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Pembrolizumab with or without Entinostat in Treating Patients with Bladder Urothelial Cancer

Trial Status: Active

This phase II trial studies the changes in immune response to pembrolizumab with or without entinostat in patients with bladder urothelial cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This study is being done to find out the effect of pembrolizumab and entinostat on tumor and immune cells. This may help the researchers to understand how pembrolizumab alone or in combination of with entinostat can help the immune system find and fightbladder urothelial cancer.

Inclusion Criteria

  • Written informed consent obtained to participate in the study and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information
  • Subjects must agree to donate tumor tissue from their transurethral resection of the bladder tumor (TURBT) and from their cystectomy, as well as agree to donate whole blood prior to initiating therapy, during study therapy and at cystectomy
  • Eastern Cooperative Oncology Group performance status of =< 2
  • Histological confirmation of urothelial carcinoma of the bladder; those with mixed histology, including a component of urothelial carcinoma, are eligible. Pure small cell carcinoma, pure adenocarcinoma, and pure squamous cell carcinoma are excluded
  • Subject has clinical stage T2-T4a N0/X M0 urothelial carcinoma. Clinical T stage is based on the pre-study standard of care transurethral resection of the bladder tumor (TURBT) sample and imaging studies (abdominal/pelvic computed tomography [CT] or magnetic resonance imaging [MRI] scan and CT scan of the chest performed within 4 weeks prior to treatment initiation)
  • Available formalin-fixed paraffin-embedded (FFPE) archival tumor specimen that contains sufficient tissue to generate at least 15 (preferably 20) unstained slides, each with tissue sections that are 5-10 microns thick
  • Subject is planned to undergo definitive surgery (radical cystectomy)
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within 10 days of treatment initiation)
  • Platelets >= 100 x 10^9/L (within 10 days of treatment initiation)
  • Hemoglobin >= 9 g/dL (within 10 days of treatment initiation)
  • Estimated glomerular filtration rate (GFR) per Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation >= 30 mL/min (within 10 days of treatment initiation)
  • Serum total bilirubin =< 1.5 mg/dL (subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level > 1.5 mg/dL if their conjugated bilirubin is < 1.5 x ULN) (within 10 days of treatment initiation)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (within 10 days of treatment initiation)
  • International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or activated partial prothrombin time (aPTT) is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)
  • Subject refuses to receive or is ineligible to receive cisplatin-based neoadjuvant chemotherapy. Determination of ineligibility for cisplatin is based on at least one of the following criteria: * Eastern Cooperative Oncology Group performance status of 2 * GFR per CKD-EPI equation =< 60 mL/min * NCI CTCAE version 5.0 grade >= 2 hearing loss * NCI CTCAE version 5.0 grade >= 2 neuropathy
  • Female subjects of childbearing potential should have a negative serum pregnancy within 72 hours prior to receiving the first dose of the study treatment. 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
  • Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
  • Male subjects of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
  • Subject is able to tolerate and retain oral medication
  • Life expectancy greater than 3 months

Exclusion Criteria

  • Subject is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of pembrolizumab
  • Subject has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Inhaled and topical steroids are allowed
  • Subject has a known history of active tuberculosis
  • Subject has known hypersensitivity to pembrolizumab or any of its excipients
  • Subject has allergy to benzamide or inactive ingredients of entinostat
  • Subject has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
  • Subject has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  • Subject has a history of (non-infectious) pneumonitis that required steroids or a current pneumonitis
  • Subject has an active infection requiring systemic therapy
  • Subject has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. Please note that subjects with grade >= 2 peripheral neuropathy, are allowed on this study in addition to subjects with grade < 2 peripheral neuropathy.
  • Subject has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • Subject is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
  • Subject has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
  • Subject has had prior systemic cytotoxic chemotherapy for urothelial carcinoma (prior intravesicular chemotherapies are permitted)
  • Subject is receiving histone deacetylase inhibitors, including valproic acid, deoxyribonucleic acid (DNA) methyltransferase inhibitors
  • Subject is receiving drugs that are known to inhibit or induce P-glycoprotein (gp)
  • Subject has gastrointestinal impairment that may significantly affect absorption of entinostat, such as ulcerative disease, malabsorption syndrome, and a history of small bowel resection
  • Subject has received prior radiation therapy to the bladder for the purpose of treating urothelial carcinoma
  • Subject has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
  • Subject has known history of hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] has been detected)
  • Subject has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
  • Subject uses drugs or herbal supplements that are known sensitive CYP substrates of CYP1A2, CYP2C8, CYP3A with narrow therapeutic range

North Carolina

Chapel Hill
UNC Lineberger Comprehensive Cancer Center
Status: ACTIVE
Contact: Tracy L. Rose
Phone: 919-962-8561

PRIMARY OBJECTIVE:

I. To characterize the changes in immune gene signature (IGS) expression in blood and tumor samples after treatment with pembrolizumab alone compared to the combination of pembrolizumab and entinostat.

SECONDARY OBJECTIVES:

I. To characterize the changes in neoantigen expression and T cell receptor (TCR) clonality in blood and tumor samples after treatment with pembrolizumab alone and the combination of pembrolizumab and entinostat.

II. To evaluate the changes in STAT and NF-kappaB gene signatures and histone acetylation (H3K9Ac, H3K27Ac, and others) levels after combination treatment with pembrolizumab and entinostat as compared to pembrolizumab alone (subset of subjects with frozen transurethral resection of a bladder tumor [TURBT] and cystectomy tissue available).

III. To document safety, tolerability, and feasibility of preoperative administration of pembrolizumab with and without entinostat in cisplatin-ineligible muscle-invasive bladder cancer (MIBC) patients prior to scheduled surgical resection (National Cancer Institute-Common Terminology for Adverse Events [NCI-CTCAE version (v) 5.0]).

IV. To define the pathologic response rate (< pT2) and pathologic complete response rate (pT0) after treatment with pembrolizumab alone and the combination of pembrolizumab and entinostat.

EXPLORATORY OBJECTIVES:

I. To evaluate changes in the urinary microbiome after treatment with pembrolizumab alone and the combination of pembrolizumab and entinostat.

II. To establish a functional platform for window of opportunity studies that will allow for rapid study of immunogenomic changes to the tumor microenvironment and peripheral blood after treatment with pembrolizumab in rational combination with immunomodulatory agents.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I: Patients receive pembrolizumab intravenously (IV) over 30 minutes on days 1 and 22 and then undergo cystectomy within 10 weeks of beginning study therapy. Patients also undergo blood and tumor tissue collection prior to receiving study drugs and at time of cystectomy.

ARM II: Patients receive entinostat orally (PO) once daily (QD) on days 1, 8, and 15, pembrolizumab IV over 30 minutes on days 1 and 22, and then undergo cystectomy within 10 weeks of beginning study therapy. Patients also undergo blood and tumor tissue collection prior to receiving study drugs and at time of cystectomy.

After completion of study treatment, patients are followed up at 4-8 weeks after cystectomy,

Trial Phase Phase II

Trial Type Treatment

Lead Organization
UNC Lineberger Comprehensive Cancer Center

Principal Investigator
Tracy L. Rose

  • Primary ID LCCC1827
  • Secondary IDs NCI-2019-03899, 183143
  • Clinicaltrials.gov ID NCT03978624