The Dosing Regimen of Pyrotinib in HER2-positive Advanced First-line Breast Cancer: a Phase I Clinical Study

This study is planned to include 200 patients with HER2-positive advanced breast cancer meeting the admission criteria between 2024-11-01 and 2026-11-01. Statistical software will be used by the randomization officers for 1:1 allocation to pyrotinib 320mg in combination with trastuzumab and paclitaxel chemotherapy group and pyrotinib 400mg in combination with trastuzumab and paclitaxel chemotherapy group.

Inclusion criteria

• The subjects voluntarily joins the study and signs the informed consent;
• Subject is an adult female or male ≥ 18 years old and ≤ 75 years old at the time of informed consent;
• HER2-positive advanced breast cancer confirmed by pathology:HER2-positive was defined as >10% of immunoreactive cells with an immunohistochemical (IHC) score of 3+ or HER2 gene amplification as a result of in situ hybridization (ISH). HER2 positivity should be verified by the pathology department of the research center;
• Recurrent or metastatic breast cancer; Patients with local recurrence had to be confirmed by the investigator as not amenable to curative resection;
• At least one measurable lesion or only bone metastases according to RECIST v1.1 criteria (including osteolytic lesions or mixed osteolytic/osteoblastic lesions);
• When randomized, Eastern Cooperative Oncology Group(ECGO) physical fitness status is 0 or 1 point;
• Vital organ function meets the following requirements (excluding the use of any blood components and cell growth factors during screening) : Absolute neutrophil (ANC) count ≥1.5×109/L; Platelet (PLT) ≥100×109/L; Hemoglobin (HB) ≥9g/dL; Total Bilirubin(TBIL) ≤ULN((Known patients with Gilbert's syndrome:Total Bilirubin(TBIL) ≤2×ULN);Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤1.5×ULN(Patients with liver metastasis:ALT and AST≤5×ULN); Alkaline phosphatase (AKP) ≤ 2.5 times ULN; Blood Urea Nitrogen and Serum creatinine (Cr) ≤1.5×ULN;Left Ventricular Ejection Fractions(LVEF)≥50%;Corrected QT Interval(QTcF)<470msec.

Exclusion criteria

• The patient has received any systemic antitumor therapy at the stage of recurrence/metastasis, including any agents targeting EGFR or HER2, systemic chemotherapy, immunotherapy, and more than first-line endocrine therapy, as well as other antitumor therapies deemed by the investigators to be excluded;
• Tyrosine kinase inhibitor (TKI) preparations or macromolecular antibodies against HER have been used at any stage of breast cancer, except for trastuzumab in the (new) adjuvant stage;
• In the stage of breast cancer (new) adjuvant therapy, the time interval from the end of systemic therapy (except endocrine therapy) to the discovery of recurrence/metastasis is <12 months;
• Patients with active brain metastases with pial metastases confirmed by MRI or lumbar puncture (brain metastases requiring mannitol treatment or with symptoms);
• Grade≥ 3 peripheral neuropathy according to CTCAE4.0.3 criteria;
• Patients judged by the investigators to be unsuitable for systematic chemotherapy;
• Use of endocrine therapy drugs within 7 days prior to randomization;
• Patients with other malignancies within the previous 5 years, excluding cured cervical carcinoma in situ, skin basal cell carcinoma, or squamous cell carcinoma (patients with other malignancies occurring more than 5 years after randomization, such as those cured only by surgery, are allowed to be included);
• Had a major surgical procedure or significant trauma within 4 weeks prior to randomization, or was expected to undergo major surgery;
• Serious heart disease or discomfort, including but not limited to the following:

Previous history of heart failure or systolic dysfunction (LVEF<50%) High-risk or treatment-requiring angina pectoris or arrhythmias (e.g., second-degree type 2 atrioventricular block or third-degree atrioventricular block, ventricular tachycardia) Clinically significant valvular heart disease ECG showed transmural myocardial infarction Poor hypertension control (systolic blood pressure >150mmHg and/or diastolic blood pressure >100mmHg);

• Inability to swallow, chronic diarrhea, intestinal obstruction, or other factors affecting the administration and absorption of medications;
• Known allergic history of the drug components of this protocol;
• A history of immunodeficiency, including HIV infection, or other acquired, congenital immunodeficiency diseases, or a history of organ transplantation;
• Presence of third-space fluid accumulation that cannot be controlled by drainage or other methods (e.g., pleural fluid and ascites);
• Pregnant and lactating female subjects, or fertile subjects who were unwilling to use effective contraception throughout the trial period and within 3 months after the last study dose;
• Have a serious concomitant disease or other co-medical condition that interferes with planned treatment or any other condition that is not suitable for participation in this study, such as active hepatitis B, a lung infection requiring treatment.