entinostat: Entinostat is an oral, selective class I histone deacetylase (HDAC) inhibitor, administered at 3 mg, 4 mg, or 5 mg once weekly on Days 1, 8, 15, and 22 of each 28-day cycle, taken 60 minutes after a meal. The dose is determined by the 3+3 dose-escalation design in Part Ib.
Pyrotinib: Pyrotinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor, administered at a fixed dose of 400 mg once daily, taken 30 minutes after a meal, in each 28-day cycle.
endocrine therapy: Physician-selected endocrine therapy based on patient's prior treatment history and menopausal status. Options include tamoxifen (20 mg daily), aromatase inhibitors (letrozole 2.5 mg daily, anastrozole 1 mg daily, or exemestane 25 mg daily), or fulvestrant (500 mg intramuscularly on Days 1, 15, 29, and once monthly thereafter). For premenopausal patients, ovarian function suppression (OFS) with GnRH agonists is added. All endocrine agents are administered according to their approved package inserts.
Study summary
This is an open-label, single-center, exploratory, Phase Ib/II clinical trial evaluating the safety and efficacy of entinostat combined with pyrotinib and endocrine therapy in patients with advanced hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-positive (HER2+) breast cancer who have failed prior trastuzumab-based therapy.
The study consists of two parts: Part I (Phase Ib) employs a 3+3 dose-escalation design to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended Phase II dose (RP2D) of entinostat when given in combination with pyrotinib (400 mg daily) and endocrine therapy. Part II (Phase II) uses a Simon two-stage design to further evaluate the efficacy and safety of the combination at the RP2D. The primary efficacy endpoint is progression-free survival (PFS) based on RECIST v1.1. A total of approximately 79-94 participants will be enrolled.
Eligibility
Sex
FEMALE
Min age
18 Years
Max age
75 Years
Healthy volunteers
No
Inclusion Criteria:
1. Age ≥ 18 and ≤ 75 years, female, premenopausal or postmenopausal.
2. Histologically confirmed HR+/HER2+ breast cancer (HER2 positive defined as IHC 3+ or FISH confirmed by the pathology department of the study center).
3. Histologically confirmed locally advanced breast cancer (not amenable to curative local therapy) or recurrent/metastatic breast cancer.
4. Prior treatment with trastuzumab and taxane-based anticancer therapy.
5. Received 1-2 prior lines of systemic anticancer therapy in the advanced setting.
6. Life expectancy ≥ 3 months.
7. At least one measurable lesion per RECIST v1.1.
8. ECOG performance status 0-2.
9. 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.
10. Adequate bone marrow function: ANC ≥ 1.5×10\^9/L, platelet ≥ 100×10\^9/L, hemoglobin ≥ 90 g/L.
11. 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.
12. Voluntarily participate and sign written informed consent. -
Exclusion Criteria:
1. Factors significantly affecting oral drug absorption, such as inability to swallow, chronic diarrhea, or intestinal obstruction.
2. Prior treatment with any HDAC inhibitor for antitumor therapy.
3. Prior or current use of any HER2-targeted tyrosine kinase inhibitor (including lapatinib, neratinib, pyrotinib, etc.).
4. Known allergy to any component of the study drugs.
5. 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.
6. Participation in another drug clinical trial within 4 weeks prior to enrollment.
7. History of immunodeficiency, including HIV positivity, other acquired or congenital immunodeficiency diseases, or history of organ transplantation.
8. 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.
9. 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.
10. 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).
11. Known history of neurological or psychiatric disorders, including epilepsy or dementia.
12. Active hepatitis (HBV: HBsAg positive with HBV DNA ≥ 500 IU/mL; HCV: HCV antibody positive with HCV RNA \> ULN).
13. Any condition that, in the investigator's judgment, makes the patient unsuitable for study participation.
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Primary outcome measure(s)
Dose-Limiting Toxicity (DLT), Maximum Tolerated Dose (MTD), and Recommended Phase II Dose (RP2D) of Entinostat in Combination with Pyrotinib and Endocrine Therapy — Cycle 1 (Day 1 to Day 28) DLT is assessed during the first 28-day cycle. MTD and RP2D are determined based on the 3+3 dose-escalation design.
Progression-Free Survival (PFS) — From first dose to disease progression or death, assessed up to 36 months PFS is defined as the time from the first dose of study treatment to the first documented disease progression per RECIST v1.1 or death from any cause, whichever occurs first.
Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) — From signing of informed consent through 28 days after the last dose of study treatment AEs and SAEs are graded according to NCI CTCAE v5.0, including hematological and non-hematological toxicities.
Trial sites (1)
Facility
City
Region
Status
Tianjin Medical University Cancer Institute and Hospital
Tianjin
Tianjin Municipality
Recruiting
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This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.
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