Study Evaluating the Addition of Pembrolizumab to Radium-223 in mCRPC

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational intervention to learn whether the intervention works
in treating a specific disease. "Investigational" means that the intervention is being
studied.

The FDA (the U.S. Food and Drug Administration) has approved radium-223 by itself as a
treatment option for the participant's disease.

The FDA has not approved pembrolizumab for the participant's specific disease, but it has
been approved for other uses, such as a type of skin cancer called melanoma.

In this research study, the investigators are evaluating the immune response, safety and
tolerability of the combination of pembrolizumab (a type of immunotherapy drug) plus
radium-223. Pembrolizumab works to block the PD-1 pathway, which plays an important role in
lessening the activity of one's immune system to fight cancer. Pembrolizumab is therefore
referred to as a PD-1 inhibitor, and acts by stimulating the patient's T cells, which are
important immune cells, to attack tumors and treat cancer. Radium-223 targets cancer that
exists in the bone directly. Radium-223 binds to minerals in the bone to deliver radiation
directly to the cancer that has spread to the bones while limiting damage to the surrounding
body tissues. Part of this study is to look at whether the investigators may more effectively
control the participant's prostate cancer by combining these drugs. Radium-223 may kill
cancer cells and release proteins specific to the tumor. The participant's immune system can
then use those proteins to teach the T cells what the cancer looks like, and identify it for
attack. Pembrolizumab can increase the number and activity of these immune cells, building a
T cell "army" specialized to recognize and attack the cancer. The way these two drugs work on
the cancer and the immune system may result in better control of the tumor than just
radium-223 alone but needs to be investigated.

Inclusion Criteria:

- Histologically confirmed adenocarcinoma of the prostate

- Castration-resistant prostate cancer requires the following 3 criteria:

- Progression after surgical castration or on GnRH agonist or antagonist

- A castrate level of testosterone (<50ng/dL)

- Prostate cancer progression documented by PSA rise or bone progression according
to PCWG2

- There is no limit to number of prior therapies

- Metastatic disease by bone scan

- Age ≥18 years

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

- Be willing to undergo a core or excisional biopsy of a bone metastasis prior to study
drug initiation for tumor tissue. Newly-obtained is defined as a specimen obtained up
to 12 weeks (84 days) prior to initiation of treatment on Day 1. Bone biopsy can have
been done prior to screening; archival specimens of bone metastasis are permitted if
done for other purpose and available.

--If biopsy is non-diagnostic, patient must undergo repeat biopsy as proof of tumor
tissue by pathology review. Proof of tumor specimen is required for eligibility.

- Be willing to undergo a second core or excisional biopsy of a bone metastasis on
therapy (approximately after 8 weeks of study therapy or after 2 doses of radium-223
if delays have occurred).

- Demonstrate adequate organ function as defined below, all screening labs for
eligibility should be performed within 30 days prior to treatment initiation.

- Hematological

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

- Platelets ≥ 100,000 / mcL

- Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L; transfusions permitted

- Renal

--Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be
used in place of creatinine or CrCl) ≤ 1.5 X institutional upper limit of normal (ULN)
OR

≥30 mL/min for subject with creatinine levels > 1.5 X institutional ULN

- Hepatic

- Serum total bilirubin ≤ 1.5 X institutional ULN OR Direct bilirubin ≤
institutional ULN for subjects with total bilirubin levels > 1.5 institutional
ULN

- AST (SGOT) and ALT (SGPT) ≤ 2.5 X institutional ULN

- Albumin > 2.5 mg/dL

- Coagulation

--International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X institutional
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 institutional ULN unless
subject is receiving anticoagulant therapy as long as PT or PTT is within
therapeutic range of intended use of anticoagulants

- Creatinine clearance should be calculated per institutional standard.

- The effects of radium-223 and pembrolizumab on the developing human fetus are unknown.
For this reason, men must agree to use adequate contraception. Specifically, they must
agree to use a condom (even men with vasectomies) and another effective method of
birth control if he is having sex with a woman of childbearing potential or agree to
use a condom if he is having sex with a woman who is pregnant while on study drug and
for 120 days (4 months) following the last dose of study drug. They must also agree
not to donate sperm during the study and for 4 months after receiving the last dose of
study drug.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- Pathology consistent with majority of specimen having small cell carcinoma of the
prostate (prostate cancer with other neuroendocrine features is acceptable).

- Prior treatment with radium-223

- Prior treatment with a PD-1, PD-L1, or PD-L2 blocking therapy

- Evidence of nodal disease greater than or equal to 15 mm in short axis as these
findings are concerning for metastases that would not be targeted with radium-223
alone (Arm B). However, lymph nodes with short axis measurements between 1.5-3cm that
have not enlarged more than 5mm (to account for reader variability) over the last 6
months and which are not inducing symptoms, causing obstruction, or in the opinion of
the investigator pose a risk of impending obstruction of any structures, will be
allowed.

- Pulmonary nodules >10 mm

--Pulmonary nodules >10mm that have been stable for >6 months and are not clearly
metastatic disease per the treating investigator are permitted

- Soft tissue components of bone metastases ≥ 1.0 cm in longest axis

--Soft tissue components of bone metastases < 1.0 cm that have been stable for >6
months (must not have enlarged > 5mm) are permitted

- Soft tissue lesions ≥ 1.0 cm in longest axis

--Soft tissue lesions < 1.0 cm that have been stable for > 6 months (must not have
enlarged > 5mm) are permitted.

- If present, primary disease in the prostate must be stable for > 6 months (defined as
no growth > 5mm)

- Evidence of local recurrence in the prostate bed

- Evidence of liver metastases or visceral disease

- Has a diagnosis of immunodeficiency

- Receiving systemic steroid therapy or any other form of immunosuppressive therapy
within 7 days prior to the first dose of trial treatment. Patients who have received
acute, low-dose, systemic immunosuppressant medications (e.g., limited low-dose
dexamethasone for nausea, multiple doses for contrast allergy) may be enrolled in the
study and would not require a 7 day washout.

- Has a known history of active TB (Bacillus Tuberculosis)

- 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.

- Has had prior systemic therapy (exception: GnRH agonist or antagonist) or radiation
therapy for prostate cancer within 2 weeks prior to study Day 1. There must be at
least a 2 week washout period from last dose of any prior systemic or radiation
therapy for prostate cancer prior to Day 1 of study treatment (including nonsteroidal
antiandrogens). Screening may commence during this washout window.

- Any patient who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events
due to a previously administered systemic agent or radiation therapy.

- Exceptions: Subjects with ≤ Grade 2 neuropathy, hot flashes, or hypertension may
qualify for the study if all other eligibility criteria met.

- Other toxicity or complications that are deemed by the treating investigator as
not clinically significant (e.g., urinary incontinence from past prostatectomy)

- Diethylstilbestrol, estrogens, saw palmetto, or other preparations that are known to
have possible endocrine effects on prostate cancer that have been started within the
past 8 weeks, as they may affect PSA levels or response. These are allowed if the
patient has been on a stable dose for at least 8 weeks prior to C1D1.

- Receiving other investigational agents

- History of allergic reactions to compounds with similar biologic or chemical
composition to pembrolizumab or Radium-223

- 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 is planned for 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. This exception does not include
carcinomatous meningitis, which is excluded regardless of clinical stability.

- 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 (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment and is allowed.

- Has known history of, or any evidence of active, non-infectious pneumonitis. A history
of radiation pneumonitis which is asymptomatic with no signs of active process is
allowed.

- 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 a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
HIV-positive participants on combination antiretroviral therapy are ineligible because
of the potential for pharmacokinetic interactions with pembrolizumab. In addition,
these participants are at increased risk of lethal infections when treated with
marrow-suppressive therapy. Appropriate studies will be undertaken in participants
receiving combination antiretroviral therapy when indicated.

- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA is
detected).

- 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.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, severe or unstable angina, myocardial infarction, symptomatic congestive
heart failure (defined as New York Heart Association Grade II or greater), arterial or
venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident
including transient ischemic attacks) or clinically significant ventricular
arrhythmias within 6 months prior to randomization; or significant vascular disease
(e.g., aortic aneurysm, aortic dissection), symptomatic peripheral vascular disease

- Evidence of QTc prolongation as defined as QTcF > 470 ms

- Inability to comply with study and/or follow-up procedures