Pembrolizumab in Treating Patients With Metastatic Castration Resistant Prostate Cancer Previously Treated With Enzalutamide

Study Overview
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Brief Summary
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This phase II trial studies how well pembrolizumab works in treating patients with prostate cancer that has spread to other places in the body and keeps growing even when the amount of testosterone in the body is reduced to very low levels despite previous treatment with enzalutamide. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Measure the anti-cancer activity of pembrolizumab in men with metastatic, castration resistant prostate cancer. SECONDARY OBJECTIVES: I. To investigate immunological and genetic parameters to evaluate for possible markers and functional changes that are predictive of a clinical response or linked to response or resistance to PD-1 inhibition. II. To collect circulating tumor cells (CTCs) and determine the degree to which tumor characteristics are shared by the CTCs. III. Changes in T cell numbers, activation, and phenotype as measured in whole blood at diagnosis and throughout therapy. IV. Systemic inflammatory markers: serum interleukin (IL)-8, IL-6, IL-1, tumor necrosis factor (TNF) and transforming growth factor (TGF)-beta. V. Objective disease response by radiographs. VI. Prostate-specific antigen (PSA) progression free survival. VII. Overall survival. VIII. Microbiome and correlation with response. TERTIARY OBJECTIVES: I. Additional genetic (deoxyribonucleic acid [DNA], ribonucleic acid [RNA]) and protein analyses will be conducted to further evaluate immunotherapy and profile/characterize disease. OUTLINE: INITIAL TREATMENT PHASE: Patients who are progressing on enzalutamide will receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. Patients continue to receive standard of care enzalutamide orally (PO) daily. MONITORING PHASE: After completion of the initial treatment phase, patients continue to receive standard of care enzalutamide PO daily for the duration of the trial. RETREATMENT PHASE: Patients with disease response or stability after the initial treatment phase will receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for an additional 4 courses in the absence of disease progression or unacceptable toxicity. Patients continue to receive standard of care enzalutamide PO daily for the duration of the trial. After completion of study treatment, patients are followed up at 30 days, and then every 12 weeks for 2.5 years.

Official Title
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Addition of Pembrolizumab Upon Progression on Enzalutamide in Men With mCRPC

Conditions
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Castration-Resistant Prostate Carcinoma, Hormone-Resistant Prostate Cancer, PSA Progression, Recurrent Prostate Carcinoma, Stage IV Prostate Adenocarcinoma AJCC v7

Intervention / Treatment
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* Drug: Enzalutamide
* Other: Laboratory Biomarker Analysis
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ENTRY CRITERIA: Metastatic, castration resistant prostate cancer progressing on enzalutamide after initial response to enzalutamide Histologically or cytologically confirmed adenocarcinoma of the prostate without pure small cell carcinoma; patients without histologically confirmed adenocarcinoma may be eligible if both the treating physician and the study principal investigator (PI) agree that the patient?s history is unambiguously indicative of advanced adenocarcinoma Be willing and able to provide written informed consent/assent for the trial Have metastatic disease Have permission to access tissue from an archival tissue sample; (absence of archival tissue will not preclude trial participation) Has a metastatic deposit that can be biopsied Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale Absolute neutrophil count (ANC) >= 1,500/mcL, performed within 28 days of treatment initiation Platelets >= 100,000/mcL, performed within 28 days of treatment initiation Hemoglobin >= 9 g/dL or >= 5.6 mmol/L, performed within 28 days of treatment initiation Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]); creatinine clearance should be calculated per institutional standard, performed within 28 days of treatment initiation Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN, performed within 28 days of treatment initiation Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases, performed within 28 days of treatment initiation International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (only if submitting to a biopsy), performed within 28 days of treatment initiation Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (only if submitting to a biopsy), performed within 28 days of treatment initiation Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy Have a PSA or radiographic progression on enzalutamide; PSA progression is defined as two consecutive increases in PSA with the second level obtained at least 3 weeks after the first, and the second level of at least 0.5 ng/mL; soft tissue disease progression defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or >= 2 new lesions on bone scan Have had either surgical castration OR be on luteinizing hormone-releasing hormone (LHRH) agonist or antagonist therapy with serum testosterone < 50 ng/dl AND agree to stay on LHRH agonist or antagonist therapy during the study Exclusion Criteria: 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 treatment 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; the use of physiologic doses of corticosteroids may be approved after consultation with the sponsor Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier; denosumab is a prohibited medication on study and for 4 weeks prior to day 1 Has had chemotherapy for castration-resistant disease; chemotherapy for castration-sensitive disease is permitted Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy 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 bladder cancer that has undergone potentially curative therapy Has known brain metastases and/or carcinomatous meningitis Has a history of seizure Has allergy to enzalutamide Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; a severe autoimmune disease is one that requires a significant medical intervention such as hospitalization; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjogren?s syndrome will not be excluded from the study Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis Has an active infection requiring systemic therapy 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 Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial Has received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-ligand (L)1, anti-PD-L2, anti-cluster of differentiation (CD)137, 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); previous treatment with sipuleucel-T is permitted Has plans to receive cytotoxic chemotherapy, immune checkpoint inhibitors (eg CTLA-4 blockade), sipuleucel-T, radiopharmaceuticals, abiraterone or other experimental therapy during this study period Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) Has known active hepatitis B (e.g., hepatitis B virus surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) Has received a live vaccine within 30 days prior to the first dose of trial treatment Has rapid progression of visceral disease and, thus is a candidate for docetaxel; this determination will be at the discretion of the treating physician

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (pembrolizumab)<br>INITIAL TREATMENT PHASE: Patients who are progressing on enzalutamide will receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. Patients continue to receive standard of care enzalutamide PO daily. MONITORING PHASE: After completion of the initial treatment phase, patients continue to receive standard of care enzalutamide PO daily for the duration of the trial. RETREATMENT PHASE: Patients with disease response or stability after the initial treatment phase will receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for an additional 4 courses in the absence of disease progression or unacceptable toxicity. Patients continue to receive standard of care enzalutamide PO daily for the duration of the trial. | Drug: Enzalutamide<br>* Given PO<br>* Other names: Xtandi;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA response, defined by a PSA decrease of at least 50% confirmed by a second measurement at least 3 weeks later | One-sample binomial test will be used to assess whether the proportion of PSA response (PSA decrease of at least 50%) is significantly greater than 0.05. Univariable logistic regression analysis will be conducted to assess the association between immunological parameters and PSA response responses. Scale in logit will be assessed for all continuous parameters that are identified to be significantly associated with PSA response. Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval. | Up to 30 days after completion of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in T cell activation as measured in whole blood | Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval, and the continuous variables will be summarized using nmissing, mean, std, median, min, and max. | Baseline to up to 4 weeks | 
| Changes in T cell numbers as measured in whole blood | Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval, and the continuous variables will be summarized using nmissing, mean, std, median, min, and max. | Baseline to up to 4 weeks | 
| Changes in T cell phenotype as measured in whole blood | Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval, and the continuous variables will be summarized using nmissing, mean, std, median, min, and max. | Baseline to up to 4 weeks | 
| Circulating tumor cells | Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval, and the continuous variables will be summarized using nmissing, mean, std, median, min, and max. | Up to 4 weeks | 
| Deoxyribonucleic acid mutation |  | Up to 2.5 years | 
| Immunohistochemistry for PD-1, PD-L1 and PD-L2 in prostate tissue | Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval, and the continuous variables will be summarized using nmissing, mean, std, median, min, and max. | Baseline | 
| Immunological parameters, including leukocytes, lymphocytes, and macrophages in prostate tissue | Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval, and the continuous variables will be summarized using nmissing, mean, std, median, min, and max. | Baseline | 
| Objective disease response by radiographs | Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval. | Up to 2.5 years | 
| Overall survival |  | Up to 2.5 years | 
| Percent change in PSA | Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval, and the continuous variables will be summarized using number (n)missing, mean, standard deviation (std), median, minimum (min), and maximum (max). | Baseline to up to 30 days after completion of study treatment | 
| PSA progression free survival, where the definition of progression will be PSA progression per Prostate Cancer Working Group 2 criteria | If there is a decline from baseline, progression is an increase in PSA that is 25% and 2 ng/ml above the nadir, which is confirmed by a second value 3 or more weeks later (i.e., a confirmed rising trend). Kaplan-Meier curve will be plotted to illustrate the PSA progression free survival for all, and for subgroups (abiraterone versus no prior abiraterone and sipuleucel-T versus no prior sipuleucel-T). Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval. | Up to 2.5 years | 
| Systemic inflammatory markers (serum IL-8, IL-6, IL-1, TNF and TGF-beta) | Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval, and the continuous variables will be summarized using nmissing, mean, std, median, min, and max. | Up to 4 weeks |