Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

Window of Opportunity Study of Pembrolizumab Alone and in Combinations in Bladder Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03978624
Recruitment Status : Recruiting
First Posted : June 7, 2019
Last Update Posted : July 19, 2019
Sponsor:
Information provided by (Responsible Party):
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).

Condition or disease Intervention/treatment Phase
Bladder Cancer Drug: Pembrolizumab Drug: Entinostat Phase 2

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.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Window of Opportunity Platform Study to Define Immunogenomic Changes With Pembrolizumab Alone and in Rational Combinations in Muscle-Invasive Bladder Cancer
Estimated Study Start Date : August 2019
Estimated Primary Completion Date : October 1, 2021
Estimated Study Completion Date : November 1, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer

Arm Intervention/treatment
Experimental: A: Pembrolizumab alone
Subjects will be administered pembrolizumab alone 200 mg IV on day 1 and day 22
Drug: Pembrolizumab
200 mg IV on day 1 and day 22
Other Name: Keytruda

Experimental: B: Pembrolizumab plus Entinostat
Subjects will be administered pembrolizumab on day 1 and day 22 and entinostat 5 mg given orally on day 1, day 8 and day 15
Drug: Pembrolizumab
200 mg IV on day 1 and day 22
Other Name: Keytruda

Drug: Entinostat
5 mg given orally on day 1, day 8 and day 15
Other Names:
  • SNDX-275
  • MS-275




Primary Outcome Measures :
  1. Change from baseline in Z-score of T cell CD8 immune 37-gene signature [ Time Frame: Less than 10 weeks ]
    The primary objective will be assessed by the change in the T cell immune gene signature in patients treated with pembrolizumab compared to those treated with pembrolizumab plus entinostat. Gene expression for each gene included in the T cell CD8 immune 37-gene signature (Bindea et al, Immunity 2013) will be quantified based on messenger RNA sequencing (mRNAseq). For each patient in each treatment group, the change in Z-score of the T cell immune gene signature will be calculated from the post-treatment tumor biopsy (cystectomy) compared with the pre-treatment biopsy and changes in Z-scores in the two groups will be compared.


Secondary Outcome Measures :
  1. Change from baseline in number and character of neoantigens [ Time Frame: Less than 10 weeks ]
    Neoantigens will be predicted based on whole exome sequencing data using mRNAseq-based filtering. The number of predicted neoantigens will be calculated in the pre-treatment biopsy specimen and the post-treatment cystectomy specimen for each patient. The change from baseline in number and character of neoantigens will be described and compared for each treatment group. Similarly, the T cell receptor (TCR) repertoire will be sequenced and clonality in blood and tumor will be compared between pre- and post-treatment samples for each patient, and change in clonality will be compared between treatment groups.

  2. Change from baseline in Signal transducer and activator of transcription factors (STAT) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) gene signatures and histone acetylation (H3K9Ac, H3K27Ac, and others) levels [ Time Frame: 10 weeks ]
    Compare changes in STAT and NF-κB 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 TURBT Gene expression for each gene in representative STAT, NF-κB, and histone acetylation gene signatures (from MSigDB) will be quantified based on mRNA sequencing. Change in Z-score of these gene signatures will be calculated from pre- and post-treatment tissue samples for patients in both cohorts (pembrolizumab alone or pembrolizumab plus entinostat), and then changes in Z-scores will be compared between cohorts.

  3. Frequency and Severity by grade of Adverse Events as Assessed by CTCAE v5.0 [ Time Frame: 10 weeks ]
    The analysis of the toxicity and safety will be based on the frequency of adverse events and their severity. Worst toxicity grades per subject will be tabulated for adverse events and laboratory measurements by using the National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE version 5.0) and will be reported in the form of frequency tables.

  4. Proportion of patients who have no cancer in tissue samples at surgery (pathologic Complete Response, or only non-invasive cancer (pathologic Partial Response) [ Time Frame: 10 weeks ]
    The proportion of patients who have a pathologic response to less than stage 2 (<pT2) will be reported along with a 95% confidence interval. Similarly, the proportion of patients who have a complete response (pT0) will be reported.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03978624


Contacts
Layout table for location contacts
Contact: Chase Thurman 9849748659 chase_thurman@med.unc.edu
Contact: GU Study Coordinator 9199664432

Locations
Layout table for location information
United States, North Carolina
Lineberger Comprehensive Cancer Center Recruiting
Chapel Hill, North Carolina, United States, 27599
Sub-Investigator: Matthew Milowsky, MD         
Principal Investigator: Tracy Rose, MD         
Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
Investigators
Layout table for investigator information
Principal Investigator: Tracy L Rose, MD UNC- Chapel HIll

Layout table for additonal information
Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT03978624     History of Changes
Other Study ID Numbers: LCCC1827
First Posted: June 7, 2019    Key Record Dates
Last Update Posted: July 19, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by UNC Lineberger Comprehensive Cancer Center:
Muscle Invasive Bladder Cancer
MIBC
pembrolizumab
entinostat

Additional relevant MeSH terms:
Layout table for MeSH terms
Pembrolizumab
Urinary Bladder Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Entinostat
Antineoplastic Agents, Immunological
Antineoplastic Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action