Pembrolizumab and Cryosurgery in Treating Patients With Newly Diagnosed, Oligo-metastatic Prostate Cancer

PRIMARY OBJECTIVES:

I. Assess feasibility via the proportion of men reaching a low prostate-specific antigen
(PSA) nadir (< 0.6 ng/ml) at 1 year.

II. Evaluate the safety of cryotherapy to the prostate combined with pembrolizumab.

TERTIARY OBJECTIVES:

I. To evaluate the effects of combination cryotherapy / pembrolizumab on programmed cell
death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) expression in the prostate as
assessed by biopsy performed 6 months post treatment.

OUTLINE:

Patients receive standard of care androgen ablation with degarelix subcutaneously (SC) once a
month for 8 months. Within 1 month of receiving degarelix, patients receive pembrolizumab
intravenously (IV) over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 6
courses in the absence of disease progression or unacceptable toxicity. Within 3 days of
receiving the first dose of pembrolizumab, patients undergo whole gland cryoablation of the
prostate.

After completion of study treatment, patients are followed up at 30 days and then every 12
weeks for up to 1 year.

Inclusion Criteria:

- Have histologically or cytologically diagnosed oligo-metastatic prostate cancer;
oligo-metastatic disease is defined to reflect men with low volume disease;
specifically, oligo-metastatic disease is defined as less than 5 extra-pelvic
metastases; metastatic lesions may be lymph nodes

- Be willing and able to provide written informed consent/assent for the trial

- Have available tissue from an archival tissue sample or newly obtained core or
excisional biopsy of a tumor lesion

- Eastern Cooperative Oncology Group (ECOG) performance scale status of 0 or 1

- Demonstrate adequate organ function, all screening labs should be performed within 14
days of treatment initiation

- Absolute neutrophil count (ANC) >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L

- Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration
rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =<
1.5 X upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels >
1.5 X institutional upper limit of normal (ULN)

- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 ULN

- 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

- International normalized ratio (INR) or prothrombin time (PT) =< 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

- 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 anticoagulant

- Have testosterone greater than 50 ng/dl

- 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

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

- 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

- 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 cervical cancer that has undergone potentially curative therapy

- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis; subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment

- 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; 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
Sjorgen's syndrome will not be excluded from the study

- Has evidence of interstitial lung disease or active, non-infectious 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

- Is expecting to 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

- Has received prior therapy with an anti-PD-1, anti-PD-L1, 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)

- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

- Has known active hepatitis B (e.g., hepatitis B 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 severe voiding symptoms (International Prognostic Scoring System [IPSS] > 20) or
urinary retention requiring a catheter

- Has contraindications to cryotherapy of the prostate, including: previous
transurethral prostatic resection (TURP) with persistent transurethral resection (TUR)
defect, existing peri-anal or recto-urethral fistula, previous external beam radiation
therapy or brachytherapy, coagulopathy, inability to tolerate anesthesia (spinal or
general), inability to tolerate transrectal ultrasound (i.e. history of previous
abdominal perineal resection)