AR-inhibitor Bicalutamide in Treating Patients With TNBC

Breast Neoplasms Clinical Trial

— Arbre  

Official title:

Bicalutamide in Treating Patients With AR-positive Metastatic Triple Negative Breast Cancer

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02353988
• Other study ID #: JinlingH-001
• Status: Not yet recruiting
• Phase: Phase 2
• First received: January 26, 2015
• Last updated: February 2, 2015
• Start date: January 2015
• Est. completion date: May 2017

Study information

• Verified date: January 2015
• Source: Jinling Hospital, China
• Contact: Xiaoxiang Guan, MD; PhD
• Phone: +86 13512510329
• Email: xguan[@]nju.edu.cn
• Is FDA regulated: No
• Health authority: China: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

Growing studies demonstrated that Androgen Receptor (AR) has an oncogenic role for the patients with AR-positive Triple Negative Breast Cancer (TNBC). AR antagonists in therapy, such as bicalutamide, completely binds to the AR, increasing AR degradation, thus are investigated for the efficacy of the treatment of patients with AR-positive TNBC in the study.

Description:

More than 70% of human breast cancers express the androgen receptor (AR), and in retrospective analysis, the expression of AR in Triple-Negative Breast Cancer (TNBC) varies from 10-43%. Recently emerging preclinical and clinical data suggest that AR may play a role in tumor proliferation. For example, Hu et al (2011) analyzed AR expression in 211 TNBC cases. He found that AR is related with an 83% increase in overall mortality, when compared with AR-negative TNBC. McGhan et al (2014) also found that AR expression tends to exist in TNBC patients with higher tumor stage and lymph metastases.

The role of AR has also been extensively studied in vitro. With targeting AR with small interfering RNA (siRNA) and treatment with anti-androgen bicalutamide, studies showed that AR has a proliferative role in TNBC cells. Robinson et al (2011) also clarified that AR can mimic estrogen receptor α (ERα) in a transcriptionally active manner directed by the forkhead box protein A1 (FoxA1). These indicate that, in ER-negative disease, AR can promote tumor progression, therefore, could serve as a therapeutic target in TNBC.

Due to the demonstration of oncogenic role for the AR in TNBC, clinical trials are underway to study the role of inhibiting androgen signaling for the treatment for TNBC. For example, Gucalp et al (2013) performed a sing-arm phase II study to investigate the role of bicalutamide in AR-positive TNBC. A total of 26 patients were enrolled in the study, and the study demonstrated a general well tolerated effect and a 6-month clinical benefit rate of 19%. Furthermore, future clinical trials are also designed to show the anti-androgen therapy such as Enzalutamide, the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate and orteronel for AR-positive TNBC. This study is investigated to study the role of bicalutamide for AR-positive TNBC, and it may help clarify the effect of bicalutamide for the specific breast cancer subtype. Furthermore, it may provide an additional therapy to treat the difficult to treat population.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 60
• Est. completion date: May 2017
• Est. primary completion date: January 2017
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Female patients with histologically or cytologically confirmed carcinoma of the breast. Every effort should be made to make paraffin embedded tissue or slides from the diagnostic biopsy or surgical specimen available for confirmation of diagnosis.

• Receptor status: Estrogen receptor- and progesterone receptor-negative,HER-2-negative, Androgen receptor-positive* NOTE: Samples are considered positive if greater than 10% of cell nuclei are immunoreactive.

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2. Life expectancy of >= 3 months.

• Adequate organ and marrow function as defined below:

leukocytes >3,000/mL; absolute neutrophil count >1,500/ml; platelets >100,000/mL; total bilirubin within normal institutional limits; aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) <2.5×institutional upper limit of normal (ULN); creatinine within normal institutional limits OR creatinine clearance >60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.

• Patients with metastatic disease progressed after one therapeutic regimen for metastatic disease, and there is no limit for the regimens of prior therapy.

• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

• Women of childbearing potential, but using (1) surgically sterile or (2) adequate measures of contraception in the opinion of the Investigator. Peri-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential.

• Patients have no other malignancy, except breast cancer.

• Patients willing and able to comply with the study protocol for the duration of the study.

• Written informed consent prior to any study-specific screening procedures with the understanding that the patient may withdraw consent at any time without prejudice.

Exclusion Criteria:

• Patients who have received any of the following treatments within four weeks before Bicalutamide or TPC treatment start: chemotherapy, radiation, trastuzumab, hormonal therapy, surgery, or any investigational drug within four weeks.

• Patients with a hypersensitivity to Bicalutamide or selected TPC treatment.

• Women who are pregnant or breast-feeding; women of childbearing potential refuse to use any measures of contraception.

• Patients have active brain metastases or leptomeningeal disease.

• Patients have important organ failure or serious marrow suppression.

• Severe/uncontrolled intercurrent illness/infection.

• Significant cardiovascular impairment (history of congestive heart failure > New York Heart Association grade II, severe valvular heart disease,unstable angina or myocardial infarction within the past six months, or serious cardiac arrhythmia, or resistant hypertension).

• Patients can't comply with the study protocol for the duration of the study.

• Patients have had a prior malignancy within five years, other than previous breast cancer.

• Participation in another clinical trial with any investigational agents within 3 weeks prior to study screening.

• Patients with known Central Nervous System (CNS) disease (primary or secondary) or leptomeningeal disease because of their poor prognosis and because they often develop progressive neurological dysfunction that would confound the evaluation of neurological and other adverse events.

• Gastrointestinal disorders interfering with absorption of the study drug.

• Difficulties with swallowing study capsules/tablets.

• Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Neoplasms

Intervention

Drug:
• Bicalutamide
Patients in experimental group are designated to take bicalutamide orally, 150mg on a continuous schedule. The investigator should pay attention to the patients' adverse event. Every month, the patients will be evaluated for the adverse event by the criterion National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 3.0. Every 2 months, the patients will be evaluated for the clinical effects. If disease progressed, the patients would be ruled out. Treatment continued until disease progression, unacceptable toxic effects, patient or physician request to discontinue, or serious protocol non-compliance. A maximum of 2 dose reductions for grade >= 3 toxicity were allowed (100 and 50 mg). A maximum of 2 weeks was permitted for treatment delays due to toxicity.

Other:
• Physician's Choice
The comparator group, treatment of physician's choice (TPC), represented a mix of agents (both approved and non-approved for metastatic breast cancer) to mirror clinical practice at the time in this setting. The 60 patients are enrolled in the study, before randomized to the two arms, each of them will be assessed for eligibility and then their proposed TPC. Treatment continued until disease progression, unacceptable toxic effects, patient or physician request to discontinue, or serious protocol non-compliance.

Locations

Country	Name	City	State
n/a

Sponsors (7)

Lead Sponsor	Collaborator
Jinling Hospital, China	Jiangsu Province Hospital of Traditional Chinese Medicine, Nanning Second People's Hospital, The First People's Hospital of Lianyungang, The Second Hospital of Nanjing Medical University, Wenzhou Medical University, Wuxi People's Hospital

References & Publications (8)

Fioretti FM, Sita-Lumsden A, Bevan CL, Brooke GN. Revising the role of the androgen receptor in breast cancer. J Mol Endocrinol. 2014 Jun;52(3):R257-65. doi: 10.1530/JME-14-0030. Epub 2014 Apr 16. Review. — View Citation

Gucalp A, Tolaney S, Isakoff SJ, Ingle JN, Liu MC, Carey LA, Blackwell K, Rugo H, Nabell L, Forero A, Stearns V, Doane AS, Danso M, Moynahan ME, Momen LF, Gonzalez JM, Akhtar A, Giri DD, Patil S, Feigin KN, Hudis CA, Traina TA; Translational Breast Cancer Research Consortium (TBCRC 011). Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer. Clin Cancer Res. 2013 Oct 1;19(19):5505-12. doi: 10.1158/1078-0432.CCR-12-3327. Epub 2013 Aug 21. — View Citation

Hu R, Dawood S, Holmes MD, Collins LC, Schnitt SJ, Cole K, Marotti JD, Hankinson SE, Colditz GA, Tamimi RM. Androgen receptor expression and breast cancer survival in postmenopausal women. Clin Cancer Res. 2011 Apr 1;17(7):1867-74. doi: 10.1158/1078-0432.CCR-10-2021. Epub 2011 Feb 15. — View Citation

Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011 Jul;121(7):2750-67. doi: 10.1172/JCI45014. — View Citation

McGhan LJ, McCullough AE, Protheroe CA, Dueck AC, Lee JJ, Nunez-Nateras R, Castle EP, Gray RJ, Wasif N, Goetz MP, Hawse JR, Henry TJ, Barrett MT, Cunliffe HE, Pockaj BA. Androgen receptor-positive triple negative breast cancer: a unique breast cancer subtype. Ann Surg Oncol. 2014 Feb;21(2):361-7. doi: 10.1245/s10434-013-3260-7. Epub 2013 Sep 18. — View Citation

Park S, Koo J, Park HS, Kim JH, Choi SY, Lee JH, Park BW, Lee KS. Expression of androgen receptors in primary breast cancer. Ann Oncol. 2010 Mar;21(3):488-92. doi: 10.1093/annonc/mdp510. Epub 2009 Nov 3. — View Citation

Robinson JL, Macarthur S, Ross-Innes CS, Tilley WD, Neal DE, Mills IG, Carroll JS. Androgen receptor driven transcription in molecular apocrine breast cancer is mediated by FoxA1. EMBO J. 2011 Jun 24;30(15):3019-27. doi: 10.1038/emboj.2011.216. Erratum in: EMBO J. 2012 Mar 21;31(6):1617. — View Citation

Shah PD, Gucalp A, Traina TA. The role of the androgen receptor in triple-negative breast cancer. Womens Health (Lond Engl). 2013 Jul;9(4):351-60. doi: 10.2217/whe.13.33. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinical benefit rate(CBR)	The proportion of stability, partial response and complete response in patients who receive bicalutamide as second-, or third-line therapy for estrogen receptor (ER)/ progesterone receptor (PgR)-negative, human epidermal growth factor receptor (HER-2)-negative and AR-positive Metastatic Breast Cancer	1 Year	No
Primary	Progression-free survival		From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months	No
Secondary	Quality of life	FACT(Functional Assessment of Cancer Therapy) -B :a 36-item compilation, subdivided into four primary QOL (Quality of life) domains and a disease specific domain - additional concerns for breast cancer	1 Year	No
Secondary	Number of adverse events (AE) and serious adverse events (SAE) during the course of the study		1 Year	Yes