
          -  (11) Those who had suffered from any heart disease, including arrhythmia which&#xD;
             requires drug treatment or is of clinical significance; myocardial infarction; heart&#xD;
             failure; and any other heart disease judged by the investigator as unsuitable for this&#xD;
             trial;&#xD;
&#xD;
          -  (12) Pregnant and lactating women; fertile women who provide positive results of&#xD;
             baseline pregnancy test; women of childbearing age who are unwilling to take effective&#xD;
             contraceptive measures during the whole study period;&#xD;
&#xD;
          -  (13) If the accompanying diseases (including, but not limited to, severe hypertension,&#xD;
             severe diabetes, and active infection, which cannot be controlled by drugs) that would&#xD;
             be a potential hazard to participant's health, or affect the completion of the study&#xD;
             as per investigator's judgement;&#xD;
&#xD;
          -  (14) A clear history of neurological or psychiatric disorders, including epilepsy or&#xD;
             dementia;&#xD;
&#xD;
          -  (15) Upon the suggestion of the investigators for other reasons&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Cai-Gang Liu, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Shengjing Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Shengjing Hospital of China Medical University</name>
      <address>
        <city>Shenyang</city>
        <state>Liaoning</state>
        <zip>110004</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>July 21, 2020</study_first_submitted>
  <study_first_submitted_qc>July 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 27, 2020</study_first_posted>
  <last_update_submitted>July 30, 2022</last_update_submitted>
  <last_update_submitted_qc>July 30, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 2, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Shengjing Hospital</investigator_affiliation>
    <investigator_full_name>Caigang Liu</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>breast cancer</keyword>
  <keyword>pyrotinib maleate</keyword>
  <keyword>letrozole</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>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Findings from this study will indicate whether pyrotinib maleate, CDK4/6 inhibitor SHR6390 and letrozole for treatment of stage II-III triple-positive breast cancer is safe and effective.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_time_frame>6 months to 5 years after publication</ipd_time_frame>
    <ipd_access_criteria>Unlimited</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/NCT04486911
org study id: MUKDEN01
nct id: NCT04486911
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The emergence of CDK4/6 inhibitors has brought hope to breast cancer patients resistant to
      endocrine therapy. In the mouse model, pyrotinib maleate combined with CDK4/6 inhibitor
      exhibits higher anti-tumor activity than any anti-tumor drug alone. Moreover, the toxicity of
      the combined therapy does not increase compared with monotherapy. This provides a good
      preclinical model for the treatment of breast cancer by pyrotinib maleate combined with
      CDK4/6 inhibitor. Based on above, it is hypothesized that pyrotinib maleate, CDK4/6 inhibitor
      SHR6390 and aromatase inhibitor letrozole in combination can provide a better neoadjuvant
      strategy for stage II-III triple-positive breast cancer.
This single-center, single-arm, open-label trial will include 89 patients with stage II-III
      triple-positive breast cancer (Simon's two-stage design). After providing written informed
      consent, the participants will undergo combined treatment of pyrotinib maleate, CDK4/6
      inhibitor SHR6390, and letrozole. The effectiveness of the combined treatment will be
      evaluated by MRI every two treatment cycles. If the disease progresses, the participant will
      withdraw from the trial. If the combined treatment has identified effectiveness, the
      participant will undergo surgical treatment within 4 weeks (over 2 weeks) after termination
      of the neoadjuvant treatment. The patients will be followed up for 5 years.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: single arm study
primary purpose: Treatment
masking: None (Open Label)
measure: Total pathological complete response (tpCR)
time frame: 1 month to 5 years after surgery
description: tpCR is defined as the absence of residual invasive cancer on resected breast specimen and the sampled regional lymph nodes as shown by hematoxylin-eosin staining after completion of the neoadjuvant treatment.
measure: Best overall response rate (BORR)
time frame: During neoadjuvant treatment (1-5 months of treatment)
description: The proportion of patients who respond to the treatment at any study time point
measure: Residual cancer burden (RCB)
time frame: 1 month to 5 years after surgery
description: RCB score is obtained according to pathological evaluation after completion of neoadjuvant treatment and surgery
measure: Change From Baseline of Functional Scales, Symptom Scales and Single Items in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30)
time frame: Baseline, the end of cycle 2, cycle 4, and before the surgery
description: The EORTC QLQ-C30 included global health status, functional scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea/vomiting, and pain) and single items (dyspnoea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Most questions used a 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale [1 'very poor' to 7 'Excellent']). Scores were averaged and transformed to 0 - 100 scale, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 - 10 points considered to be a minimally important difference to participants. A positive value means an increase, while a negative value means a decrease, in score at the indicated time-point(the end of cycle 2, cycle 4, and before the surgery) relative to the score at baseline .
measure: Change From Baseline of Four Functioning Scales and Four Symptom Scales in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Breast Cancer (QLQ-BR23)
time frame: Baseline, the end of cycle 2, cycle 4, and before the surgery
description: EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual enjoyment, sexual functioning, future perspective [FP]) and four symptom scales (systemic side effects [SE], upset by hair loss, arm symptoms, breast symptoms). Questions used 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Scores averaged and transformed to 0-100 scale. High score for functional scale indicated high/better level of functioning/healthy functioning. Higher scores for symptom scales represent higher levels of symptoms/problems. For functional scales, positive change from baseline indicated deterioration in quality of life (QOL) and negative change from baseline indicated an improvement in QOL. For symptom scales, positive change from baseline indicated an improvement in quality of life (QOL) and negative change from baseline indicated a deterioration in QOL.
measure: Overall survival (OS)
time frame: Within 5 years after surgery
description: It refers to the length of time from the start of treatment to the death of the patient.
measure: Disease-free survival (DFS)
time frame: Within 5 years after surgery
description: It refers to the length of time from the start of medication after enrollment to the death of the patient because of the recurrence, distant metastasis of the disease, invasive contralateral breast cancer, or any other cause.
arm group label: Pyrotinib maleate, SHR6390, letrozole
arm group type: Experimental
description: After providing written informed consent, the participants will undergo combined treatment of pyrotinib maleate, CDK4/6 inhibitor SHR6390, and letrozole. The effectiveness of the combined treatment will be evaluated by MRI every two treatment cycles. If the disease progresses, the participant will withdraw from the trial. If the combined treatment has identified effectiveness, the participant will undergo surgical treatment within 4 weeks (over 2 weeks) after termination of the neoadjuvant treatment. The patients will be followed up for 5 years.
intervention type: Drug
intervention name: Pyrotinib maleate, SHR6390, letrozole
description: After providing written informed consent, the participants will undergo combined treatment of pyrotinib maleate, CDK4/6 inhibitor SHR6390, and letrozole. The effectiveness of the combined treatment will be evaluated by MRI every two treatment cycles. If the disease progresses, the participant will withdraw from the trial. If the combined treatment has identified effectiveness, the participant will undergo surgical treatment within 4 weeks (over 2 weeks) after termination of the neoadjuvant treatment. The patients will be followed up for 5 years.
arm group label: Pyrotinib maleate, SHR6390, letrozole
other name: combined treatment
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Cai-Gang Liu, MD
role: Principal Investigator
affiliation: Shengjing Hospital
facility: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Shengjing Hospital
investigator full name: Caigang Liu
investigator title: Professor
mesh term: Breast Neoplasms
mesh term: Letrozole
sharing ipd: Yes
ipd description: Findings from this study will indicate whether pyrotinib maleate, CDK4/6 inhibitor SHR6390 and letrozole for treatment of stage II-III triple-positive breast cancer is safe and effective.
ipd info type: Study Protocol
ipd time frame: 6 months to 5 years after publication
ipd access criteria: Unlimited