Entinostat with or without anlotinib plus fulvestrant for HR-positive, HER2-negative advanced breast cancer after endocrine therapy

A Phase II Clinical Study Evaluating Entinostatwit h or Without Anlotinib + Fulvestrant for the Treatment of Hormone Receptor (HR) -Positive, Human Epidermal Growth Factor Receptor-2 (HER-2) -Negative Advanced Breast Cancer That Relapsed or Progressed After Endocrine Therapy

This trial tests whether adding entinostat, with or without anlotinib, to fulvestrant helps women with HR+/HER2- advanced breast cancer whose disease progressed after endocrine therapy and CDK4/6 inhibitors.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 118 (estimated)
• Ages: 18 Years and up
• Sex: Female
• Sponsor: Zhejiang Cancer Hospital (Academic / other)
• Drugs / interventions: apatinib, anlotinib, chemotherapy
• Locations: 1 site (Zhejiang, Hangzhou)
• Trial ID: NCT07330544 on ClinicalTrials.gov

What this trial studies

This open-label Phase II trial used a Simon two-stage design and enrolled 118 patients with HR+/HER2- advanced or recurrent breast cancer after prior endocrine therapy and CDK4/6 inhibitor exposure. An initial cohort of 20 eligible patients received entinostat plus fulvestrant; the trial proceeded to a randomized phase when predefined response thresholds were met. In the randomized phase patients were assigned 1:1.5 to entinostat plus fulvestrant (Group 1, n=39) or anlotinib plus entinostat plus fulvestrant (Group 2, n=59). Treatment continued until disease progression, unacceptable toxicity, withdrawal, or other protocol-specified reasons.

Who should consider this trial

Good fit: Adult women with HR-positive, HER2-negative unresectable locally advanced or metastatic breast cancer who progressed after endocrine therapy and CDK4/6 inhibitors, with ECOG 0–1 and expected survival of at least three months are ideal candidates.

Not a fit: Patients with HER2-positive disease, poor performance status (ECOG >1), inadequate organ function, or those who have not received prior endocrine plus CDK4/6 inhibitor therapy are unlikely to match the enrolled population or benefit from these specific regimens.

Why it matters

Potential benefit: If successful, the combination could prolong disease control and delay progression for patients with HR+/HER2- advanced breast cancer after CDK4/6 inhibitor failure.

How similar studies have performed: Prior trials of entinostat added to endocrine therapy have shown mixed signals and remain inconclusive, so combining entinostat and anlotinib with fulvestrant is somewhat experimental.

Eligibility criteria

Inclusion Criteria:

1. Sign an informed consent form;
2. Female, aged 18 or above;
3. The patient's Eastern Tumor Collaboration Group (ECOG) physical status is 0-1;
4. The patient's expected survival time is ≥3 months;
5. Breast cancer patients diagnosed as HR-positive and HER-2 negative by tumor histopathological and molecular pathological typing (based on the most recent report); 1) Hormone receptor positive refers to estrogen receptor (ER) positive, progesterone receptor (PR) negative or positive (≥1% positive staining cells are considered receptor positive); 2) HER-2 negative means: the immunohistochemical result of the pathological specimen test is 0 or 1+; Or an immunohistochemical result of 2+ and a negative ISH or FISH test.
6. The subject has received at least one line of endocrine therapy as well as CDK 4/6 inhibitor therapy at an unresectable stage of locally advanced recurrence or metastasis; Or disease recurrence occurred during ET combined with CDK4/6 inhibitors as adjuvant therapy or within 12 months after the end of treatment.
7. The subject has not received chemotherapy or ADC therapy for metastatic disease
8. At least one measurable target lesion was evaluated by the investigator in accordance with RECIST 1.1
9. No known active brain metastases or leptomeningeal disease
10. The patient must have adequate organ function within 1 week (7 days) prior to the initiation of study administration, as defined below:

    * Hematology: Hemoglobin (HgB) ≥80 g/L, platelet count ≥100×109 /L, absolute neutrophil count ≥1.0×10 /L.

Note: Platelet transfusion is not allowed within 3 days before these laboratory tests, red blood cell transfusion is not allowed within 14 days, and hematopoietic growth factor (pegylated G-CSF, 14 days for erythropoietin) is not allowed within 7 days. No blood transfusion or use of auxiliary white blood cell, platelet increase drugs such as cytokines or erythropoietin drugs within 2 weeks prior to the screening test

* Renal function: Serum creatinine (Cre) ≤1.5× upper limit of normal (ULN), or glomerular filtration rate (eGFR) ≥60 mL/min/1.73m2. Urine protein \<2+ or 24-hour urine protein quantification \<1g
* Liver function: Total bilirubin ≤1.5×ULN; If Gilbert syndrome is present, total bilirubin ≤3 mg/dL; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3×ULN; If there is liver metastasis, both ALT and AST should be ≤5×ULN; Alkaline phosphatase (ALP) ≤2.5×ULN; If there is bone metastasis, it should be ≤5×ULN.

  9\. Echocardiography shows left ejection fraction (LVEF) ≥50% and QTc interval ≤480 ms.

  10\. Female patients in the premenopausal or perimenopausal period who agree to use the concomitant luteinizing hormone-releasing hormone (LHRH) agonist can be enrolled. Those who meet any of the following criteria may be considered to have reached menopause, but those who do not meet the criteria for being considered premenopausal or perimenopausal:
* Having undergone bilateral oophorectomy in the past;
* Age ≥60 years;
* Age \<60 years old, natural menopause ≥12 months, no chemotherapy, tamoxifen, torremifen or ovarian function castration during this period, blood follicle-stimulating hormone (FSH) and estradiol (E2) levels within postmenopausal range (judged in combination with the reference range of the research center); 11. Patients who are fertile must agree to use recognized effective methods of contraception (including condoms with inactivated sperm, vaginal separators, oral or injectable contraceptives, etc.) or abstain from sexual activity during their participation in the study and for 3 months after the cessation of study treatment.

Exclusion Criteria:

* Patients should not be enrolled if any of the following conditions occur:

  1. Symptomatic visceral metastases or other conditions, visceral crisis, or the investigator deems it inappropriate to use endocrine therapy;
  2. The patient has a past or present central nervous system metastases, or leptomeningeal disease, brain metastases;
  3. Previous use of selective estrogen receptor degraders (SERD, such as fulvestrant) or histone deacetylase (HDAC) inhibitors (such as entectamine, chidamide, etc.) or small molecule multi-target tyrosine kinase inhibitors (such as apatinib, anlotinib, etc.) or PAM pathway inhibitors (such as PI3K inhibitor Alpelisib, AKT inhibitor Capivasertib, MTOR inhibitor everolimus, etc.
  4. Known allergy to SERD, entinostat, or other drugs with a benzamide structure (such as typapride, remopilib, cloprapride, etc.), anlotinib;
  5. Pregnant or lactating women;
  6. Coexisting with other malignant tumors, unless radical treatment has been administered and there is no evidence of recurrence or metastasis;
  7. There is pericardial effusion requiring drainage, pleural effusion with obvious clinical symptoms or ascites;
  8. Other circumstances that the investigator deems unsuitable for inclusion.

Where this trial is running

Zhejiang, Hangzhou

• Zhejiang Cancer Hospital — Zhejiang, Hangzhou, China (Recruiting)

Study contacts

• Study coordinator: Rong Wang

Conditions Breast Cancer