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.
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.
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.
Single group
entinostat
DrugEntinostat 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
DrugPyrotinib 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
DrugPhysician-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.
Dose-Limiting Toxicity (DLT), Maximum Tolerated Dose (MTD), and Recommended Phase II Dose (RP2D) of Entinostat in Combination with Pyrotinib and Endocrine Therapy
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)
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)
AEs and SAEs are graded according to NCI CTCAE v5.0, including hematological and non-hematological toxicities.
Objective Response Rate (ORR)
ORR is defined as the proportion of participants with a best overall response of complete response (CR) or partial response (PR) based on RECIST v1.1.
Disease Control Rate (DCR)
DCR is defined as the proportion of participants with a best overall response of CR, PR, or stable disease (SD) based on RECIST v1.1.
Clinical Benefit Rate (CBR)
CBR is defined as the proportion of participants with a best overall response of CR, PR, or SD lasting for at least 6 months based on RECIST v1.1.
Duration of Response (DoR)
DoR is defined as the time from the first documented CR or PR to the first documented disease progression per RECIST v1.1 or death from any cause.
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Tianjin Medical University Cancer Institute and Hospital
Lead sponsor
Taizhou EOC Pharma Co., Ltd.
Collaborator
