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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase III Trial of Chidamide in Combination With Exemestane in Patients With Hormone Receptor-Positive Advanced Breast Cancer (ACE)

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Chidamide
* Drug: exemestane
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18   75 years old, postmenopausal women; Histological or cytological confirmation of hormone receptor-positive [estrogen receptor (ER) positive and progesterone receptors (PgR) positive or negative] breast cancer; Disease progression or recurrence after at least one endocrine therapy (either in advanced/metastatic setting or adjuvant setting); ≤4 prior therapies (either in advanced/metastatic setting or adjuvant setting), patients may have received one prior chemotherapy; The disease condition is inoperable, stage III or stage IV, at least one measurable lesion or simple bone metastases with no measurable lesions; 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; Eastern Cooperative Oncology Group Performance Status: 0 1; Absolute neutrophil count ≥ 1.5×109 / L, platelet count ≥ 100×109 / L, hemoglobin ≥ 90 g/L; Life expectancy ≥ 3 months; Have signed informed consent. Exclusion Criteria: Patients have known central nervous system (CNS) metastases or a history of CNS metastases , or with leptomeningeal disease; Patients with human epidermal growth factor receptor-2 (Her-2) positive; Patients previously received treatment with exemestane; Patients received radiotherapy ≤ 4 weeks prior to study entry; Patients with no measurable lesion (except simple bone metastasis), such as pleural or pericardial effusion, ascites, et al; Patients have uncontrolled or significant cardiovascular disease, including: Myocardial infarction (< the last 12 months) Uncontrolled angina (< the last 6 months) Congestive heart failure (< the last 6 months), or Left Ventricular Ejection Fraction (LVEF) < 50% prior to study entry History of any significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or TdP) History of significant QT interval prolongation, or Corrected QT Interval (QTc) > 450 ms prior to study entry History of cerebrovascular accident Symptomatic coronary heart disease requiring treatment with agents The size of fluid area detected by cardiac ultrasonography in cavum pericardium is ≥10mm during diastolic period; History of organ transplantation; Patients have not recovered from all clinically relevant toxicities to grade 1 due to prior therapies; 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; 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; Patients had organ surgery < 6 weeks prior to study entry; 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); 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; Any mental or cognitive disorder, that would interfere the ability to understand the informed consent document or the operation and compliance of study; 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; Any other condition which is inappropriate for the study in the opinion of the investigators.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chidamide + exemestane, open-label<br>Patients receive 30 mg Chidamide per week and 25 mg exemestane QD. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. | Drug: Chidamide<br>* 30 mg, administered orally twice per week (BIW)<br>* Other names: CS055;Drug: exemestane<br>* 25 mg, PO daily<br>* Other names: Aromasin;|
| Experimental: Chidamide + exemestane, double-blinded<br>Patients receive 30 mg Chidamide twice per week and 25 mg exemestane QD. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. | Drug: Chidamide<br>* 30 mg, administered orally twice per week (BIW)<br>* Other names: CS055;Drug: exemestane<br>* 25 mg, PO daily<br>* Other names: Aromasin;|
| Placebo Comparator: placebo + exemestane, double-blinded<br>Patients receive placebo twice per week and 25 mg exemestane PO QD. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. | Drug: exemestane<br>* 25 mg, PO daily<br>* Other names: Aromasin;Drug: placebo<br>* Administered orally twice per week (BIW)<br>* Other names: Simulation tablet of Chidamide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression-free survival (PFS), double-blinded period | PFS is measured from the date of randomization until progression or death, whichever is first met | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years | 
| pharmacokinetic profiles of Chidamide, open-label period | The pharmacokinetic parameters include Area under the plasma concentration versus time curve (AUC) , Peak Plasma Concentration (Cmax), time to reach Cmax (Tmax), mean concentration at steady state (Css) | 0,1,2,4,8,12,24,48,72 hours after the first dose of Chidamide on day 2 at induced stage (4 days in total); 0,1,2,4,8,12,24,48,72 hours post-dose on day 1 of cycle 1 at combination treatment stage | 
| pharmacokinetic profiles of exemestane, open-label period | The pharmacokinetic parameters include Area under the plasma concentration versus time curve (AUC) , Peak Plasma Concentration (Cmax), time to reach Cmax (Tmax), mean concentration at steady state (Css) | 0,1,2,4,8,12,24 hours after the first dose of exemestane on day 1 at induced stage (4 days in total); 0,1,2,4,8,12,24,48,72 hours post-dose on day 1 of cycle 1 at combination treatment stage | 
| acetylation level of histone H3, open-label period | The acetylation level of histone H3 is assayed by enzyme-linked immuno sorbent assay (ELISA). | pre-dose of Chidamide on day 2 at induced stage (4 days in total); pre-dose of Chidamide on day 1 of cycle 2 at combination treatment stage | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall survival, double-blinded period | OS is measured from the date of randomization until death | Time from randomization to death from any cause, assessed up to 6 years | 
| duration of response (DOR), double-blinded period | DOR is measured from the first date when criteria for response is met until the first date when the criteria for progression is met | From the first date of response until the date of first documented progression, assessed up to 3years | 
| objective response rate (ORR), open-label period and double-blinded period | ORR is defined as percentage of participants with Complete Response and Partial Response, assessed by the investigators according to the Response Evaluation Criteria in Solid Tumors (RECIST) | Response is assessed once every 6 weeks, assessed up to 3 years | 
| clinical benefit rate (CBR), open-label period and double-blinded period | ORR is defined as percentage of participants with Complete Response, Partial Response or Stable Disease ≥ 24 weeks, assessed by the investigators according to the Response Evaluation Criteria in Solid Tumors (RECIST) | Response is assessed once every 6 weeks, assessed up to 3 years | 
| PFS, open-label period | PFS is measured from the start of treatment until progression or death, whichever is first met | Time from the start of treatment to the earliest of documented disease progression, or death, assessed up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chidamide, breast cancer, exemestane, Estrogen Receptor