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

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


  • Org Study ID: LCCC1827
  • Secondary ID:
  • NCT ID: NCT03978624
  • NCT Alias:
  • Sponsor: UNC Lineberger Comprehensive Cancer Center - Other
  • Source: UNC Lineberger Comprehensive Cancer Center

Brief Summary

This is a non-randomized, open-label, window of opportunity platform study in patients with muscle-invasive bladder cancer (MIBC) deemed ineligible to receive cisplatin, who are scheduled to undergo definitive surgery (radical cystectomy). The primary objective of this study is to assess changes to immunogenomic markers after treatment with pembrolizumab alone and in rational combination with epigenomic or other immunomodulatory agents currently in development for urothelial carcinoma (UC).

Detailed Description


As an initial proof of concept, the investigators will investigate immunogenomic changes with
pembrolizumab alone and in combination with a selective class I histone deacetylase (HDAC)
inhibitor (entinostat).

The study will enroll 20 subjects with a confirmed diagnosis of MIBC (cT2-T4aN0M0) who are
ineligible for (based on consensus criteria)[1] or refuse neoadjuvant cisplatin-based
chemotherapy. Subjects must consent to having tissue collected for research purposes during
the scheduled surgery prior to study entry. After screening and enrollment, 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 radical cystectomy. Subjects will be administered pembrolizumab alone 200 mg IV
on day 1 and day 22 (Arm 1) or pembrolizumab on day 1 and day 22 and entinostat 5 mg given
orally on day 1, day 8 and day 15 (Arm 2).

Blood and tumor will then be collected from each subject at the time of cystectomy (within 10
weeks after initiation of protocol therapy) [2][3]. 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 [4]. 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.

Overal Status Start Date Phase Study Type
Recruiting August 2019 Phase 2 Interventional

Primary Outcomes:

Primary Outcome 1 - Measure: Change from baseline in Z-score of T cell CD8 immune 37-gene signature

Primary Outcome 1 - Time Frame: Less than 10 weeks

Condition:

  • Bladder Cancer

Eligibility

Criteria:
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.

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.

- 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 is receiving drugs that are known to inhibit or induce P-gp (see Appendix B).

- 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., 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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Gender: All

Minimum Age: 18 Years

Maximum Age: 99 Years

Healthy Volunteers: No

Official Information

Name: Tracy L Rose, MD

Role: Principal Investigator

Affiliation: UNC- Chapel HIll

Overall Contact

Name: Chase Thurman

Phone: 9849748659

Email: chase_thurman@med.unc.edu

Location

Facility Status Contact
Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina 27599
United States
Recruiting