Window of Opportunity Platform Study to Define Immunogenomic Changes With Pembrolizumab Alone and in Rational Combinations in Muscle-Invasive Bladder Cancer

  • End date
    Nov 1, 2023
  • participants needed
  • sponsor
    UNC Lineberger Comprehensive Cancer Center
Updated on 28 October 2022
radical cystectomy
bladder cancer
invasive bladder cancer
transitional cell carcinoma
transurethral resection
bladder tumor
bladder carcinoma


This is an open-label, window of opportunity platform study for subjects with muscle-invasive bladder cancer (MIBC) who are deemed ineligible or refuse cisplatin-based neoadjuvant chemotherapy and are scheduled to undergo definitive surgery (radical cystectomy), or are planning to undergo trimodality therapy (maximal transurethral resection of the bladder tumor followed by concurrent chemoradiation).

The primary objective of this study is to assess changes to immunogenomic markers after treatment with pembrolizumab alone and in combination with the selective class I histone deacetylase (HDAC) inhibitor (entinostat).


The study will enroll 20 subjects with a confirmed diagnosis of MIBC (cT2-T4aN0M0) who are planned for definitive therapy with either radical cystectomy without cisplatin-based neoadjuvant chemotherapy or trimodality therapy. Subjects who are planned to undergo radical cystectomy must be deemed ineligible for (based on consensus criteria) [1] or refuse neoadjuvant cisplatin-based chemotherapy. Prior to study entry, subjects must consent to having tissue collected for research purposes during the scheduled cystectomy or maximal TURBT. After screening and enrollment, baseline blood and archived transurethral resection of the bladder tumor (TURBT) tumor tissue will be collected from each subject for baseline analyses. Subjects will then start on clinical trial treatment followed by either radical cystectomy or maximal TURBT followed by chemoradiation.

Blood and tumor will be collected from each subject at the time of cystectomy or maximal TURBT. The investigators do not anticipate delays in surgery due to the planned schedule of the preoperative treatment administration for the purposes of this study and based on the phase II ENCORE 601 trial (pembrolizumab and entinostat in melanoma) which reported an acceptable safety profile. Phase I data identified grade 1/2 fatigue as the most common entinostat-related toxicity, with neutropenia and anemia only occurring at doses exceeding those proposed for this study. Safety stopping rules for drug-related toxicity will dictate whether the trial should be halted if subjects are experiencing drug-related toxicity that delays or interferes with standard of care procedures.

Condition Bladder Cancer
Treatment Pembrolizumab, entinostat
Clinical Study IdentifierNCT03978624
SponsorUNC Lineberger Comprehensive Cancer Center
Last Modified on28 October 2022


Yes No Not Sure

Inclusion Criteria

Written informed consent obtained to participate in the study and 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, and at cystectomy
Age ≥18 years at the time of consent
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 CT or 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)
Subject demonstrates adequate organ function as defined by the protocol; all screening laboratory assessments should be performed 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
Glomerular filtration rate (GFR) per Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation ≤ 60 mL/min
NCI CTCAE v5.0 Grade ≥ 2 hearing loss
NCI CTCAE v5.0 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
Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in Appendix D, 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 as outlined in Appendix D, starting with the first dose of study therapy
through 120 days after the last dose of study therapy
Subject is able to tolerate and retain oral medication
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
Life expectancy greater than 3 months
for the subject

Exclusion Criteria

Subject has a known history of active tuberculosis
Subject is currently participating in or has participated in a study of an
Subject has known hypersensitivity to pembrolizumab or any of its excipients
investigational agent or using an investigational device within 4 weeks of the first
Subject has allergy to benzamide or inactive ingredients of entinostat
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 an active infection requiring systemic therapy
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 is receiving drugs that are known to inhibit or induce P-gp (see Appendix B)
Subject has active autoimmune disease that has required systemic treatment in the past
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 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
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, DNA
methyltransferase inhibitors
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
Subject has known history of Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g
HCV 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-Guérin (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 cytochromes P450
(CYP) substrates of CYP1A2, CYP2C8, CYP3A with narrow therapeutic range
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