Window of Opportunity Study of Pembrolizumab Alone and in Combinations in Bladder Cancer
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|ClinicalTrials.gov Identifier: NCT03978624|
Recruitment Status : Recruiting
First Posted : June 7, 2019
Last Update Posted : March 19, 2020
|Condition or disease||Intervention/treatment||Phase|
|Bladder Cancer||Drug: Pembrolizumab Drug: Entinostat||Phase 2|
This study 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) 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). 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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||20 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|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 :||March 31, 2020|
|Estimated Primary Completion Date :||October 1, 2022|
|Estimated Study Completion Date :||November 1, 2022|
Experimental: A: Pembrolizumab alone
Subjects will be administered pembrolizumab alone 200 mg IV on day 1 and day 22
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
200 mg IV on day 1 and day 22
Other Name: Keytruda
5 mg given orally on day 1, day 8 and day 15
- 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.
- 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.
- 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.
- 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.
- 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.
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
|Contact: Rachel Munozemail@example.com|
|Contact: Julie Maccarone||9199664432|
|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|
|Principal Investigator:||Tracy L Rose, MD||UNC- Chapel HIll|