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

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 (deoxyribonucelic 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.

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