Window of Opportunity Trial of Entinostat in Patients With Newly Diagnosed Stage I-IIIC,TNBC

NCT03361800 | Terminated Early Phase 1 DMC FDA Drug

• 2 other identifiers: LCCC 1639P50CA058223
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

This study is investigational and is not designed to treat cancer. In other words, the study drug, entinostat, is not being given to treat cancer. Instead, the study team is looking at the effects of entinostat on tumor tissue for research purposes only. Approximately 246,660 cases of breast cancer were diagnosed in the United States in 2016. Its detection and treatment remains a major concern in women's healthcare. In particular, TNBC accounts for approximately 15-20% of all breast cancers. Research into treatment for breast cancer relies more and more on understanding how the cancer cells act when they are exposed to an anti-cancer drug. How most cancer cells act when exposed to anti-cancer drugs and which patients as a result may benefit the most from these drugs is not well known. Additional studies are required to determine the cells' reactions. The purpose of part 1 of this study is to better understand how TNBC tumors react to one particular cancer drug, entinostat. Entinostat is currently being studied across multiple clinical trials for the treatment of breast cancer, other solid tumors and blood cancers. Entinostat is investigational and has not yet been FDA approved for the treatment of cancer. Studies have shown that a good way to determine how cancer acts when exposed to anti-cancer drugs is a short-term preoperative window study. In this type of study, subjects receive a study drug a couple of days before surgery. Leftover tissue from surgery is then used to determine some of the effects that a study drug may have on the tumor. In this study, subjects will receive two doses of entinostat prior to undergoing planned surgery. Leftover tissue from this surgery will then be used to determine the effects entinostat has on tumor cells. For example, the study team will examine if the types of genes and proteins that the tumor expresses as a result of entinostat exposure increases or decreases the likelihood that the tumor will not continue to grow. A gene is a unit of DNA. Genes make up the chemical structure carrying your genetic information that may determine human characteristics (i.e., eye color, height and sex). This study will focus on discovering how entinostat affects a wide variety of genes in tumor cells.

Conditions

Breast Cancer; Invasive Breast Cancer; ER-Negative PR-Negative HER2-Negative Breast Cancer

Keywords

Breast Cancer; ER Negative Breast Cancer; Triple Negative Breast Cancer; PR Negative Breast Cancer; ER Positive PR Positive Breast Cancer

Outcome Measures

Primary Outcomes (1)

• Decrease in Ki-67 mRNA following treatment with entinostat across TNBC breast cancers

  RNA will be extracted from tumor samples using the Qiagen RNEasy Mini RNA extraction kit. mRNA-Seq libraries will made according to the Illumina TruSeq RNA Access protocol. Determination of molecular subtypes and relative expression of genes (i.e. Ki-67 as primary objective) and gene signatures from mRNA-seq data will be done. Change (decrease) in Ki-67 mRNA expression from will be measured by log2 fold-change in Ki-67 mRNA-seq expression from pre-treatment to post-treatment within each patient.

  9 days from start of entinostat (day of surgery)

Secondary Outcomes (6)

• mRNA gene expression changes following treatment with entinostat, across TNBC

  9 days from start of entinostat (day of surgery)

• Changes in the proliferation signature by mRNA expression following treatment with entinostat across TNBC

  9 days from start of entinostat (day of surgery)

• Differential kinome activation before and after treatment with entinostat across TNBC

  9 days from start of entinostat (day of surgery)

• Correlation of mutation and/or copy number variations by whole exome sequencing (WES) with mRNA gene expression changes and reduction of proliferation signature following treatment with entinostat across TNBC.

  9 days from start of entinostat (day of surgery)

• Correlation of protein lysine hyperacetylation in peripheral blood and tumor from pre- and post-entinostat treated TNBCs

  9 days from start of entinostat (day of surgery)

Study Arms (1)

Entinostat

EXPERIMENTAL

Nine days prior to their scheduled surgery, entinostat 5mg PO given once weekly on day 1 and day 8

Drug: Entinostat

Interventions

Entinostat DRUG

oral drug, 5mg tablet given once weekly x 2 doses

Entinostat

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Is female, age ≥ 18 years of age.
• For Part 1: Has histologically confirmed newly diagnosed Stage I-IIIC invasive breast cancer that is triple negative (ER/PR \<1%, Her2 negative) and is scheduled to undergo definitive surgery (either lumpectomy, mastectomy) and meets the criteria listed below:
• Scheduled for lumpectomy or mastectomy and not considered a candidate for neoadjuvant systemic treatment
• No prior or current therapy for breast cancer
• Amenable to a baseline research breast biopsy
• For Part 2: Has histologically confirmed newly diagnosed Stage I-IIIC invasive breast cancer that is ER positive (+/- PR positive) and is scheduled to undergo definitive surgery (either lumpectomy, mastectomy) and meets the criteria listed below:
• Scheduled for lumpectomy or mastectomy and not considered a candidate for neoadjuvant systemic treatment b. No prior or current therapy for breast cancer c. Amenable to a baseline research breast biopsy
• Must have sufficient time to receive two doses of entinostat 7 days apart or exemestane for 8 consecutive days with or without entinostat prior to surgery.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
• Demonstrates adequate organ function
• Has normal cardiac function based on an electrocardiogram (ECG) with no clinically significant abnormalities or risks including any of the following:
• Current uncontrolled hypertension (systolic \>150 mm Hg and/or diastolic \>100 mmHg) or unstable angina
• History of serious cardiac arrhythmia requiring treatment (exceptions: atrial fibrillation, paroxysmal supraventricular tachycardia)
• History of myocardial infarction within 6 months of day 1 of dosing
• History of congestive heart failure according to New York Heart Association (NYHA) criteria.

You may not qualify if:

• Stage IV breast cancer.
• Has clinically significant a) abnormal laboratory or ECG findings, b) history of myocardial infarction or arterial thromboembolic events within 6 months of screening or c) unstable angina, d) New York Heart Association (NYHA) Class III or IV disease or e) a corrected QT (QTc) interval \> 470 msec.
• Medical history of uncontrolled hypertension (NCI CTCAE grade 3 or 4) or diabetes mellitus.
• Known active central nervous system metastases and/or carcinomatous meningitis.
• Prior history of another cancer within the previous 5 years with the exception of adequately treated basal cell carcinoma or cervical intraepithelial neoplasia, cervical carcinoma in situ or melanoma in situ.
• Another known malignancy other than breast cancer that is progressing or requires active treatment.
• Is pregnant or lactating, or is of child-bearing potential and not willing to use an approved method of contraception.
• Has a concomitant medical condition that precludes adequate study treatment compliance or assessment, such as bleeding disorders or any other medical condition that would increase risks of additional core biopsy for biomarkers.
• Is currently receiving treatment with a medication on the prohibited medication list for entinostat (See section 11.1 Appendix A and section 4.5).
• Has allergy to benzamides or inactive components of the study medication (entinostat).
• Inability to take oral medications (eg, impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral medications such as ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
• Is participating in another therapeutic clinical trial or has received another investigational agent within 30 days prior to informed consent.
• Known human immunodeficiency virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection which is allowed).
• Has acute or currently active/requiring anti-viral therapy, hepatic or biliary disease (with the exception of patients with Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator assessment).
• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.

Sponsors & Collaborators

• UNC Lineberger Comprehensive Cancer Center: lead
• Syndax Pharmaceuticals: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Lineberger Comprehensive Cancer Center at University of North Carolina, Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

MeSH Terms

Conditions

Breast Neoplasms; Triple Negative Breast Neoplasms

Interventions

entinostat

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Lisa Carey, MD

  UNC Lineberger Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 28, 2017
• First Posted: December 5, 2017
• Study Start: November 28, 2018
• Primary Completion: September 18, 2019
• Study Completion: October 11, 2019
• Last Updated: March 25, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)