Pembrolizumab in Metastatic Castration Resistant Prostate Cancer (mCRPC) With or Without DNA Damage Repair Defects

This is a multicenter phase 2 open label study of pembrolizumab in patients with metastatic
castrate resistant prostate cancer (mCRPC) with or without DNA damage repair defects.

All subjects will receive pembrolizumab 200mg intravenously (IV) every 3 weeks until disease
progression or unacceptable toxicity. The primary endpoint of the study is objective response
rate (ORR) according to immune-mediated response criteria (irRC).

Inclusion Criteria:

1. Histologically documented adenocarcinoma of the prostate.

2. Metastatic castration resistant prostate cancer with castrate-level testosterone (<50
ng/dL).

a. Subjects must maintain a castrate-level testosterone during the study.

3. Disease progression defined by one or more of the following three criteria:

1. PSA > 2.0 ng/mL and rising PSA by at least 2 consecutive measurements a minimum
of 1-week apart.

2. Soft tissue progression as defined by RECIST v1.1 criteria

3. Bone disease progression as defined by Prostate Cancer Clinical Trials Working
Group 3 (PCWG3)

4. Have measurable disease based on RECIST v.1.1 and irRC for response assessment.

a. Must have at least one lesion that is 10mm in longest diameter for a soft tissue
lesion or 15mm in short axis for a lymph node.

5. Have received prior abiraterone and/or enzalutamide.

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

7. Be ≥ 18 years of age on day of signing informed consent.

8. Be willing to provide archival tissue from prior biopsy or surgery for prostate
cancer, if available.

9. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
Performance Scale.

10. Patients must discontinue antiandrogen therapy (i.e. bicalutamide, flutamide,
nilutamide) at least 4-6 weeks prior to registration with no evidence of PSA decline
after washout.

1. Bicalutamide: Washout period at least 6 weeks

2. Flutamide and nilutamide: Washout period at least 4 weeks

11. Patients must discontinue therapies for mCRPC, with the exception of
Gonadotropin-releasing hormone (GnRH) agent, for 5 half-lives or 28 days, whichever is
shorter.

1. For patients on abiraterone/prednisone, prednisone should be discontinued for at
least 7 days before starting study treatment.

2. Prior chemotherapy is allowed if no progression of disease on chemotherapy.

3. Prior treatment with sipuleucel-T, radium-223, or poly adenosine diphosphate
(ADP) ribose polymerase (PARP) inhibitor (e.g. olaparib) is allowed.

4. Tissue biopsy may be performed during washout period.

12. Demonstrate adequate organ function as defined as follows, all screening labs should
be performed within 10 days of treatment initiation.

a. Hematological

i. Absolute neutrophil count (ANC): ≥ 1,500 /microliters (mcL)

ii. Platelets: ≥ 100,000 / mcL

iii. Hemoglobin: ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or erythropoietin (EPO)
dependency (within 7 days of assessment)

b. Renal

i. Serum creatinine OR Measured or calculated a creatinine clearance (GFR can also be
used in place of creatinine or CrCl): ≤ 1.5 X upper limit of normal (ULN) OR ≥ 60
mL/min for subject with creatinine levels > 1.5 X institutional ULN

c. Hepatic

i. Serum total bilirubin: ≤ 1.5 X ULN

ii. Aspartate Aminotransferase (AST) (SGOT) and Alanine Aminotransferase (ALT) (SGPT):
≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases

iii. Albumin: > 2.5 mg/dL

d. Coagulation

i. 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

ii. 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

13. Male subjects of childbearing potential must 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.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
for the subject.

Exclusion Criteria:

1. Significant liver metastasis or disease-related bone pain requiring scheduled
narcotics.

2. Prior taxane-based chemotherapy with progressive disease on chemotherapy.

1. Prior docetaxel for metastatic hormone sensitive prostate cancer is allowed, if
no progression of disease on docetaxel as defined by RECIST v1.1 and PCWG3.

2. Prior taxane-based chemotherapy (i.e. docetaxel or cabazitaxel with or without
platinum agent) for mCRPC is allowed if no progression of disease on chemotherapy
as defined by RECIST v1.1 and PCWG3.

3. Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment.

4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy >10mg/day
or any other form of immunosuppressive therapy within 7 days prior to the first dose
of trial treatment.

5. Has a known history of active Bacillus Tuberculosis (TB).

6. Hypersensitivity to pembrolizumab or any of its excipients.

7. Has had a prior anti-cancer monoclonal antibody (mAb) 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.

8. 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.

1. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
may qualify for the study.

2. Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting
therapy.

9. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.

10. 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. This exception does not include
carcinomatous meningitis which is excluded regardless of clinical stability.

11. Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy < 10 mg of prednisone/day for adrenal or pituitary insufficiency,
etc.) is not considered a form of systemic treatment.

12. Has known history of, or any evidence of active, non-infectious pneumonitis.

13. Has an active infection requiring systemic therapy.

14. 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.

15. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.

16. 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.

17. Has received prior therapy with an anti-programmed cell death protein 1 (PD-1),
anti-PD-L1, or anti-PD-L2 agent.

18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., hepatitis C
virus [HCV] RNA [qualitative] is detected).

20. Has received a live vaccine within 30 days of planned start of study therapy. Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed.