Entinostat Plus Pyrotinib and Endocrine Therapy in Advanced Triple-Positive Breast Cancer After Trastuzumab Failure

Background: Triple-positive breast cancer (TPBC), characterized by co-expression of HR and HER2, accounts for approximately 10% of all breast cancer cases. Despite the availability of anti-HER2 targeted therapies, patients with TPBC often have suboptimal responses to chemotherapy-containing regimens, and endocrine therapy resistance remains a clinical challenge. Histone deacetylase (HDAC) inhibitors have shown synergistic effects with HER2-targeted agents and endocrine therapy through epigenetic modulation, potentially reversing drug resistance and enhancing anti-tumor immunity.

Objective: To explore the DLT, MTD, and RP2D of entinostat in combination with pyrotinib and endocrine therapy, and to preliminarily evaluate the safety and efficacy of this regimen in HR+/HER2+ advanced breast cancer patients who have failed trastuzumab therapy.

Study Design: This is a two-part study. Part I (Phase Ib) is a single-arm, open-label, dose-escalation trial following the traditional 3+3 design. Entinostat is administered at escalating doses (3 mg, 4 mg, and 5 mg) once weekly, in combination with a fixed dose of pyrotinib (400 mg daily) and physician-selected endocrine therapy, in 28-day cycles. The DLT observation period is the first cycle.

Part II (Phase II) is a single-arm, two-stage (Simon's optimal design) trial. Participants will receive entinostat at the MTD/RP2D established in Part I, combined with pyrotinib (400 mg daily) and endocrine therapy. A total of 76 evaluable participants are planned for Part II, with an interim analysis after the first 24 participants. The study is expected to enroll approximately 79-94 participants over 24 months, with an additional 12 months of follow-up.

Key Eligibility: Female patients aged 18-75 years with histologically confirmed HR+/HER2+ locally advanced or metastatic breast cancer, who have received prior trastuzumab and taxane therapy, with 1-2 prior lines of systemic therapy in the advanced setting, ECOG PS 0-2, and measurable disease per RECIST v1.1.

Statistical Methods: PFS will be estimated using the Kaplan-Meier method. ORR, DCR, CBR, DoR, and PRO will be summarized with descriptive statistics and 95% confidence intervals. Safety data will be tabulated by type, severity, and relationship to study drugs.

Inclusion criteria

• Age ≥ 18 and ≤ 75 years, female, premenopausal or postmenopausal.
• Histologically confirmed HR+/HER2+ breast cancer (HER2 positive defined as IHC 3+ or FISH confirmed by the pathology department of the study center).
• Histologically confirmed locally advanced breast cancer (not amenable to curative local therapy) or recurrent/metastatic breast cancer.
• Prior treatment with trastuzumab and taxane-based anticancer therapy.
• Received 1-2 prior lines of systemic anticancer therapy in the advanced setting.
• Life expectancy ≥ 3 months.
• At least one measurable lesion per RECIST v1.1.
• ECOG performance status 0-2.
• All acute toxicities from prior anticancer therapy resolved to Grade 0-1 (per NCI CTCAE v5.0), except alopecia and toxicities deemed by the investigator to pose no safety risk.
• Adequate bone marrow function: ANC ≥ 1.5×10^9/L, platelet ≥ 100×10^9/L, hemoglobin ≥ 90 g/L.
• Adequate hepatic and renal function: TBIL ≤ 1.5×ULN; ALT and AST ≤ 2.5×ULN (or ≤ 5×ULN in the presence of liver metastases); BUN and Cr ≤ 1.5×ULN with creatinine clearance ≥ 50 mL/min.
• Voluntarily participate and sign written informed consent. -

Exclusion criteria

• Factors significantly affecting oral drug absorption, such as inability to swallow, chronic diarrhea, or intestinal obstruction.
• Prior treatment with any HDAC inhibitor for antitumor therapy.
• Prior or current use of any HER2-targeted tyrosine kinase inhibitor (including lapatinib, neratinib, pyrotinib, etc.).
• Known allergy to any component of the study drugs.
• Other malignancy within 5 years prior to enrollment, except cured papillary thyroid carcinoma, cervical carcinoma in situ, basal cell carcinoma, or squamous cell carcinoma of the skin.
• Participation in another drug clinical trial within 4 weeks prior to enrollment.
• History of immunodeficiency, including HIV positivity, other acquired or congenital immunodeficiency diseases, or history of organ transplantation.
• Uncontrolled significant cardiovascular disease: clinically significant QTc interval prolongation or QTc > 450 ms at screening; severe cardiac impairment (NYHA > Class II); unstable angina or myocardial infarction within 6 months; or severe arrhythmia.
• Pregnant or lactating women, or positive pregnancy test at baseline; or women of childbearing potential who are unwilling to use effective contraception during the study and for at least 8 weeks after the last dose.
• Concomitant diseases that, in the investigator's judgment, could seriously endanger patient safety or affect study completion (e.g., severe hypertension, diabetes, thyroid disease, active infection).
• Known history of neurological or psychiatric disorders, including epilepsy or dementia.
• Active hepatitis (HBV: HBsAg positive with HBV DNA ≥ 500 IU/mL; HCV: HCV antibody positive with HCV RNA > ULN).
• Any condition that, in the investigator's judgment, makes the patient unsuitable for study participation.

-