Dalpiciclib With or Without Entinostat and Letrozole in HR+/HER2- Early Breast Cancer

An Open-Label, Randomized, Phase II Study of Dalpiciclib in Combination With Entinostat and Letrozole Versus Dalpiciclib Plus Letrozole as Neoadjuvant Therapy in Patients With HR-positive, HER2-negative Early Breast Cancer

Brief Summary This is an open-label, randomized, phase II clinical study designed to evaluate neoadjuvant treatment regimens in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) early breast cancer.

A total of 60 premenopausal, perimenopausal, and postmenopausal patients with HR+/HER2- breast cancer who meet the inclusion criteria will be enrolled. During the study, clinical information will be collected according to standard practice, including demographic data, tumor imaging, and pathological results (e.g., Ki-67). Investigator-assessed outcomes will be used as the final results.

After 14 days of treatment, patients who provide consent will undergo a second biopsy to evaluate the rate of complete cell-cycle arrest. Safety assessments and imaging evaluations will be performed at treatment completion or upon study withdrawal. Informed consent must be obtained at each study center before participation.

Treatment arms:

Arm A (30 patients):

Dalpiciclib 125 mg orally once daily on Days 1-21 of each 28-day cycle (3 weeks on, 1 week off), for 6 cycles Letrozole 2.5 mg orally once daily continuously for 6 cycles Entinostat 3 mg orally once weekly (Days 1-28 of each 28-day cycle), for 6 cycles

Arm B (30 patients):

Dalpiciclib 150 mg orally once daily on Days 1-21 of each 28-day cycle, for 6 cycles Letrozole 2.5 mg orally once daily continuously for 6 cycles Premenopausal and perimenopausal women will also receive ovarian function suppression (OFS), such as with a GnRHa agent.

After signing informed consent, patients will begin neoadjuvant therapy with dalpiciclib plus entinostat and letrozole ± OFS. Ultrasound assessments will be conducted every two treatment cycles and before surgery under the same imaging conditions as baseline. Bone scans will be performed at the end of neoadjuvant treatment. MRI of the breast will be performed at baseline, after two cycles, and before surgery to assess treatment efficacy. Treatment discontinuation will occur if toxicity is intolerable, consent is withdrawn, or the investigator determines it is necessary.

Adjuvant therapy:

After surgery, patients will receive physician's choice of therapy (TPC).

Safety follow-up:

Patients will be followed until they start another anticancer therapy, all adverse events have resolved to Grade 0-1 or baseline level, or death-whichever occurs first.

For patients with HR-positive, HER2-negative early or locally advanced breast cancer, achieving a clinical complete response with traditional neoadjuvant chemotherapy is challenging, and treatment tolerance is often suboptimal. Endocrine therapy plays an important role in both early-stage and advanced HR+/HER2- breast cancer; however, its efficacy in the neoadjuvant setting remains to be further clarified. Existing studies have shown that, compared with neoadjuvant chemotherapy, neoadjuvant endocrine therapy in HR+/HER2- breast cancer yields comparable clinical complete response and breast-conserving surgery rates, with substantially lower toxicity. Therefore, strategies to further improve response to neoadjuvant endocrine therapy may be more meaningful than intensifying chemotherapy in this population.

With the clinical availability of CDK4/6 inhibitors, the efficacy of neoadjuvant endocrine therapy has been further improved. Results from DAWNA-1, DAWNA-2, and DAWNA-A have strengthened the evidence base supporting the use of the domestically developed CDK4/6 inhibitor dalpiciclib in the adjuvant treatment of breast cancer.

However, some studies have found that increased histone deacetylase (HDAC) activity in the estrogen receptor (ER) promoter region can suppress ER expression and lead to endocrine therapy resistance. Entinostat is an oral HDAC inhibitor that selectively inhibits class I (primarily HDAC1 and HDAC3) and class IV HDACs. In the phase III study EOC103A3101 conducted in China, entinostat significantly improved median progression-free survival (PFS) compared with placebo (6.32 vs. 3.72 months), reducing the risk of disease progression or death by 24% (HR 0.76). Median overall survival (OS) was also prolonged in the entinostat group (38.39 months), with a 17% reduction in mortality risk (HR 0.83), demonstrating clinically meaningful survival benefits.

Based on these findings, the present study aims to further evaluate whether the combination of dalpiciclib, entinostat, and letrozole as neoadjuvant therapy for patients with HR-positive, HER2-negative early breast cancer may provide an improved clinical strategy compared with current standards.

Inclusion Criteria:

- Inclusion Criteria

1. Female patients aged ≥18 and <75 years, including postmenopausal, premenopausal, or perimenopausal. Postmenopause is defined as:Prior bilateral oophorectomy, or age ≥60 years; orAge <60 years, natural postmenopause (spontaneous cessation of menses for ≥12 months without other pathological or physiological cause) with estradiol (E2) and FSH in postmenopausal range; orPremenopausal or perimenopausal women willing to receive LHRH agonist (OFS) therapy during the study.
2. Histologically confirmed estrogen receptor (ER)-positive (>10%) invasive breast cancer, regardless of PR expression, and HER2-negative according to the 2018 ASCO/CAP HER2 testing guidelines (IHC 0+ or IHC 2+ with ISH-negative, amplification ratio <2.0).
3. At least one measurable lesion according to RECIST 1.1; clinical stage T1c-T2, cN1-2, or T3-T4, cN0-2.
4. No prior anticancer therapy for breast cancer, including chemotherapy,endocrine therapy, or targeted therapy.
5. Ability to swallow oral medications.
6. Baseline left ventricular ejection fraction (LVEF) ≥50%.
7. Adequate organ function:Hematology (within 1 week):Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L;White blood cell count (WBC) ≥3.0 × 10⁹/L;Platelet count ≥90 × 10⁹/L;Hemoglobin ≥90 g/L Liver and kidney function (within 1 week):Total bilirubin (TBIL) ≤ upper limit of normal (ULN);ALT and AST ≤1.5 × ULNBUN and creatinine ≤1.5 × ULN, with creatinine clearance ≥60 mL/min (Cockcroft-Gault formula)
8. ECG: Corrected QT interval ≤470 ms (12-lead ECG)
9. Willingness and ability to undergo all required biopsy procedures.
10. Women of childbearing potential must have a negative pregnancy test before study entry and agree to use medically acceptable contraception during the study; postmenopausal women are exempt.
11. Voluntary participation with signed informed consent, good compliance, and willingness to adhere to follow-up requirements.

Exclusion Criteria:

- Exclusion Criteria

1. Pregnant or breastfeeding women, or women with a positive pregnancy test at baseline; women of childbearing potential unwilling to use effective contraception during the study.
2. Bilateral breast cancer or inflammatory breast cancer.
3. Stage IV (metastatic) breast cancer at initial diagnosis.
4. History of congestive heart failure, unstable angina, significant arrhythmia, or myocardial infarction.
5. Active pulmonary disease, including interstitial lung disease, pneumonia, pulmonary fibrosis, or other acute lung conditions.
6. Significant liver disease, such as acute or fulminant hepatitis, impaired coagulation factor synthesis, or other severe hepatic dysfunction.
7. For patients positive for HBsAg or HBV core antibody, peripheral blood HBV DNA must be <1×10³ IU/mL to be eligible.
8. Any concurrent disease or condition that may interfere with study participation or affect patient safety (e.g., active or uncontrolled infection).
9. Other invasive malignancies (including second primary breast cancer) that may interfere with study outcomes or compliance.
10. Prior chemotherapy, endocrine therapy, or biologic therapy for breast cancer (except diagnostic biopsy for primary breast cancer).
11. Major surgery within 4 weeks prior to study entry or unresolved significant medical conditions.
12. Tumors that are non-measurable during the study treatment.
13. Any other condition that, in the investigator's judgment, makes the subject unsuitable for participation.