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

Phase 2

Active, not recruiting

Conditions: Recurrent Prostate Carcinoma
Hormone-Resistant Prostate Cancer
Stage IV Prostate Adenocarcinoma Cancer AJCC v8
Castration-Resistant Prostate Carcinoma
PSA Progression

Interventions: Drug: Enzalutamide
Other: Laboratory Biomarker Analysis
Biological: Pembrolizumab

Registration Number: NCT02312557

Lead Sponsor: OHSU Knight Cancer Institute

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: Male

Target Recruitment: 58

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
Be >= 18 years of age on day of signing informed consent
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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (pembrolizumab)	Pembrolizumab	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.
Treatment (pembrolizumab)	Laboratory Biomarker Analysis	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.
Treatment (pembrolizumab)	Enzalutamide	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.

Primary Outcome Measures

Name	Time	Method
PSA Response, Defined by a PSA Decrease of at Least 50% Confirmed by a Second Measurement at Least 3 Weeks Later	Up to 30 days after completion of study treatment, up to approximately 2.5 years total.	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.

Secondary Outcome Measures

Name	Time	Method
Changes in T Cell Activation as Measured in Whole Blood	Baseline to up to 4 weeks	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.
Changes in T Cell Numbers as Measured in Whole Blood	Baseline to up to 4 weeks	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.
Changes in T Cell Phenotype as Measured in Whole Blood	Baseline to up to 4 weeks	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.
Circulating Tumor Cells	Up to 4 weeks	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.
Deoxyribonucleic Acid Mutation	Up to 2.5 years
Immunohistochemistry for PD-1, PD-L1 and PD-L2 in Prostate Tissue	Baseline	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.
Immunological Parameters, Including Leukocytes, Lymphocytes, and Macrophages in Prostate Tissue	Baseline	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.
Objective Disease Response by Radiographs	Up to 2.5 years	Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval.
Overall Survival	Up to 2.5 years
Percent Change in PSA	Baseline to up to 30 days after completion of study treatment	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).
PSA Progression Free Survival, Where the Definition of Progression Will be PSA Progression Per Prostate Cancer Working Group 2 Criteria	Up to 2.5 years	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.
Systemic Inflammatory Markers (Serum IL-8, IL-6, IL-1, TNF and TGF-beta)	Up to 4 weeks	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.