Clinical trial NCT04999540: Tucidinostat and Fulvestrant in Hormone-receptor Positive Advanced Breast Cancer
Official title: Trial of Tucidinostat in Combination With Fulvestrant in Patients With Hormone-receptor Positive Advanced Breast Cancer
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Breast Cancer
Lead sponsor: Guangdong Women and Children Hospital
Sponsor class: OTHER
First posted: 2021-08-11
Enrollment: 73
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of the study is evaluate the efficacy and safety of tucidinostat in combination with fulvestrant in patients with hormone-receptor positive advanced breast cancer.

Detailed description: Hormone-receptor positive breast cancer is the most common subtype in breast cancer. Tucidinostat is an oral subtype-selective histone deacetylase inhibitor, which showed preliminary signs of encouraging anti-tumour activity in patients with advanced hormone-receptor positive breast cancer in the previous studies. The aim of this study is to evaluate the efficacy and safety of Tucidinostat in combination with fulvestrant in patients with recurrent or metastatic hormone-receptor positive breast cancer.

Eligibility criteria: Inclusion Criteria:

1. Female patients aged 18-75 years (including cutoff value);
2. The disease condition is inoperable, recurrent breast cancer, or metastatic breast cancer;
3. Histological or cytological confirmation of hormone receptor-positive \[estrogen receptor (ER) positive and progesterone receptors (PgR) positive or negative\] breast cancer;
4. At least one measurable lesion according to RECIST 1.1;
5. Prior treatment: have not received systemic chemotherapy for recurrent or metastatic breast cancer;
6. Eastern Cooperative Oncology Group Performance Status of 0-1;
7. Adequate function of major organs meets the following requirements):

   Absolute Neutrophils count≥ 1.5×10\^9/L; Platelets count≥ 90×10\^9/L; Hemoglobin ≥ 90g/L; Total bilirubin≤ 1.5 × the upper limit of normal (ULN); ALT and AST ≤ 2.5 × ULN; BUN and Cr ≤ 1.5 × ULN; Left ventricular ejection fraction (LVEF) ≥ 50%; QTcF(Fridericia correction) ≤ 470 ms; International normalized ratio(INR)≤1.5 × ULN; activated partial thromboplastin time(APTT) ≤ 1.5 × ULN;
8. Life expectancy ≥ 3 months;
9. Have signed informed consent.

Exclusion Criteria:

1. Patients have untreated central nervous system (CNS) metastases;
2. Patients with no measurable lesion according to RECIST 1.1;
3. Patients with bilateral breast cancer;
4. Patients with human epidermal growth factor receptor-2 (Her-2) positive;
5. Recurrent or metastatic disease occurs within 2 years during adjuvant endocrine therapy;
6. Patients previously received systemic chemotherapy for recurrent or metastatic breast cancer;
7. Patients previously received any HDAC inhibitor or fulvestrant treatment;
8. There are ascites, pleural effusion, pericardial effusion with clinical symptoms at baseline, those who need drainage, or those who have undergone drainage of serous effusion within 4 weeks before the first dose;
9. Inability to swallow, intestinal obstruction or other factors affecting the administration and absorption of the drug;
10. Patients with other invasive malignancies within 5 years or at the same time, with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ;
11. Patients with a history of allergies to the drug components of this regimen;
12. Patients with active HBV and HCV infection; stable hepatitis B after drug treatment (HBV virus copy number is higher than the upper limit of reference value) and cured hepatitis C patients (HCV virus copy number exceeds the lower limit of detection method) can be included;
13. Patients with a history of immunodeficiency, including HIV positive, or other acquired or congenital immunodeficiency disease, history of organ transplantation;
14. 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;
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. Any other condition which is inappropriate for the study in the opinion of the investigators.

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: From date of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years.
Secondary outcomes:
measure: overall survival (OS)
timeFrame: Time from treatment to death from any cause, assessed up to 3 years.
measure: Objectivel response rate (ORR)
timeFrame: Response is assessed once every 8 weeks, from the day of treatment to the date of first documented progression, assessed up to 3 years.
measure: Duration of response (DOR)
timeFrame: From the day of treatment to the date of first documented progression, assessed up to 3 years.
measure: 4.Clinical Benefit Rate (CBR)
timeFrame: From the day of treatment to the date of first documented progression, assessed up to 3 years.
measure: Adverse event(AE)
timeFrame: From the day of treatment to the date of first documented progression, assessed up to 3 years.
Other outcomes:
Locations:
Study officials:
References:
citation: Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med. 2011;62:233-47. doi: 10.1146/annurev-med-070909-182917.
citation: Saxena NK, Sharma D. Epigenetic Reactivation of Estrogen Receptor: Promising Tools for Restoring Response to Endocrine Therapy. Mol Cell Pharmacol. 2010;2(5):191-202.
citation: Turner NC, Ro J, Andre F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M; PALOMA3 Study Group. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2015 Jul 16;373(3):209-19. doi: 10.1056/NEJMoa1505270. Epub 2015 Jun 1.
citation: Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, Park IH, Tredan O, Chen SC, Manso L, Freedman OC, Garnica Jaliffe G, Forrester T, Frenzel M, Barriga S, Smith IC, Bourayou N, Di Leo A. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol. 2017 Nov 10;35(32):3638-3646. doi: 10.1200/JCO.2017.75.6155. Epub 2017 Oct 2.
citation: Falkenberg KJ, Johnstone RW. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov. 2014 Sep;13(9):673-91. doi: 10.1038/nrd4360. Epub 2014 Aug 18.
citation: Jones PA, Issa JP, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet. 2016 Sep 15;17(10):630-41. doi: 10.1038/nrg.2016.93.
citation: Shi Y, Dong M, Hong X, Zhang W, Feng J, Zhu J, Yu L, Ke X, Huang H, Shen Z, Fan Y, Li W, Zhao X, Qi J, Huang H, Zhou D, Ning Z, Lu X. Results from a multicenter, open-label, pivotal phase II study of chidamide in relapsed or refractory peripheral T-cell lymphoma. Ann Oncol. 2015 Aug;26(8):1766-71. doi: 10.1093/annonc/mdv237. Epub 2015 Jun 23.
citation: Zhang Q, Wang T, Geng C, Zhang Y, Zhang J, Ning Z, Jiang Z. Exploratory clinical study of chidamide, an oral subtype-selective histone deacetylase inhibitor, in combination with exemestane in hormone receptor-positive advanced breast cancer. Chin J Cancer Res. 2018 Dec;30(6):605-612. doi: 10.21147/j.issn.1000-9604.2018.06.05.
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.
citation: Sabnis GJ, Goloubeva OG, Kazi AA, Shah P, Brodie AH. HDAC inhibitor entinostat restores responsiveness of letrozole-resistant MCF-7Ca xenografts to aromatase inhibitors through modulation of Her-2. Mol Cancer Ther. 2013 Dec;12(12):2804-16. doi: 10.1158/1535-7163.MCT-13-0345. Epub 2013 Oct 3.