Neoadjuvant Pyrotinib Versus Placebo Combined With Chemotherapy in HR-positive and HER2-low Early Breast Cancer

Study Overview
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Brief Summary
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This is a multi-center, double blind, prospective, placebo controlled, randomized phase III clinical trial to further validate the efficacy and safety of neoadjuvant pyrotinib combined with chemotherapy in HR-positive/HER2-low (IHC 2+/FISH-negative) early breast cancer

Official Title
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Neoadjuvant Pyrotinib Versus Placebo Combined With Chemotherapy in HR-positive/HER2-low (IHC 2+/FISH-negative) Early Breast Cancer: a Double Blind, Multi-center, Randomized Phase III Trial

Conditions
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Breast Cancer Invasive, Hormone-receptor-positive Breast Cancer, HER2 Low Breast Carcinoma, Early-stage Breast Cancer

Intervention / Treatment
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* Drug: Pyrotinib, epirubicin or doxorubicin, cyclophosphamide, paclitaxel
* Drug: Placebo, epirubicin or doxorubicin, cyclophosphamide, paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must participate voluntarily, sign the informed consent form, and have good compliance Aged ≥ 18 and ≤ 70 years old with ECOG PS score of 0-1 Histopathological newly diagnosed, unilateral, primary invasive breast cancer Histopathological hormone receptor-positve ( estrogen receptor and/or progesterone receptor ≥ 10% stained cells) and HER2-low (immunochemistry 2+ with fluorescent in situ hybridization negative) TNM stage-IIb/III, or TNM stage-IIa with high risk (N+, G3, G2 with Ki67 ≥ 20%) At least one evaluable target breast lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Left ventricular ejection fraction ≥ 55%, Fridericia-corrected QT interval < 450 ms in males and < 470 ms in females White blood cell count: ≥ 3.0 × 10^9/L, absolute neutrophil count: ≥ 1.5 × 10^9/L, platelet count: ≥ 100 × 10^9/L, hemoglobin: ≥ 90 g/L Aspartate aminotransferase and alanine aminotransferase: ≤ 2.5 × ULN, alkaline phosphatase: ≤ 2.5 × ULN, blood total bilirubin: ≤ 1.5 × ULN, serum creatinine: ≤ 1.5 × ULN Non-menopausal or non-surgically sterilized female patients identified as non-pregnant and non-lactating and consented to contraception both during the trial and within 6 months after the last administration of the test drug Exclusion Criteria: Metastatic BC, bilateral BC, occult BC, inflammatory BC, or with other malignant tumors Known history of hypersensitivity to the study drugs Patients who need receive other anti-tumor treatments (except for OFS) during neoadjuvant therapy as judged by the investigators With severe cardiac disease or discomfort that is not expected to tolerate treatment, including but not limited to: a) arrhythmia that requires medication or is clinically significant, or high-grade atrioventricular block, b) unstable angina, myocardial infarction, heart failure or clinically significant heart valve disease, c) poorly controlled hypertension or any heart disease unsuitable for participation in this trial as determined by the investigators Patients who participated in a clinical trial of another drug within 4 weeks prior to randomization or underwent BC-free surgery within 4 weeks or had not fully recovered after BC-free surgery Other malignancy in the past 5 years, other than cured cervical carcinoma in situ, basal or squamous cell carcinoma of skin Patients who had basic gastrointestinal diseases (especially long-term history of diarrhea or/and constipation), inability to swallow, intestinal obstruction or other factors will affect drugs administration and absorption Presence of accompanying diseases that may pose serious risks to the safety of the patient or may affect the patient's ability to complete the study (including but not limited to severe diabetes mellitus, active infection, thyroid disorders, etc.) as judged by the investigator With a history of immunodeficiency, including acquired or congenital immunodeficiencies, or a history of organ transplantation Past history of confirmed neurological or mental disorders, including epilepsy or dementia Other conditions of the subject determined by the investigator to be unsuitable for the study

Ages Eligible for Study
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Minimum Age: 17 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant pyrotinib combined with chemotherapy<br> | Drug: Pyrotinib, epirubicin or doxorubicin, cyclophosphamide, paclitaxel<br>* Pyrotinib 320 mg orally once daily, and epirubicin 90 mg/m² or doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² intravenously on day 1 for four 3-week cycles followed by paclitaxel 175 mg/m² intravenously on day 1 or four 3-week cycles.<br>|
| Placebo Comparator: Neoadjuvant chemotherapy<br> | Drug: Placebo, epirubicin or doxorubicin, cyclophosphamide, paclitaxel<br>* Placebo orally once daily, and epirubicin 90 mg/m² or doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² intravenously on day 1 for four 3-week cycles followed by paclitaxel 175 mg/m² intravenously on day 1 or four 3-week cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Residual Cancer Burden 0/1 rate as assessed by independent central review | The proportion of patients with RCB 0/I after neoadjuvant therapy according to the online Residual Cancer Burden Calculator provided by the MD Anderson Cancer Center as assessed by independent central review | Within 4 weeks after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Residual Cancer Burden 0/1 rate as assessed by local pathology review | The proportion of patients with RCB 0/I after neoadjuvant therapy according to the online Residual Cancer Burden Calculator provided by the MD Anderson Cancer Center as assessed by local pathology review | Within 4 weeks after surgery | 
| Pathological complete response rate | The proportion of patients with no residual invasive tumor cells in the breast and axillary nodes, regardless of ductal carcinoma in situ | Within 4 weeks after surgery | 
| Objective response rate | The percentage of patients who achieved a complete or partial response in breast according to the RECIST, version 1.1, based on MRI, at the end of cycle 2 neoadjuvant therapy and at the end of cycle 8 neoadjuvant therapy | Within 2 weeks of breast MR examination | 
| Breast conservation surgery rate | The proportion of patients who had successful breast conservation surgery after neoadjuvant therapy | Within 4 weeks after surgery | 
| Health-related Quality of Life 1 | The score of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (version 3) | Within 7 days before the first treatment and the end of each cycle (each cycle is 21 days) | 
| Health-related Quality of Life 2 | The score of Breast Cancer-Specific Module (QLQ-BR23) | Within 7 days before the first treatment and the end of each cycle (each cycle is 21 days) | 
| 5-year event-free survival | the time from random assignment until any relapse, unequivocal tumor progression, or any-cause death | During the 5 years after random assignment | 
| 5-year overall survival | the time from random assignment until any-cause death | During the 5 years after random assignment | 
| Safety (AEs+SAEs) | General safety will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Ovarian toxicity will be evaluated by menstrual status and FSH and E2 | from signing the informed consent form until 2 years after completion of neoadjuvant treatment | 
| Biomarkers (Immune cell subpopulations quantities) | The association between immune cell subpopulations quantities and RCB | Within 4 weeks after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pyrotintb, HER2-low EBC, neoadjuvant, HR-positive