Clinical Trials /

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

NCT03978624

Description:

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).

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: LCCC1827
  • NCT ID: NCT03978624

Conditions

  • Bladder Cancer

Interventions

DrugSynonymsArms
PembrolizumabKeytrudaA: Pembrolizumab alone
EntinostatSNDX-275, MS-275B: Pembrolizumab plus Entinostat

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
A: Pembrolizumab aloneExperimentalSubjects will be administered pembrolizumab alone 200 mg IV on day 1 and day 22
  • Pembrolizumab
B: Pembrolizumab plus EntinostatExperimentalSubjects will be administered pembrolizumab on day 1 and day 22 and entinostat 5 mg given orally on day 1, day 8 and day 15
  • Pembrolizumab
  • Entinostat

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
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Change from baseline in Z-score of T cell CD8 immune 37-gene signature
Time Frame:Less than 10 weeks
Safety Issue:
Description: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

Measure:Change from baseline in number and character of neoantigens
Time Frame:Less than 10 weeks
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure:Frequency and Severity by grade of Adverse Events as Assessed by CTCAE v5.0
Time Frame:10 weeks
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:UNC Lineberger Comprehensive Cancer Center

Trial Keywords

  • Muscle Invasive Bladder Cancer
  • MIBC
  • pembrolizumab
  • entinostat

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