Trial of Chidamide in Combination With Exemestane in Patients With Advanced Breast Cancer

This study was to evaluate the efficacy and safety of Chidamide in combination with exemestane in postmenopausal patients with hormone-receptor positive advanced breast cancer.

This study including two parts: (1) Part A, open-label design, 20 patients will be enrolled and receive 30 mg Chidamide BIW and 25 mg exemestane QD. The main object of part A is to evaluate the pharmacokinetic and pharmacodynamic profile of Chidamide when in combination with exemestane. (2) Part B, randomized and double-blinded design, 328 patients will be assigned randomly in a 2:1 ratio to experiment group (30 mg Chidamide BIW + 25 mg exemestane QD) and control group (placebo BIW + 25 mg exemestane QD), to evaluate the efficacy and safety of Chidamide when in combination with exemestane in patients with locally advanced or metastatic estrogen receptor-positive breast cancer progressing on endocrine therapy.

Eligibility Criteria:
Inclusion Criteria:

1. 18 \~ 75 years old, postmenopausal women;
2. Histological or cytological confirmation of hormone receptor-positive \[estrogen receptor (ER) positive and progesterone receptors (PgR) positive or negative\] breast cancer;
3. Disease progression or recurrence after at least one endocrine therapy (either in advanced/metastatic setting or adjuvant setting);
4. ≤4 prior therapies (either in advanced/metastatic setting or adjuvant setting), patients may have received one prior chemotherapy;
5. The disease condition is inoperable, stage III or stage IV, at least one measurable lesion or simple bone metastases with no measurable lesions;
6. Last prior therapy intervals: (a) if the last treatment was endocrine therapy, the interval must ≥ 2 weeks; (b) if the last treatment was chemotherapy therapy, the interval must ≥ 4 weeks;
7. Eastern Cooperative Oncology Group Performance Status: 0\~1;
8. Absolute neutrophil count ≥ 1.5×109 / L, platelet count ≥ 100×109 / L, hemoglobin ≥ 90 g/L;
9. Life expectancy ≥ 3 months;
10. Have signed informed consent.

Exclusion Criteria:

1. Patients have known central nervous system (CNS) metastases or a history of CNS metastases , or with leptomeningeal disease;
2. Patients with human epidermal growth factor receptor-2 (Her-2) positive;
3. Patients previously received treatment with exemestane;
4. Patients received radiotherapy ≤ 4 weeks prior to study entry;
5. Patients with no measurable lesion (except simple bone metastasis), such as pleural or pericardial effusion, ascites, et al;
6. Patients have uncontrolled or significant cardiovascular disease, including:

   1. Myocardial infarction (\< the last 12 months)
   2. Uncontrolled angina (\< the last 6 months)
   3. Congestive heart failure (\< the last 6 months), or Left Ventricular Ejection Fraction (LVEF) \< 50% prior to study entry
   4. History of any significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or TdP)
   5. History of significant QT interval prolongation, or Corrected QT Interval (QTc) \> 450 ms prior to study entry
   6. History of cerebrovascular accident
   7. Symptomatic coronary heart disease requiring treatment with agents
7. The size of fluid area detected by cardiac ultrasonography in cavum pericardium is ≥10mm during diastolic period;
8. History of organ transplantation;
9. Patients have not recovered from all clinically relevant toxicities to grade 1 due to prior therapies;
10. Patients have clinical significant gastrointestinal abnormality, e.g., unable to swallow, chronic diarrhea, ileus, that would interfere the ingestion,transportation or absorption of oral agents;
11. Active infection \[Suffered from active infection of bacteria, virus, fungi, mycobacteria, parasites, or other infections (excluding nail bed fungal infections), or require intravenous antibiotic therapy, or antiviral therapy, or hospitalization due to any significant infection events\], or persistent fever within 14 days prior to study entry;
12. Patients had organ surgery \< 6 weeks prior to study entry;
13. Abnormal liver function \[total bilirubin \> 1.5×upper limit of normal (\> 3×upper limit of normal in case of Gilbert syndrome); Transaminases (ALT, AST) \>2.5×upper limit of normal (\>5x upper limit of normal patients with liver metastases), abnormal renal function (serum creatinine \> 1.5×upper limit of normal);
14. Patients with prior invasive malignancies with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ, unless received curative treatment and with documented evidence of no recurrence in the past five years;
15. Any mental or cognitive disorder, that would interfere the ability to understand the informed consent document or the operation and compliance of study;
16. Patients are currently enrolled in another investigational drug study, or completed within 4 weeks prior to study entry, with the exception of patients only in overall survival follow-up;
17. Any other condition which is inappropriate for the study in the opinion of the investigators.