Clinical trial NCT02482753: Trial of Chidamide in Combination With Exemestane in Patients With Advanced Breast Cancer
Official title: A Phase III Trial of Chidamide in Combination With Exemestane in Patients With Hormone Receptor-Positive Advanced Breast Cancer (ACE)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: Chidamide
breast cancer
exemestane
Estrogen Receptor
Lead sponsor: Chipscreen Biosciences, Ltd.
Sponsor class: INDUSTRY
First posted: 2015-06-26
Enrollment: 365
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Primary outcomes:
measure: progression-free survival (PFS), double-blinded period
timeFrame: 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
measure: pharmacokinetic profiles of Chidamide, open-label period
timeFrame: 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
measure: pharmacokinetic profiles of exemestane, open-label period
timeFrame: 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
measure: acetylation level of histone H3, open-label period
timeFrame: 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 outcomes:
measure: overall survival, double-blinded period
timeFrame: Time from randomization to death from any cause, assessed up to 6 years
measure: duration of response (DOR), double-blinded period
timeFrame: From the first date of response until the date of first documented progression, assessed up to 3years
measure: objective response rate (ORR), open-label period and double-blinded period
timeFrame: Response is assessed once every 6 weeks, assessed up to 3 years
measure: clinical benefit rate (CBR), open-label period and double-blinded period
timeFrame: Response is assessed once every 6 weeks, assessed up to 3 years
measure: PFS, open-label period
timeFrame: Time from the start of treatment to the earliest of documented disease progression, or death, assessed up to 3 years
Other outcomes:
Locations:
city: Hefei
country: China
facility: Anhui Provincial Hospital
state: Anhui
city: Hefei
country: China
facility: The First Affiliated Hospital of Anhui Medical University
state: Anhui
city: Beijing
country: China
facility: The 307th Hospital of Chinese people's Liberation Army
state: Beijing
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
city: Guangzhou
country: China
facility: Sun Yat-sen University Cancer Center
state: Guangdong
city: Shenzhen
country: China
facility: Peking University Shenzhen Hospital
state: Guangdong
city: Cangzhou
country: China
facility: Cangzhou Central Hospital
state: Hebei
city: Shijiazhuang
country: China
facility: Tumor Hospital of Hebei Province
state: Hebei
city: Ha'erbin
country: China
facility: Harbin Medical University Cancer Hospital
state: Heilongjiang
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
state: Henan
city: Changsha
country: China
facility: Hunan Cancer Hospital
state: Hunan
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital
state: Jiangsu
city: Nanjing
country: China
facility: Jiangsu Cancer Hospital
state: Jiangsu
city: Nanjing
country: China
facility: Jiangsu Province Hospital
state: Jiangsu
city: Nanchang
country: China
facility: The Third Hospital of Nanchang
state: Jiangxi
city: Changchun
country: China
facility: Jilin Cancer Hospital
state: Jilin
city: Changchun
country: China
facility: The First Hospital of Jilin University
state: Jilin
city: Shenyang
country: China
facility: Liaoning Cancer Hospital & Institute
state: Liaoning
city: Jinan
country: China
facility: Jinan Central Hospital
state: Shandong
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center
state: Shanghai
city: Shanghai
country: China
facility: Fudan University ZhongShan Hospital
state: Shanghai
city: Tianjin
country: China
facility: Tianjin Medical University Cancer Institute and Hospital
state: Tianjin
Study officials:
affiliation: 307 Hospital of PLA
name: Zefei Jiang
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jiang Z, Li W, Hu X, Zhang Q, Sun T, Cui S, Wang S, Ouyang Q, Yin Y, Geng C, Tong Z, Cheng Y, Pan Y, Sun Y, Wang H, Ouyang T, Gu K, Feng J, Wang X, Wang S, Liu T, Gao J, Cristofanilli M, Ning Z, Lu X. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Jun;20(6):806-815. doi: 10.1016/S1470-2045(19)30164-0. Epub 2019 Apr 27.