PD-L1 Inhibition as ChecKpoint Immunotherapy for NeuroEndocrine Phenotype Prostate Cancer

Inclusion Criteria:

1. Neuroendocrine-like prostate cancer, based on histology OR based on clinical
presentation as defined by meeting one of the two below criteria. All subjects must
submit their primary tumor or metastatic biopsy pathology specimens to the Duke Cancer
Institute where they will be centrally reviewed by Duke Pathology. Central Duke
pathologic review is not required for screening but rather for confirmation of
histologic subtype. Local pathologic review is sufficient for eligibility
determination.

1. Criterion 1: Presence of 1 of 3 histologically proven diagnoses: 1) Primary small
cell carcinoma of the prostate, defined by classic histologic features such as
small tumor cells with scanty cytoplasm, darkly stained nuclei with homogeneous
chromatin pattern. The tumor cells do not form glandular structure but grow as
solid sheets with frequent mitotic figures and necrosis; 2) Intermediate atypical
carcinoma of the prostate, which has histologic features distinct from small cell
carcinoma or adenocarcinoma. The tumor grows as solid sheets or vague glandular
structures. The tumor cells have moderate amounts of cytoplasm and centrally
located, round and regular nuclei with fine, granular and homogeneous chromatin.
Mitosis and necrosis are absent; 3) mixed histology tumors of the prostate,
containing both adenocarcinoma and neuroendocrine or small cell components.

2. Criterion 2: Presence of histologically proven adenocarcinoma of the prostate
without any sign of neuroendocrine or small cell histology that is
radiographically progressing despite castrate levels of testosterone (<50 ng/mL)
with the following poor risk features:

i. Prior progression despite therapy with either abiraterone acetate and/or
enzalutamide ii. At least one of the following: 1) Liver metastases; 2) Bulky
radiographic progression (≥2 cm short axis lymph nodes or ≥1 cm long axis visceral
metastases) combined with low serum PSA (<10ng/mL); 3) High serum LDH (>1X upper limit
of normal).

2. Measurable disease as defined by modified PCWG3 using iRECIST criteria

3. Available tumor tissue for pathologic review and correlative studies. Tumor tissue
(localized or metastatic) does not need to be received but rather identified and
available (slides and/or blocks) to be sent to Duke.

4. Documented progressive metastatic CRPC based on at least one of the following
criteria:

1. PSA progression defined as 25% increase over baseline value with an increase in
the absolute value of at least 2.0 ng/mL that is confirmed by another PSA level
with a minimum of a 1 week interval and a minimum PSA of 2.0 ng/mL. Note: If
confirmed rise is the only indication of progression, a minimal starting value of
1.0 ng/mL is acceptable, unless pure small-cell carcinoma.

2. Soft-tissue progression based on new lesions or growth of existing soft tissue
metastases.

3. Progression of bone disease (evaluable disease) or (new bone lesion(s)) by bone
scan.

5. Castrate levels of serum total testosterone (<50 ng/dl) OR ongoing documented ADT
unless pure small cell prostate cancer is present.

6. Previous use of radiation to metastatic site(s) at any time prior to enrollment is
allowed, provided that this site is not the only measurable disease present or unless
that solitary site is progressing following radiation.

7. Patients should have received at least one line of approved chemotherapy and/or
hormonal therapy

8. Previous cytotoxic chemotherapy including cisplatin, carboplatin, oxaliplatin,
etoposide, docetaxel, cabazitaxel, and gemcitabine is allowed, up to 3 prior regimens.

9. Karnofsky performance status of 70 or higher.

10. Acceptable initial laboratory values within 14 days of Cycle 1 Day 1 according to the
below table:

ANC ≥ 1500/µl Hemoglobin ≥ 9.0 g/dL(prior transfusion permitted) Platelet count ≥
100,000/µl Creatinine ≤ 2.0 x the institutional upper limit of normal (ULN) OR
creatinine clearance >30 ml/min Potassium ≥ 3.5 mmol/L (within institutional normal
range) Bilirubin ≤ 1.5 x ULN (unless documented Gilbert's disease) SGOT (AST) ≤ 2.5x
ULN, or <5x ULN in patients with documented liver metastases SGPT (ALT) ≤ 2.5x ULN or
<5x ULN in patients with documented liver metastases

11. Age >18

12. Highly effective contraception for male subjects with childbearing potential
throughout the study and for at least 60 days after last avelumab treatment
administration if the risk of conception exists.

13. Willing and able to provide written informed consent and HIPAA authorization for the
release of personal health information.

14. Life expectancy of over 3 months as determined by treating physician.

Exclusion Criteria:

1. Prior usage of PD-1 inhibitors, programed-death ligand 1 and/or 2 inhibitors, CTLA-4
inhibitors including but not limited to ipilimumab, nivolumab, avelumab, durvalumab,
tremelimumab, and pembrolizumab.

2. Active on-going immunologic or autoimmune disease including but not limited to
systemic or cutaneous lupus erythematosus, cutaneous psoriasis, psoriatic arthritis,
rheumatoid arthritis, scleroderma, sicca syndrome, polymyalgia rheumatica,
polyarteritis nodosa, granulomatous polyangiitis, microscopic polyangiitis,
polyarteritis nodosa, temporal arteritis, giant cell arteritis, dermatomyositis,
Kawasaki disease.

3. Previous malignancy within 3 years other than non-melanomatous skin cancers or cancers
of low malignant potential such as non-invasive urothelial carcinoma.

4. Any other on-going chemotherapeutic, biologic, radiopharmaceutical, or investigational
agent currently or within 28 days of Cycle 1 Day 1.

5. Prior use of abiraterone and other hormonal agents used to treat prostate cancer are
permitted but abiraterone acetate should be stopped prior to study treatment
initiation.

6. Current usage of immunosuppressant medication except for a) intranasal, inhaled, and
topical corticosteroids and b) systemic corticosteroids equivalent to ≤ 10 mg/day of
prednisone, c) steroids as premedication for hypersensitivity reactions (e.g. CT scan
premedication).

7. Prior organ transplantation including allogeneic stem-cell transplants.

8. Active bacterial or viral infections requiring systemic therapy.

9. Current active infections with HIV/AIDS, Hepatitis B, and Hepatitis C requiring
treatment.

10. Live virus vaccination within 4 weeks of the first dose of avelumab (inactivated
vaccines are allowed).

11. Known prior hypersensitivity to the investigational product or any component
formulations, including known severe hypersensitivity reactions to monoclonal
antibodies.

12. Clinically significant (i.e. active) cardiovascular disease: cerebral vascular
accident (<6 months prior to enrollment), myocardial infarction (<6 months prior to
enrollment), unstable angina, congestive heart failure (≥ New York Heart Association
Classification Class II), or serious cardiac arrhythmia requiring medication.

13. Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1); however,
alopecia, sensory neuropathy Grade ≤ 2, Grade 2 anemia, or other Grade ≤ 2 not
constituting a safety risk based on investigator's judgment are acceptable.

14. Other severe acute or chronic medical conditions including colitis, inflammatory bowel
disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent
(within the past year) or active suicidal ideation or behavior; or laboratory
abnormalities that may increase the risk associated with study participation or study
treatment administration or may interfere with the interpretation of study results
and, in the judgment of the investigator, would make the patient inappropriate for
entry into this study.