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Entinostat and Capecitabine in Treating Patients with HER2 Negative Stage I-IV Invasive Breast Cancer

Trial Status: Active

This phase I / II trial studies side effects and best dose of entinostat and capecitabine in treating patients with HER2 negative stage I-IV invasive breast cancer. Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving entinostat and capecitabine may work better in treating patients with breast cancer.

Inclusion Criteria

  • Willingness and ability to provide written informed consent and to comply with the study protocol as judged by the investigator
  • PART A: DOSE-ESCALATION PHASE: Patients must have a histologically confirmed diagnosis of stage IV invasive breast cancer
  • PART A: DOSE-ESCALATION PHASE: Patients can have breast cancer with positive OR negative estrogen and progesterone receptor status. Patients must have negative HER-2 receptor status. Estrogen, progesterone, and HER2 receptor status must be assessed according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines. Estrogen receptor (ER) or progesterone receptor (PR) positivity is defined as >= 1% positive nuclear staining. HER-2 is negative if tumor testing shows: a) Immunohistochemistry (IHC) negative (0 or 1+) or b) In situ hybridization (ISH) negative using single probe or dual probe. If HER-2 IHC is 2+, ISH must be performed and negative. HER-2 equivocal is not eligible
  • PART B: EXPANSION PHASE: Patients must have a histologically confirmed diagnosis of stage I-III invasive breast cancer
  • PART B: EXPANSION PHASE: Patients with multifocal, multicentric, synchronous bilateral and primary inflammatory breast cancers are allowed * Multifocal disease is defined as more than one invasive cancer < 2 cm from the largest lesion within the same breast quadrant * Multicentric disease is defined as more than one invasive cancer >= 2 cm from the largest lesion within the same breast quadrant or more than one lesion in different quadrants * Synchronous bilateral disease is defined as invasive breast cancer with positive lymph nodes (axillary or intramammary) in at least one breast, diagnosed within 30 days of each other. NOTE: The tumor with the highest recurrence score should be used
  • PART B: EXPANSION PHASE: Patients can have breast cancer with positive OR negative estrogen and progesterone receptor status. Patients must have negative HER-2 receptor status. Estrogen, progesterone, and HER2 receptor status must be assessed according to ASCO/CAP guidelines. ER or PR positivity is defined as >= 1% positive nuclear staining. HER-2 is negative if tumor testing shows: a) IHC negative (0 or 1+) or b) ISH negative using single probe or dual probe. If HER-2 IHC is 2+, ISH must be performed and negative. HER-2 equivocal is not eligible
  • PART B: EXPANSION PHASE: Patients must have been treated with standard neoadjuvant chemotherapy with at least three cycles of taxane or anthracycline based regimen. Patients must be registered within 36 weeks after last dose of chemotherapy
  • PART B: EXPANSION PHASE: Patients must have histologically confirmed residual invasive carcinoma at the time of surgery (ypT1mi or greater) or positive lymph nodes (ypN0[itc] or greater)
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  • Subject must have a life expectancy >= 6 months
  • Absolute neutrophil count (ANC) >= 1,000 cells/mm^3
  • Platelets >= 100,000 cells/mm^3
  • Hemoglobin >= 9 g/dl (Note: The use of transfusion to achieve hemoglobin [Hgb] >= 9 g/dl is acceptable)
  • Serum creatinine =< 1.5 x institutional upper limit normal (IULN) OR glomerular filtration rate (GFR) >= 60 mL/min for patient with creatinine levels > 1.5 x institutional ULN
  • Bilirubin =< 1.5 x IULN OR direct bilirubin =< ULN for patients with total bilirubin levels > 1.5 x ULN
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 IULN
  • Alkaline phosphatase =< 2.5 IULN
  • If a female is of childbearing potential, she has a negative serum blood pregnancy test during screening and a negative urine pregnancy test within 3 days prior to receiving the first dose of study drug. If the screening serum test is done within 3 days prior to receiving the first dose of study drug, a urine test is not required
  • If a patient is of childbearing potential the patient must agree to use effective contraception during the study and for 120 days after the last dose of study drug * Non-childbearing potential is defined as (by other than medical reasons): ** >= 45 years of age and has not had menses for > 2 years ** Amenorrheic for < 2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation ** Post hysterectomy, oophorectomy or tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure otherwise the patient must be willing to use 2 adequate barrier methods throughout the study, starting with the screening visit through 120 days after the last dose of study drug
  • Non-vasectomized males must agree to use adequate contraception for at least 120 days after the last dose of study drug. Males must also abstain from sperm donations for at least 120 days after the last dose of study drug
  • Experienced resolution of toxic effect(s) of the most recent prior anti-cancer therapy to grade =< 2 (except alopecia and grade 3 neuropathy)

Exclusion Criteria

  • Subjects who have had chemotherapy, biological therapy, immunological therapy, radiation therapy, or hormonal therapy within 3 weeks prior to entering the study
  • Subjects who are unable or unwilling to discontinue use of prohibited medications
  • Subject is unable or unwilling to participate in a study related procedure
  • Subject is a prisoner
  • Subject has evidence or history of an uncontrolled bleeding disorder. Patients with chronic bleeding disorders that are controlled with treatment or not clinically relevant are allowed
  • Subjects with history of central nervous system (CNS) disease including primary brain tumor, seizures not controlled with standard medical therapy, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA), or subarachnoid hemorrhage within six months of study entry
  • Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment AND enrolling in the metastatic dose escalation phase of present study only
  • History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating investigator, including, but not limited to: * Myocardial infarction or arterial thromboembolic events within 6 months prior to screening or severe or unstable angina, New York Heart Association (NYHA) class III or IV disease, or a corrected QT (QTc) interval > 470 msec * Uncontrolled hypertension (defined as blood pressure [BP] > 160/100) or diabetes mellitus * Another known malignancy that is progressing or requires active treatment * Any prior history of other cancer within the prior 2 years with the exception of adequately treated non-melanoma skin cancer or cervical intraepithelial neoplasia ([CIN]/cervical carcinoma in situ or melanoma in situ) * Active infection requiring systemic therapy
  • Any contraindication to oral agents or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the investigator, would preclude adequate absorption
  • Allergy to benzamide or inactive components of entinostat
  • Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study
  • Currently participating and receiving investigational therapy on another study. If prior participation in a study of an investigational agent/device, last dose of investigational therapy or use of an investigational device must be greater than 4 weeks from the first dose of study drug in the present study
  • Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies), due to concerns for potential drug-drug interactions with entinostat and anti-retroviral medications
  • Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid [qualitative]). Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBc Ab] and absence of hepatitis B surface antigen [HBsAg]) are eligible. HBV DNA test must be performed in these patients prior to study treatment. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
  • If female, is pregnant or breastfeeding
  • The following medications are prohibited while the patient is receiving entinostat: * Any other HDAC inhibitor, including valproic acid * DNA methyltransferase inhibitors * Any additional anticancer agents (excluding entinostat and capecitabine), such as chemotherapy, immunotherapy, targeted therapy, biological response modifiers, or endocrine therapy, will not be allowed, even if utilized as treatment of non-cancer indications * Any investigational agents * Radiation therapy * Traditional herbal medicines; these therapies are not fully studied and their use may result in unanticipated drug-drug interactions that may cause or confound the assessment of toxicity

New York

Rochester
University of Rochester
Status: ACTIVE
Contact: Ajay Dhakal

Virginia

Charlottesville
University of Virginia Cancer Center
Status: ACTIVE
Contact: Patrick Michael Dillon
Phone: 434-924-9333

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose combination (MTDC) of entinostat and capecitabine in participants with metastatic breast cancer. (Part A)

II. To assess the safety of the MTDC from Part A in participants with high risk breast cancer after neo-adjuvant therapy. (Part B)

SECONDARY OBJECTIVES:

I. To assess the safety of the combination therapy through the evaluation of incidence and severity of adverse events (AEs). (Part A)

II. To estimate the tolerance of the combination of entinostat and capecitabine at the MTDC. (Part B)

III. To obtain preliminary estimates of disease-free survival after adjuvant treatment with capecitabine and entinostat. (Part B)

EXPLORATORY OBJECTIVES:

I. To describe the relationship of circulating tumor deoxyribonucleic acid (DNA) and circulating tumor cell measurement after surgery with the presence of residual disease at the time of surgery. (Part B)

II. To describe any changes in circulating tumor DNA and circulating tumor cells following treatment with entinostat and capecitabine. (Part B)

III. To describe the relationship of circulating tumor (ct)DNA or circulating tumor cells (CTCs) with disease free survival. (Part B)

IV. To describe any differences in mutation profiles between primary tumor and circulating tumor DNA. (Part B)

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive entinostat orally (PO) on days 1, 8, and 15, and capecitabine PO twice daily (BID) on days 1-14. Treatment repeats every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 21-31 days, every 3 months for 2 years, then every 6 months up to year 5, and then annually up to year 10.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
University of Virginia Cancer Center

Principal Investigator
Patrick Michael Dillon

  • Primary ID 20218
  • Secondary IDs NCI-2018-03617, Breast 49
  • Clinicaltrials.gov ID NCT03473639