PD-L1 Inhibition as ChecKpoint Immunotherapy for NeuroEndocrine Phenotype Prostate Cancer
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: Andrew J. Armstrong, MD

 
Cover Page for Protocol 
 
 
Sponsor Name 
Duke Cancer Institute  
NCT Number 
NCT03179410 
Official title of Study 
PD-L1 Inhibition as ChecKpoint Immunotherapy for NeuroEndocrine 
Phenotype Prostate Cancer (PICK NEPC) 
Document date 
27 November 2018 
 

CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and 
regulations.  Written authorization from the coordinating site and sponsor is required for disclosure otherwise. 
 
PD-L1 Inhibition as ChecKpoint Immunotherapy for 
NeuroEndocrine Phenotype Prostate Cancer 
(PICK NEPC) 
 
 
 
 
 
 
 
 
 
Sponsor-Investigator: 
Andrew Armstrong, MD, ScM – Duke Cancer Institute 
 
Funding Source: 
Pfizer 
 
Protocol Source: 
Andrew Armstrong, MD, ScM – Duke Cancer Institute 
 
Duke IRB#: 
IND:  
Pro00080869 
135136 
 
 
 
 
 
 
 
Principal Investigator 
Andrew Armstrong, MD 
 
 
 
 
 
 
Sub-Investigator(s) 
Daniel George, MD 
 
 
Michael Harrison, MD 
 
 
Tian Zhang. MD 
 
 
Megan McNamara. MD 
 
 
 
 
 
 
Statistician 
Susan Halabi, PhD 
 
 
 
 
 
 
 
 
Ver 01: 
Ver 02: 
Ver 03: 
Ver 04: 
Ver 05: 
Ver 06: 
Ver 07: 
17 April 2017 
15 May 2017 
12 June 2017 
09 October 2017 
07 March 2018 
11 April 2018 
27 November 2018 
 
 

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Responsible Study Personnel 
Principal Investigator 
Andrew Armstrong, MD 
  
 
 
 
 
Study Coordinator 
 
 
 
Catrin Davies, PhD, BSc, BSN, RN 
 
 
 
 
 
 
Data Manager 
Monika Anand, PhD, CCRP 
 
 
  
  
 
 
Regulatory Coordinator 
 
Kathleen Ashcraft, PhD 
 
 
 
 
 
  
 
 
 
 
 
External Sites Participating in This Study 
TBD 
 

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Contents 
1 
PROTOCOL SYNOPSIS ............................................................................................................................ 6 
2 
STUDY SCHEMA ................................................................................................................................... 13 
3 
BACKGROUND AND SIGNIFICANCE ..................................................................................................... 13 
3.1 
Study Disease: Neuroendocrine-like Prostate Cancer ................................................................ 13 
3.2 
Immune Checkpoint Blockade in Prostate Cancer ...................................................................... 15 
3.3 
Study Agent ................................................................................................................................. 16 
3.4 
Purpose and Rationale ................................................................................................................ 22 
4 
OBJECTIVES AND ENDPOINTS ............................................................................................................. 23 
4.1 
Primary Endpoint ........................................................................................................................ 23 
4.2 
Secondary Endpoints .................................................................................................................. 23 
4.3 
Exploratory Endpoints ................................................................................................................. 23 
5 
INVESTIGATIONAL PLAN ..................................................................................................................... 23 
5.1 
Study Design ................................................................................................................................ 23 
5.2 
Drug Discontinuation Criteria ..................................................................................................... 24 
5.3 
Trial Stopping Rules ..................................................................................................................... 25 
5.4 
Treatment Modification Guidelines for Infusion-Related Reactions .......................................... 25 
5.5 
Management of Immune-mediated Adverse Reactions ............................................................. 26 
5.6 
Concomitant Medications ........................................................................................................... 32 
5.7 
Study Drug Blinding ..................................................................................................................... 33 
5.8 
Randomization ............................................................................................................................ 33 
5.9 
Rationale for Selection of Dose, Regimen, and Treatment Duration ......................................... 33 
5.10 
Definition of Evaluable Subjects, On Study, and End of Study ................................................... 33 
5.11 
Early Study Termination .............................................................................................................. 33 
6 
STUDY DRUG ....................................................................................................................................... 33 
6.1 
Names, Classification, and Mechanism of Action ....................................................................... 33 
6.2 
Packaging and Labeling ............................................................................................................... 34 
6.3 
Supply, Receipt, and Storage ...................................................................................................... 34 
6.4 
Special Precautions for Administration ...................................................................................... 34 
7 
SUBJECT ELIGIBILITY ............................................................................................................................ 34 
7.1 
Inclusion Criteria ......................................................................................................................... 34 
7.2 
Exclusion Criteria ......................................................................................................................... 36 

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8 
SCREENING AND ON-STUDY TESTS AND PROCEDURES ...................................................................... 38 
8.1 
Screening Examination ................................................................................................................ 41 
8.2 
Subject Registration and Enrollment .......................................................................................... 41 
8.3 
Run-In Period .............................................................................................................................. 42 
8.4 
Treatment Period ........................................................................................................................ 42 
8.5 
End of Treatment ........................................................................................................................ 42 
8.6 
Follow up period ......................................................................................................................... 43 
8.7 
End of Study ................................................................................................................................ 43 
8.8 
Early Withdrawal of Subjects(s) .................................................................................................. 44 
8.9 
Study Assessments  and Definitions ........................................................................................... 44 
8.10 
Response Criteria ........................................................................................................................ 48 
8.11 
Confirmatory Measures/Duration of Response .......................................................................... 53 
9 
SAFETY MONITORING AND REPORTING ............................................................................................. 54 
9.1 
Adverse Events ............................................................................................................................ 54 
9.2 
Serious Adverse Events ............................................................................................................... 55 
9.3 
Reporting of SAEs ........................................................................................................................ 55 
9.4 
Emergency Unblinding of Investigational Treatment ................................................................. 56 
9.5 
Procedure in case of pregnancy .................................................................................................. 56 
9.6 
Safety Oversight Committee (SOC) ............................................................................................. 56 
10 QUALITY CONTROL AND QUALITY ASSURANCE .................................................................................. 57 
10.1 
Monitoring .................................................................................................................................. 57 
10.2 
Data Management and Processing ............................................................................................. 58 
11 STATISTICAL METHODS AND DATA ANALYSIS .................................................................................... 59 
11.1 
Sample Size Estimation ............................................................................................................... 59 
11.2 
Analysis Sets ................................................................................................................................ 59 
11.3 
Patient Demographics and Other Baseline Characteristics ........................................................ 59 
11.4 
Treatments .................................................................................................................................. 59 
11.5 
Primary Objective ........................................................................................................................ 60 
11.6 
Secondary Objectives .................................................................................................................. 60 
11.7 
Exploratory Objectives ................................................................................................................ 61 
11.8 
Interim Analysis ........................................................................................................................... 61 
11.9 
Accrual and Follow-Up ................................................................................................................ 61 
12 ADMINISTRATIVE AND ETHICAL CONSIDERATION .............................................................................. 61 
12.1 
Regulatory and Ethical Compliance ............................................................................................ 61 

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12.2 
DUHS Institutional Review Board and DCI Cancer Protocol Committee .................................... 61 
12.3 
Informed Consent ....................................................................................................................... 62 
12.4 
Study Documentation ................................................................................................................. 62 
12.5 
Privacy, Confidentiality, and Data Storage ................................................................................. 63 
12.6 
Data and Safety Monitoring ........................................................................................................ 63 
12.7 
Protocol Amendments ................................................................................................................ 63 
12.8 
Records Retention ....................................................................................................................... 63 
12.9 
Conflict of Interest ...................................................................................................................... 64 
13 REFERENCES ........................................................................................................................................ 65 
14 Appendix A: Performance Status Criteria ........................................................................................... 68 
15 Appendix B: FACT-P (version 4) ........................................................................................................... 69 
 
 
 

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1 PROTOCOL SYNOPSIS 
Study Title:  PD-L1 Inhibition as ChecKpoint Immunotherapy for NeuroEndocrine Phenotype Prostate Cancer 
(PICK NEPC) 
Protocol Number 
Pro00080869 
Phase 
II 
Type 
Interventional 
Condition/Disease:  Neuroendocrine prostate cancer (NEPC) 
Number of Subjects 
18 in stage 1,  
49 overall 
Duration of Subject Participation 
3 years 
Number of Study 
Centers 
3-4 
Duration of Study  8 years 
Anticipated 12-18 months 
accrual time per stage, up to 
3 years follow up 
Rationale:  
Neuroendocrine Prostate Cancer 
Using the SEER database, there are an estimated 180,890 new cases of prostate cancer in the United Stated in 2016 
with an associated 26,120 deaths for that year.1 Of those cases, most have adenocarcinoma histology with an 
estimated 586.0 cases per million per year, but there are multiple other non-adenocarcinoma histologies as well.2 
Although a much less common form of prostate cancer,  men with neuroendocrine differentiation of their prostate 
cancer have a much worse prognosis with median overall survival (OS) of 7 months (mo) compared with years in 
men with adenocarcinoma.3 Much of the poor survival related to these patients is related to the fact that all the 
currently approved therapies for metastatic castration resistant prostate cancer (mCRPC) including docetaxel,4 
cabazitaxel,5 abiraterone,6,7 enzalutamide,8,9 radium-223,10 Sipuleucel-T11 are only proven and effective in patients 
with adenocarcinoma. Therefore to date there are no phase 3 studies that definitively show an overall survival 
benefit in men with neuroendocrine differentiation which highlights the need for more effective therapies in these 
men.  
 
Neuroendocrine prostate cancer (NEPC) lies on a spectrum of aggressive prostate cancer along with small cell 
prostate cancer (SCPC) and was defined originally by histology that was similar to neuroendocrine tumors of other 
origins.12 SCPC has classic histologic features such as small tumor cells with scanty cytoplasm, darkly stained nuclei 
with homogeneous chromatin pattern and do not form glandular structures but grow as solid sheets with frequent 
mitotic figures and necrosis. Different from SCPC, NEPC has been harder to classify as a group and is now being 
redefined to be intermediate atypical carcinoma (IAC) of the prostate with histologic features distinct from small 
cell carcinoma or adenocarcinoma.13 IAC grows as solid sheets or vague glandular structures, has moderate amounts 
of cytoplasm and centrally located, round and regular nuclei with fine, granular and homogeneous chromatin. 
Mitosis and necrosis are absent. NEPC spectra histologies have a very aggressive clinical phenotype and often have 
low PSA (as these tumors do not make it), predominant visceral spread, osteolytic and not osteoblastic bone lesions, 
bulky lymphadenopathy, and the development of castration resistance within 6 months of androgen deprivation 
therapy (ADT).14 In addition, NEPC tumors have a higher mutational burden than typical adenocarcinoma suggesting 
an opportunity for immunotherapy in this disease.15   
 
NEPC can not only be present from the onset of diagnosis but also transform out of treated mCRPC and is likely 
found in 20-30% of castration-resistant tumors compared to 5-10% at initial diagnosis.12 Since this treatment-
related NEPC is becoming more recognized and common and since it is very resistant to the conventional therapies 
of mCRPC, new therapies need to be developed for men with this disease.  
 
Treatments for NEPC and Study Rationale 
Currently the standard of care for treating NEPC and its spectrum of diseases is to start with ADT as most NEPCs are 
mixed with adenocarcinoma. Once the cancer has become CRPC or if the histology at diagnosis was small cell 

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prostate cancer (SCPC), the therapy tends to focus on using platinum combination therapy. Although there are no 
phase 3 trials looking at these therapies the literature shows that many patients have been treated with cisplatin 
and etoposide.14,16-18 Although platinums appear to have a benefit in NEPC, none of them have been curative or led 
to long term remission in the vast majority of men. In mCRPC platinums have been tested alone or in combination 
with other chemotherapies and the results have shown some dramatic successes with soft tissue response rates in 
the 70s and 80s in some studies while other have been in the teens.19 Platinums act through DNA damage and it is 
conjectured that patients with inherited DNA-repair gene mutation, which is approximately 12% of metastatic 
prostate cancer,20 or acquired DNA-repair gene mutations may benefit from them as shown in the TOPARP trial,21 
a single arm phase II trial that showed that patients with mCRPC that had DNA-repair defects had better survival 
and response rates to olaparib a poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor.  
 
Immune checkpoint blockade is a novel systemic approach in which the patient’s own immune system is stimulated 
to better recognize and destroy cancer cells. Ipilimumab and nivolumab, blocking monoclonal antibodies to CTLA-4 
and programed-death receptor-1 (PD-1) respectively, acts to over stimulate the immune system and both have 
been studied in melanoma both as single agents and in combination to improve the overall survival of patients with 
melanoma.22,23  
 
Although the small cell histology is rare in prostate cancer, it is common in lung cancer. Small cell lung cancer (SCLC) 
like that of the prostate has a poor overall survival. Currently the mainstay of chemotherapy in SCLC is combination 
cisplatin with etoposide which is where SCPC got the direction to be treated by these agents given the similarity of 
histology. Recently a phase 1/2 trial was performed that enrolled patients with progressive lung SCLC to nivolumab 
with and without ipilimumab in varying dose combinations.24 The results demonstrated that the nivolumab alone 
arm had 15% with partial response and 22.5% with stable disease compared to 5% (1 patient) with a complete 
response, 20% with partial response, and 30% with stable disease in the combination arm. Not only were there 
responses in each arm, some appeared to be durable.  These data suggest efficacy of PD-1 inhibition in patients 
with neuroendocrine lung cancers. 
 
Avelumab 
Avelumab is a fully human antibody that specifically targets and blocks PD-L1, thus removing the suppressive effects 
of PD-L1 on the anti-tumor CD8+ T cells. It has been studies in Phase I and II trials including patients with non-small 
cell lung cancer, ovarian cancer, and Merkel cell carcinoma. The NSCLC expansion cohort had an objective response 
rate (ORR) of 14.1% (26 of 184 NSCLC subjects).25 An ovarian cancer expansion cohort had an ORR of 10.7% (8 of 75 
subjects).26 The Phase II trial in Merkel Cell carcinoma gave avelumab to 88 patients and resulted in an objective 
response in 31.8%, including 8 complete responses.27 
 
Data supporting PD-L1 inhibition in prostate cancer was found when enzalutamide resistant cell lines and xenografts 
on mice had increased PD-L1.28 Our own cell lines established at Duke that are enzalutamide resistant also 
demonstrate upregulation of PD-L1 at the protein and RNA level as compared with the parental cell lines, suggesting 
that PD-L1 is an adaptive response to stress and is highly dynamic (data unpublished). Further, we have also looked 
at a cohort of patients with NEPC/SCPC using a tissue microarray for PD-L1 expression by immunohistochemistry 
and have found that a small subset (~20% small cell, ~10% adenocarcinoma) of these cases express high levels of 
PD-L1 (data unpublished). Further still is evidence showing that there is a high burden of genetic mutations in NEPC29 
which has been seen in other cancers to confer susceptibility to immunotherapy. 
 
Given the emerging role of immunotherapy across multiple tumor types to produce durable responses, and given 
the similarity of small cell by both histology and its response to current chemotherapy, we hypothesize that 
avelumab will produce a clinical and radiographic response in NEPC that will be durable in a subset of patients. In 
this study, we are defining the NEPC “phenotype” based on clinical poor risk features of AR-independence or based 
on histologic evidence of NEPC in tissue or serum. 
 

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Primary Objective:  To determine the efficacy of PD-L1 inhibition with avelumab as measured by a modified 
PCWG3,30 where RECIST 1.131 is replaced with iRECIST, a modified RECIST 1.1 for immune-based therapeutics,32 
radiographic response rate in men with metastatic neuroendocrine-like prostate cancer. 
 
Secondary Objectives:  
1. To describe the efficacy of PD-L1 inhibition with avelumab as measured by PCWG3 using RECIST1.1 
2. To describe the radiographic progression free survival (rPFS) of PD-L1 inhibition with avelumab using 
modified PCWG3 with both RECIST 1.1 and iRECIST criteria in this setting. 
3. To describe the overall survival of PD-L1 inhibition in this setting. 
4. To described the toxicities and safety of PD-L1 inhibition with avelumab in men with metastatic 
neuroendocrine-like prostate cancer. 
Exploratory Objectives: 
1. To describe the impact of PD-L1 inhibition with avelumab on blood-based biomarker changes over time, 
including PSA, chromogranin-A, cell free DNA, LDH, and alkaline phosphatase. 
2. To determine if levels of circulating biomarkers secreted by neuroendocrine-like prostate cancers correlate 
with clinical and radiographic treatment response 
3. To determine if the presence of different immunohistochemical markers on the pre-biopsy specimens 
prognosticates clinical and radiographic treatment response 
4. To determine if the level of different circulating immune cells correlate with both progressive addition of 
immunotherapy as well as clinical and radiographic treatment response or disease progression 
5. To determine if levels of cell free DNA correlate with clinical and radiographic treatment response 
6. To isolate prostate neuroendocrine-like CTCs for ex vivo growth and culture and characterization studies. 
 
Hypothesis: 
We hypothesize that PD-L1 inhibition with avelumab will be efficacious based on radiographic responses in a subset 
of men with metastatic neuroendocrine-like prostate cancer and be reasonably well tolerated, meeting criteria for 
further study in larger phase 2 and 3 trials based on meeting pre-specified efficacy rates and prolonged PFS in some 
men.   
 

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Design:   
This is a phase 2, open-label, single arm trial of avelumab in men with metastatic neuroendocrine-like prostate 
cancer.  Men who meet inclusion criteria (without exclusions) will be started on avelumab 10 mg/kg IV every 2 
weeks and will stay on therapy until progression or intolerable side effects. Cycles will be 4 weeks long and thus 
include 2 doses of avelumab.  Baseline tissue will be assessed histologically for eligibility at Duke and for correlative 
tissue biomarkers.  Treatment beyond radiologic or PSA progression is permitted after approval of the PI of the 
study and if the providing physician and patient determine that there is potential for clinical benefit with continued 
therapy. 
 
At radiologic progression a standard of care post-treatment progression biopsy will be collected at the discretion of 
the treating provider, and if proper consent is obtained, additional tissue will be collected for research tests 
including assessments of resistance mechanisms and immune checkpoint status.  The additional research tissue will 
be banked in the Biospecimen Repository & Processing Core (BRPC) under Pro00080869. The study team will also 
pursue dual consent to BRPC Pro00035974 for future unspecified research. 
 
Men will continue on their ADT used at entry into study per investigator with subsequent changes made per 
investigator. Men not on ADT at time of entry due to being purely SCPC may remain off ADT. Men with SCPC on 
ADT at study entry should remain on ADT per investigator while all men with mixed histologies should remain on 
active ADT during trial participation. 
 
Men will be allowed to receive palliative radiation to any disease site indicated by the treating physician at any time 
during the study, provided that another untreated site of measureable disease is present at baseline. All subjects 
will be followed for disease progression and mortality for up to 3 years from the date that the subjects were enrolled 
to the protocol. 
 
Study Population: This is a non-blinded single arm-arm phase II study of approximately 49 subjects, to assess the 
safety and efficacy of avelumab in patients with mCRPC. Eligible men will have metastatic CRPC with NEPC 
phenotype with measureable disease at baseline. 
The target sample size is 18 in stage 1, and overall 49 evaluable subjects.  For stage 1, Duke will serve as the single 
site for this study.  For stage 2, the study would be expanded to include additional sites through the Department of 
Defense Prostate Cancer Clinical Trials Consortium (DOD PCCTC). All subjects will be followed for disease 
progression and death from the date that the subjects were enrolled to the protocol. 
Selection of Subjects:   
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 
(Dr. Jiaoti Huang). Central Duke pathologic review is not required for screening but rather for confirmation 
of histologic subtype. Local pathologic review is sufficient for eligibility determination.  
a. 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. 

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b. 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:    
a. 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. 
b. Soft-tissue progression based on new lesions or growth of existing soft tissue metastases.  
c. 
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 is 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.  

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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. 
Study Intervention and Administration:   
The study agent avelumab will be administered at a dose of 10 mg/kg by IV every 2 weeks until progression or 
intolerable side effects. Cycles will be 4 weeks long and thus include 2 doses of avelumab. In order to mitigate 
infusion related reactions, a premedication with an antihistamine and with paracetamol (acetaminophen) 30 to 60 
minutes prior to each dose of avelumab is mandatory. Avelumab should be administered in a setting that allows for 
immediate access to an intensive care unit or equivalent environment and administration of therapy for anaphylaxis, 
such as the ability to implement immediate resuscitation measures. Avelumab should be given over 2 hours (-10 
min/+20min).  Steroids (dexamethasone 10 mg), epinephrine (1:1,000 dilution), allergy medications (IV 
antihistamines), bronchodilators, or equivalents, and oxygen should be available for immediate access. Following 
avelumab infusions, subjects must be observed for 30 minutes post infusion for potential infusion related reactions.   
Avelumab will be provided by Pfizer and distributed by DCI Investigational Chemotherapy Service.   
 
Study Assessments:   
Vital signs, performance status, physical exam, adverse events and concomitant medications will be assessed at each 
visit.   The following laboratory studies will be obtained at intervals specified in the study flow chart to assess subject 
safety:  complete blood count, serum chemistries, TSH and free T4.  Testosterone, blood-based biomarkers (such as 
PSA, CEA, chromogranin A, etc), immune cells, and cell free DNA will also be assessed for disease status and 
correlative science. A bone scan and either CT or MRI scans of the chest, abdomen, and pelvis will be performed to 
assess disease status at baseline as well as every 8 weeks or at treatment discontinuation. Patient reported 
outcomes will be collected using the Functional Assessment of Cancer Therapy – Prostate (FACT-P) at baseline and 

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every 3 cycles to  assess quality of life.  The pre-biopsy specimen obtained during screening and the optional post-
progression biopsy will be assessed for correlative biomarkers and resistance mechanisms. 
 
Data Analysis and Statistical Considerations: 
This study will use the optimal two-stage Simon design to test the hypothesis about modified PCWG3 using iRECIST 
radiologic response rate in subjects with NEPC treated with avelumab. Response will be defined as a complete (CR) 
or partial response (PR) using iRECIST criteria.  Assuming that the response rate among subjects treated is 5%, the 
trial is designed to have 88% power with a one-sided type I error rate=5% to reject the null hypothesis of response 
rate of 5% when the true response rate was 20%. In the first stage, 18 subjects will be enrolled and if one or fewer 
responses are observed the trial will be terminated. However, if two or more responses are observed, an additional 
26 subjects will be enrolled at the second stage for a total of 44 subjects. If five or more subjects respond, this new 
agent would be declared to have promising activity. This design has 88% power to conclude an agent is promising 
if its true objective response proportion is 20%; Type 1 error rate (one-sided) is 0.05 (this is the probability to 
conclude that a given agent is promising if its true objective response proportion is 5%).The probability of early 
termination under the null hypothesis is 0.77.  These operating characteristics were selected to represent a 
reasonable compromise between high power, low false positive rates, and desire for small sample sizes, especially 
in the first stage. Allowing for 10% unevaluable rate, the target sample size is 49 subjects.   
 
With 44 subjects, the objective response rate will be estimated with a standard error no greater than 10.7 
percentage points. The Kaplan-Meier method will be used to estimate progression-free survival and overall survival 
distributions. Summary statistic will be computed for the duration of time on treatment distribution. The correlative 
science analyses will be considered exploratory and interpreted as such. 
 
 
 

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2 STUDY SCHEMA 
 
3 BACKGROUND AND SIGNIFICANCE 
3.1 
Study Disease: Neuroendocrine-like Prostate Cancer 
 
Using the SEER database, there are an estimated 180,890 new cases of prostate cancer in the United 
Stated in 2016 with an associated 26,120 deaths for that year.1 Of those cases, most have 
adenocarcinoma histology with an estimated 586.0 cases per million per year, but there are multiple 
other non-adenocarcinoma histologies as well.2 Although a much less common form of prostate 
cancer,  men with neuroendocrine differentiation of their prostate cancer have a much worse 
prognosis with median overall survival (OS) of 7 months (mo) compared with years in men with 
adenocarcinoma.3 Much of the poor survival related to these patients is related to the fact that all 
the currently approved therapies for metastatic castration resistant prostate cancer (mCRPC) 
including docetaxel,4 cabazitaxel,5 abiraterone,6,7 enzalutamide,8,9 radium-223,10 Sipuleucel-T11 are 
only proven and effective in patients with adenocarcinoma. Therefore to date there are no phase 3 
studies that definitively show an overall survival benefit in men with neuroendocrine differentiation 
which highlights the need for more effective therapies in these men.  
 
One difficulty in studying prostate cancer with neuroendocrine differentiation is that diagnostically 
these cancers are very heterogeneous. Originally neuroendocrine prostate cancer (NEPC) was 
defined by histology that was similar to neuroendocrine tumors of other origins and includes the 
subtypes of small-cell, large-cell, and carcinoid.12 SCPC has classic histologic features such as small 
tumor cells with scanty cytoplasm, darkly stained nuclei with homogeneous chromatin pattern and 
do not form glandular structures but grow as solid sheets with frequent mitotic figures and necrosis. 
Different from SCPC, NEPC has been harder to classify as a group and is now being redefined to be 
intermediate atypical carcinoma (IAC) of the prostate with histologic features distinct from small cell 
carcinoma or adenocarcinoma.13 IAC grows as solid sheets or vague glandular structures, has 
moderate amounts of cytoplasm and centrally located, round and regular nuclei with fine, granular 
and homogeneous chromatin. Mitosis and necrosis are absent. The new definition of IAC is also 

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complimented by having a unique 50 gene signature with 97% accuracy.13 But in addition to 
histology, these men with NEPC had a very aggressive clinical phenotype and often had low PSA (as 
these tumors do not make it), predominant visceral spread, osteolytic and not osteoblastic bone 
lesions, bulky lymphadenopathy, and the development of castration resistance within 6 months of 
androgen deprivation therapy (ADT).14 In addition, NEPC tumors have a higher mutational burden 
than typical adenocarcinoma suggesting an opportunity for immunotherapy in this disease.15 
Circulating tumor cells from NEPC patients have been studied and shown to have low or absent AR 
expression, lower cytokeratin expression, and smaller morphology relative to typical CRPC.33 This 
disease has also been referred to as aggressive variant prostate cancer or anaplastic prostate cancer, 
reflecting that some of these tumors with de-differentiation lack neuroendocrine biomarkers but 
still remain AR independent.  
 
In addition to the difficult classification of the NEPC phenotype, NEPC can not only be present from 
the onset of diagnosis but also transform out of treated mCRPC and is likely found in 20-30% of 
castration-resistant tumors compared to 5-10% at initial diagnosis.12 Since this treatment-related 
NEPC is becoming more recognized and common and since it is very resistant to the conventional 
therapies of mCRPC, new therapies need to be developed for men with this disease.  
 
Currently the standard of care for treating NEPC and its spectrum of diseases is to start with ADT as 
most NEPCs are mixed with adenocarcinoma. Once the cancer has become CRPC or if the histology 
at diagnosis was small cell prostate cancer (SCPC), the therapy tends to focus on using platinum 
combination therapy. Although there are no phase 3 trials looking at these therapies the literature 
shows that many patients have been treated with cisplatin and etoposide,16-18 and a systematic 
review with a pooled-analysis using all available published material on NEPC patients found that 
chemotherapy had a statistically significant benefit for overall survival (hazard ratio (HR) 0.38 95% 
confidence interval (CI)(0.17-0.85)).3 A large phase 2 trial at MD Anderson took men who fit the 
spectrum of NEPC and treated them with first line docetaxel which does have proven benefit in 
mCRPC and combined it with carboplatin as it was less toxic than cisplatin in combination.14 The trial 
then treated them with combination cisplatin etoposide at first progression. Of the 113 men 
enrolled, 74 (65.4%) were progression free after 4 cycles of docetaxel/carboplatin and of the 71 
patients that received second line therapy, 24 (33.8%) were progression free after 4 cycles. Using 
the same NEPC spectra as the previous trial, a randomized phase 2 trial randomized men with mCRPC 
stratified by NEPC or not to receive cabazitaxel with and without carboplatin. The trial found a PFS 
benefit in those men with NEPC of 5.7 mo versus 3.8 mo (P=0.009).34 The other regimen that may be 
useful in NEPC patients is gemcitabine with oxaliplatin, and was tested in a phase 2 single arm trial 
with mCRPC men who failed docetaxel.35 The trial included 33 men and demonstrated a PSA 
response rate of 55% and radiographic response rate of 82%. Although it did not comment on those 
with NEPC, this regimen deserves further study given the trend that other platinums are beneficial. 
Thus, although platinums appear to have a benefit in NEPC, none of them have been curative or led 
to long term remission in the vast majority of men. 
 
In mCRPC platinums have been tested alone or in combination with other chemotherapies and the 
results have shown some dramatic successes with soft tissue response rates in the 70s and 80s in 
some studies while other have been in the teens.19 Platinums act through DNA damage and it is 
conjectured that patients with inherited DNA-repair gene mutation, which is approximately 12% of 
metastatic prostate cancer,20 or acquired DNA-repair gene mutations may benefit from them as 
shown in the TOPARP trial,21 a single arm phase II trial that showed that patients with mCRPC that 

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had DNA-repair defects had better survival and response rates to olaparib a poly(adenosine 
diphosphate [ADP]-ribose) polymerase inhibitor. 
3.2 
Immune Checkpoint Blockade in Prostate Cancer 
 
Immune checkpoint blockade is a novel systemic approach in which the patient’s own immune 
system is stimulated to better recognize and destroy cancer cells. Ipilimumab is a monoclonal 
antibody and works by blocking the CTLA-4 receptor on T-cells during antigen presentation from a 
dendritic cell and leads to an inhibition of recognizing self from non-self. It thus stimulates more T-
cells to target tumor cells that were evading the immune system. Ipilimumab was the first type of 
targeted immunotherapy that when compared to a novel melanoma vaccine showed a significant 
benefit in response rate including achieving complete responses and showed durable responses in 
metastatic melanoma.23 Nivolumab, another monoclonal antibody, also acts to over stimulate the 
immune system and works by blocking the programed-death receptor-1 (PD-1) and prevents the 
binding of programed death ligand 1 and 2 (PD-L1/2). These ligands are presented on the surface of 
cells targeted by T-cells and when bound to PD-1 on the T-cells, results in halting immune 
destruction. Many cancers have evaded the immune system by overexpressing these ligands. 
Nivolumab was first definitively studied in melanoma patients in the first line setting by randomizing 
them to nivolumab versus decarbazine.22 The results demonstrated a median PFS of 5.1 mo versus 
2.2 mo (P<0.001) and a response rate of 40% versus 13.9% (P<0.001). Similar results were shown in 
another trial that randomized patients who had failed ipilimumab to nivolumab or treating 
physician’s choice of chemotherapy.36 Given the benefit of these individual therapies, a phase 1 trial 
was designed that randomized new metastatic melanoma patients to ipilimumab vs a combination 
nivolumab with ipilimumab. At the trial’s end the median PFS was not reached in the combination 
group and was 4.4 mo in the ipilimumab alone group (P<0.001).37 These results all show the benefit 
of immunotherapy in melanoma and now they are being studied in other cancer types. 
 
Given the benefits of immune therapy in other cancer, ipilimumab was tested in patients with 
mCRPC against a placebo. Unfortunately the study did not show a clear survival benefit with p=0.053 
when compared with placebo.38 However since there appeared to be a  synergy with androgen 
receptor blockers, a single arm phase II trial was done in men with mCRPC who progressed on 
enzalutamide using pembrolizumab with continuation of enzalutamide. An early report of this trial 
documented that 3 of 10 patients had a dramatic PSA reduction to ≤0.2 ng/mL.39 Of these 3 patients, 
2 had measureable disease at entry and both achieved a partial response.   
 
Although the small cell histology is rare in prostate cancer, it is common in lung cancer. Small cell 
lung cancer (SCLC) like that of the prostate has a poor overall survival but if found early has the 
potential to be cured with a combination of chemotherapy with radiotherapy. However once it has 
become widespread, the prognosis is poor even with chemotherapy. Currently the mainstay of 
chemotherapy in SCLC is combination cisplatin with etoposide which is where SCPC got the direction 
to be treated by these agents given the similarity of histology. Recently a phase 1/2 trial was done 
that enrolled patients with progressive lung SCLC to nivolumab with and without ipilimumab in 
varying dose combinations.24 The results demonstrated that the nivolumab alone arm had 15% with 
partial response and 22.5% with stable disease compared to 5% (1 patient) with a complete 
response, 20% with partial response, and 30% with stable disease in the combination arm. Not only 
were there responses in each arm, some appeared to be durable.  

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3.3 
Study Agent 
 
The active pharmaceutical ingredient in avelumab drug product is a fully human antibody (calculated 
molecular weight of 143832 Dalton) of the immunoglobulin G (IgG) 1 isotype that 
specifically targets and blocks PD-L1, the ligand for PD-1, thus removing the suppressive effects of 
PD-L1 on the anti-tumor CD8+ T cells. Avelumab drug product is a sterile, clear, and colorless 
concentrate for solution intended for intravenous (IV) infusion. The drug is presented at a 
concentration of 20 mg/mL in single-use glass vial containing 200 mg of avelumab. Avelumab drug 
product must be stored at 2°C to 8°C until use, and it must not be frozen. Rough shaking of avelumab 
product must be avoided. Avelumab drug product must be diluted with 0.9% saline solution; 
alternatively a 0.45% saline solution can be used if needed. It is recommended that the diluted 
avelumab solution is used immediately. If not used immediately, the diluted drug product can be 
stored up to 8 hours at room temperature or up to 24 hours at 2°C to 8°C. For further data on 
avelumab please refer to the current Investigator’s Brochure.  
3.3.1 Preclinical Experience 
The nonclinical pharmacology studies have shown that avelumab functionally enhances T cell 
activation in vitro and significantly inhibits the growth of PD-L1 expressing tumors in vivo. Avelumab 
binds to human PD-L1 with a high affinity of 0.7 nM and not to any other B7 family proteins, and 
competitively blocks the interaction of PD-L1 with PD-1. The in vitro study results have shown that 
by binding to PD-L1, avelumab effectively enhances T cell activation as measured by interleukin-2 or 
interferon-gamma production. In addition, as a fully human IgG1 antibody, avelumab has the 
potential to trigger the antibody-dependent cell-mediated cytotoxicity (ADCC) against target cells 
expressing PD-L1. As a monotherapy, avelumab has demonstrated anti-tumor activity against murine 
MC38 colon carcinoma tumors that are characterized by a high level of PD-L1 expression. A dose-
dependent trend was observed, and 400 μg per dose (20 mg/kg, approximately) was identified as 
the optimally effective dose when given every third day for 3 total doses. The in vivo anti-tumor 
effects were found to be primarily mediated by CD8+ T cells as evidenced by the observation that in 
vivo depletion of this cell type completely abrogated the anti-tumor efficacy of avelumab. The 
contribution of ADCC as a potential mechanism of anti-tumor activity was further demonstrated in 
vivo using a deglycosylated version of avelumab to abrogate fragment crystalline receptor binding 
or via the systemic depletion of natural killer (NK) cells. In both settings, loss of in vivo ADCC potential 
significantly reduced the anti-tumor activity.  
 
The combination of avelumab with commonly used cancer treatments, such as cytotoxic agents and 
radiation therapy, resulted in an improved anti-tumor activity. Chemotherapy with combination 
therapy (with folinic acid, 5-fluorouracil, and oxaliplatin [FOLFOX], and radiation therapy showed the 
better tumor growth inhibition. In particular, radiation therapy was found to be a highly synergistic 
combination with avelumab capable of causing complete regression of established tumors probably 
through generating anti-tumor immune memory. Various immunomonitoring assays were 
incorporated into the in vivo studies. Treatment with avelumab resulted in a consistent increase in 
the percentage of CD8+PD-1+ T cells and an increased frequency of CD8+ T cells with an effector 
memory (TEM) phenotype as determined by flow cytometry. Furthermore, these changes correlated 
with the anti-tumor effect. Increases in tumor antigen-specific T cell responses, as measured by 
enzyme-linked immunosorbent spot and pentamer immunoassays, were evident following 
treatment with avelumab and these responses were enhanced when combined with FOLFOX or 
radiation. Hence, increases in CD8+PD-1+ T cells, CD8+ TEM cells, and antigen-specific T cell 

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responses, may be leveraged as pharmacodynamics (PD) biomarkers with translational relevance to 
the clinical setting. For further data, please refer to the current Investigator’s Brochure for avelumab. 
 
3.3.1.1 Preclinical Pharmacokinetics and Metabolism 
 
Full pharmacokinetic (PK) profiles were evaluated in mice and cynomolgus monkeys, since these 
species have similar binding affinity to PD-L1 to humans, and therefore these species are likely to 
have similar target-mediated clearance. Additional toxicokinetic (TK) data were obtained during the 
course of repeated toxicity studies with avelumab in mice, rats, and cynomolgus monkeys, with 
molecules MSB0010294 and MSB0010682 being the precursors to the final molecule avelumab. The 
anti-PD-L1 antibodies from research batches and precursor molecules tested in single-dose PK 
studies in mice and cynomolgus monkeys demonstrated pronounced nonlinear PK characteristics in 
mice and cynomolgus monkeys in single-dose studies at doses below 20 mg/kg, suggesting a 
combination of first order catabolic clearance and saturable target-mediated clearance. Similar 
terminal half-lives (t1/2) ranging from 58 to 70 hours at doses between 20 and 140 mg/kg were 
observed in toxicity studies in mice and monkeys. 
 
Since avelumab represents a foreign protein to the immune system of animals, anti-avelumab 
antibodies in rodents and nonhuman primates were observed and have been considered in 
interpreting the nonclinical data, with higher doses generally resulting in lower immunogenicity 
incidence. This is potentially due to the interference of avelumab trough concentrations with the 
measurement of antidrug antibody (ADA), and did not affect exposure or impact the conclusions of 
the toxicity studies. The immunogenicity incidence against the human antibody avelumab in animals 
is not deemed predictive for human subjects. The clearance from the clinical population PK model is 
well predicted by allometric scaling from the cynomolgus monkey, confirming its suitability as the 
primary nonclinical PK species.  
 
For further data, please refer to the current Investigator’s Brochure for avelumab. 
 
3.3.1.2 Preclinical Toxicology 
 
The toxicological profile of avelumab was evaluated in vivo in mice, rats, and cynomolgus monkeys. 
In addition, in vitro cytokine release assays (CRA) in human and cynomolgus monkey whole blood 
and peripheral blood mononuclear cells (PBMCs) as well as tissue cross reactivity (TCR) studies in 
normal human and cynomolgus monkey tissues were performed. 
 
On the basis of the binding affinity data, the cynomolgus monkey and the mouse were selected as 
relevant species for the nonclinical safety testing of avelumab. In repeat dose toxicity studies in CD-
1 mice with avelumab IV bolus injections, mortality occurred mainly after the 3rd administration. Due 
to severe post-dose anaphylactic reactions after repeated administration of avelumab in mice and 
the low binding affinity in rats, rodent species are not considered appropriate for nonclinical safety 
testing of avelumab and therefore, a single species approach (cynomolgus monkey only) was 
followed and confirmed with Health Authorities. 
 
In cynomolgus monkeys neither in the pilot 4-week IV repeat-dose toxicity study nor in the pivotal 
13-week study, clinical signs of hypersensitivity or avelumab-related infusion reactions have been 

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seen after repeated treatment with avelumab at dose levels of 20, 60, and 140 mg/kg, respectively. 
For the pilot 4-week study as well as for the pivotal 13-week IV repeat-dose toxicity study, a no 
observed adverse effect level (NOAEL) of 140 mg/kg for systemic toxicity was established. 
 
No reproductive toxicity studies were conducted. However, the reproductive and developmental 
toxicity potentially associated with avelumab treatment is considered adequately established based 
on available data, from repeat-dose studies and public sources and in view of the pursued indications 
and targeted indications (life threatening cancer diseases, advanced-stage cancer subjects). 
Considering that disruption of PD-1/PD-L1 communication has been reported to significantly 
increase the risk of fetal loss during pregnancy, the potential for adverse outcomes on embryofetal 
development cannot be excluded and adequate protections must be in place to prevent risk of 
pregnancies. 
 
Initial CRA in human and cynomolgus monkey whole blood and PBMCs revealed no clear-cut 
evidence for release of pro-inflammatory cytokines. However, a subsequent, optimized CRA 
demonstrated evidence of potential cytokine release in phytohemagglutinin (PHA) prestimulated 
PBMCs. There was no evidence of phototoxicity on evaluation of UV absorption. Overall, the 
nonclinical safety profile established for avelumab is considered adequate to support the use of 
avelumab in the planned therapeutic indication in humans.  For further data, please refer to the 
current Investigator’s Brochure for avelumab. 
 
3.3.2 Clinical Experience 
Avelumab is currently in clinical development across Phases I, II, and III.  We have highlighted the 
following 4 clinical trials: 
 
• 
EMR 100070-001: A Phase I, open-label, multiple ascending dose trial to investigate the 
safety, tolerability, pharmacokinetics, biological and clinical activity of avelumab in subjects 
with metastatic or locally advanced solid tumors and expansion to selected indications 
• 
EMR 100070-002: A Phase I trial to investigate the tolerability, safety, pharmacokinetics, 
biological and clinical activity of avelumab in Japanese subjects with metastatic or locally 
advanced solid tumors, with expansion part in Asian subjects with gastric cancer  
• 
EMR 100070-003: A Phase II, single arm, open-label, multicenter trial to investigate the 
clinical activity and safety of avelumab in subjects with Merkel cell carcinoma (MCC) 
• 
EMR 100070-004: A Phase III open-label, multicenter trial of avelumab versus docetaxel in 
subjects with non-small cell lung cancer that has progressed after a platinum-containing 
doublet 
 
EMR 100070-001 is a Phase I, open-label, multiple ascending dose trial to investigate the safety, 
tolerability, PK, biological and clinical activity of avelumab in subjects with metastatic or locally 
advanced solid tumors and expansion to selected indications. This trial consists of 2 parts. In the 
dose escalation part, sequential cohorts of subjects were enrolled at progressively higher dose levels 
(ranging from 1.0, 3.0, 10.0, and 20.0 mg/kg once every 2 weeks) with a 3 + 3 algorithm design for 
determination of the maximum tolerated dose (MTD) of avelumab; in the treatment expansion 
phase, subjects in different tumor cohorts are being treated with 10 mg/kg of avelumab once every 
2 weeks until, confirmed progression, unacceptable toxicity, or any reason for withdrawal occurs. 
More than 1500 subjects have been enrolled in the EMR 100070-001 trial. The 3 + 3 dose escalation 

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algorithm to determine the MTD is complete and a dose of 10 mg/kg once every 2 weeks was 
determined for the tumor expansion cohorts on the basis of safety, PK, and PD observations.  The 
treatment expansion part of the trial consists of 16 tumor treatment cohorts. As of 09 June 2016, 53 
subjects in the dose escalation part had received avelumab (4, 13, 15, and 21 subjects had received 
1.0, 3.0, 10.0, and 20.0 mg/kg of avelumab, respectively) and 1738 subjects in the pooled safety 
dataset part (Study EMR100070-001 and EMR100070-003 Part A) had received 10 mg/kg avelumab.  
 
Most of the observed adverse events (AEs) were either in line with those expected in subjects with 
advanced solid tumors or with class effects of monoclonal antibody blocking of the PD-1/PD-L1 axis. 
Infusion-related reactions including drug hypersensitivity reactions and immune-mediated adverse 
reactions have been identified as important risks for avelumab. Respective risk mitigation measures 
have been implemented in all ongoing clinical studies with avelumab.  
 
EMR 100070-004 is an ongoing phase III, open-label trial with a primary objective of demonstrating 
superiority with regard to OS of avelumab versus docetaxel in subjects with PD-L1 positive NSCLC 
after failure of a platinum-based doublet. As of 17 December 2016, safety data can only be presented 
in a blinded manner, meaning that an assessment to study medication (avelumab or docetaxel) is 
not possible. Overall, a total of 533 SAEs (385 cases) have been reported at the data cutoff of 17 
December 2016. Of those SAEs, 416/533 (298 cases) were reported in subjects receiving any study 
medication. From these 416 SAEs 146 SAEs (111 cases) were reported as treatment related. 
 
On March 23, 2017 the FDA announced that avelumab injection 20 mg/mL, for intravenous use, has 
been approved for treatment of adults and pediatric patients 12 years and older with metastatic 
Merkel cell carcinoma.  
 
For further data, please refer to the current Investigator’s Brochure for avelumab. 
 
3.3.2.1 Pharmacokinetics 
 
Pharmacokinetic assessments have been performed in ongoing Trials EMR 100070-001 and EMR 
100070-002. The results are based on the data available as of 19 May 2015 (Trial EMR 100070-001) 
and 13 October 2014 (Trial EMR 100070-002). 
 
Pharmacokinetics following the first 1-hour infusion and dose proportionality of avelumab have been 
characterized in 77 mainly Caucasian subjects treated in the dose escalation and expansion cohort 
of the Phase I Trial EMR 100070-001 by standard non-compartmental analysis based on rich serum 
concentration-time data obtained over a complete dosing interval of 2 weeks (= tau). The exposure 
parameters maximum concentration (Cmax) and area under the concentration-time curve (AUC) 
after first dose generally increased in an approximately dose-proportional manner in the range 
between 3 to 20 mg/kg). The concentration at the end of dose interval (Cmin) increased 
proportionally with dose between 10 to 20 mg/kg, but more than proportionally for doses between 
1 to 10 mg/kg. The total systemic clearance was low, 0.37 mL/h/kg ± 0.11 mL/h/kg at the 10 mg/kg 
dose (n=40). 
 

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The terminal half-life increased with the dose. However, the average values were 102 hours (4.3 
days) and 120 hours (5.0 days) for 10 mg/kg and 20 mg/kg doses, respectively, with no significant 
difference between these two dose groups.  
 
PK appears to be similar across different tumor types. The trough concentrations from cohorts with 
different tumor types were in a similar range, consistent with those obtained in the all-comer tumor 
patients in the dose escalation cohort who received the 10 mg/kg dose and had a serial PK sampling 
(Cmin in the dose escalation cohorts is 22 ± 12 and 25 ± 16 μg/mL for Day 15 and Day 29, 
respectively). A preliminary analysis of the PK data was performed based on the serum concentration 
(as of 13 October 2014) of avelumab obtained from 5 Japanese subjects treated with 3 mg/kg, 6 
Japanese subjects treated with 10 mg/kg and 6 Japanese subjects treated with 20mg/kg as a 1-hour 
IV infusion once every 2 weeks. Preliminary non-compartmental PK parameter calculation was 
performed based on non-QA concentrations obtained during the first infusion using scheduled 
sample collection times and an infusion duration of 1 hour. Exposure values Cmax and AUC increased 
almost proportional with dose. For the 10 mg/kg dose, the total systemic clearance was low (0.45 
mL/h/kg ± 0.20 mL/h/kg). Mean trough levels obtained immediately before next infusion and mean 
peak levels obtained immediately after infusion end (at Days 15, 29, 43 and 85) remained at fairly 
constant levels indicating no accumulation following multiple infusions. This result is in line with the 
calculated apparent t1/2 and the applied dosing scheme (once every 2 weeks) and is similar to that 
reported in Trial EMR 100070-001. 
 
Trial EMR 100070-001 is a global trial performed mainly in Caucasian subjects while Trial EMR 
100070-002 is performed exclusively in Japan. The preliminary concentrations obtained over time 
and the clearance during the first dosing interval was similar in Japanese and Caucasian subjects. 
This was confirmed during the population PK analysis. Population PK analysis was performed based 
on data of 410 subjects from ongoing Trials EMR 100070-001 and EMR 100070-002. Eighty-three 
subjects with rich PK profiles, 9 subjects with peak and trough concentrations and 318 subjects with 
only trough concentrations were included in this analysis. In order to describe the non-linear PK at 
low concentration levels, presumably due to target mediated elimination, a 2 compartment model 
with mixed linear plus Michaelis-Menten elimination was evaluated. Limited by very few 
observations collected in low concentration range showing non-linear elimination, the estimation 
precision of Michaelis-Menten elimination was rather poor (Maximal elimination (Vmax)=0.07 mg/h 
[relative standard error=94%], Michaelis-Menten constant (Km)=0.9 ug/mL [relative standard 
error=448%]). The additional non-linear elimination component did not improve the overall data 
fitting at the statistical significance of p-value below 0.01. Covariate multivariate relationships 
including body weight, body surface area, lean body mass, age, gender, race, creatinine clearance, 
serum albumin, serum bilirubin, aspartate transaminase, alanine transaminase, and tumor type 
were explored. Serum albumin was found to significantly correlate (negatively) with clearance with 
an effect size on AUC ranging from -41% to 27%, which corresponds to serum albumin level ranging 
from 18 g/L to 52 g/L. Lean body mass was found to significantly correlate (positively) with the 
central volume of distribution with effect size ranging from -23% to 33%, which corresponds to lean 
body mass ranging from 29.75 kg to 80.92 kg. The clearance of male subjects was found to be 14% 
higher than of female subjects. This finding may be explained by the correlation between gender 
and lean body mass, the latter of which showed a weaker (and small) covariate effect to the 
clearance when gender effect was not considered. It is to be further investigated as new data 
accumulate. No other covariate effect reached statistical significance (at a pre-set p-value of 0.001). 
Neither body weight, nor body surface area nor lean body mass was found to be significantly 

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correlated to the clearance. Additional analysis is planned to further confirm these preliminary 
findings. 
 
In order to determine the levels of anti-PD-L1 target occupancy (TO) towards PD-L1 on CD3+ T 
lymphocytes at the end of the dosing interval, blood samples were taken at Cmin after the first dose 
(Day 15) in a small number of subjects during the initial dose escalation part of Trial EMR 100070-
001 (n=3 at the 1 mg/kg dose, n=2 at the 3 mg/kg dose, and n=4 at the 10 mg/kg dose). After the 10 
mg/kg dose, TO was greater than 90% at the end of the dosing interval at avelumab trough serum 
levels ranging  between 12.69 to 26.87 μg/mL. After the 3 mg/kg dose, TO also exceeded 90%, at 
trough drug concentrations of 4.56 and 6.99 μg/mL. After the 1 mg/kg dose, 2 out of 3 subjects 
displayed less than 90% TO at trough serum concentrations, which were below the quantification 
limit of 0.2 μg/mL in these 2 subjects. 
 
Earlier studies showed a concentration of 1 μg/mL avelumab was required in whole blood to reach 
a target saturation plateau of >95% TO. The population PK analysis showed non-linear Michaelis-
Menten elimination of avelumab at very low serum concentrations with a Vmax=0.07 mg/h and a 
Km=0.9 μg/mL. Despite the large imprecision obtained, these results are consistent with the in vitro 
blood concentrations required to achieve target saturation. Based on these analysis and trough 
serum levels of the drug observed in the dose escalation cohorts in EMR 100070-001, TO would reach 
or exceed > 95% occupancy throughout the entire dosing interval for 10 out of 13 subjects who 
received 3 mg/kg, and for all (15/15) subjects who received 10 mg/kg, in the dose escalation group 
in Trial EMR 100070-001. Thus, it appears that a 10 mg/kg dose of avelumab would achieve maximal 
TO in blood in the majority of subjects based on in vitro studies. Therefore, in order to achieve target 
saturation during the whole treatment period in the majority of subjects, the dose of 10 mg/kg every 
2 weeks was selected as the dose for further investigation in treatment expansion cohorts in the 
Phase I Trial EMR 100070-001 and for future Phase III studies. 
 
For further data, please refer to the current Investigator’s Brochure for avelumab. 
 
3.3.2.2 Efficacy 
 
The clinical efficacy information summarized here includes data from the NSCLC and ovarian cancer 
expansion cohorts of the ongoing Phase I Trial EMR 100070-001, the 20 subjects in the gastric cancer 
expansion cohort of the ongoing Phase I Trial EMR 100070-002, and the 88 patients in the Phase II 
EMR 100070-003 Trial in Merkel Cell carcinoma.  
 
The NSCLC expansion cohort in the ongoing Phase I Trial EMR 100070-001 had a cutoff date of 15 
January 2015, 6 months after start of avelumab treatment of the last subject in this expansion cohort 
(a total of 184 treated subjects).25 The objective response rate (ORR) based on confirmed and 
unconfirmed responses for subjects treated in the NSCLC expansion cohort was 14.1% (26 of 184 
NSCLC subjects). Progression free survival (PFS) and overall survival (OS) were all evaluated for all 
NSCLC subjects treated in the expansion phase. As of 15 January 2015, the median PFS and OS for 
the NSCLC treatment expansion cohort were 11.6 weeks and 8.4 months, respectively. A total of 142 
out of the 184 subjects in the second-line NSCLC expansion cohort provided tumor samples that 
were evaluable for PD-L1 expression. Antitumour activity was seen in tumors defined as PD-L1+ and 
PD-L1− using prespecified PD-L1 expression levels on tumour cells (1%, 5%, and 25%) and tumour-

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associated immune cells. In patients with PD-L1+ vs PD-L1− tumours, there was no significant 
difference in response rates or OS, whereas PFS was longer in those patients with PD-L1+ tumours 
compared with PD-L1− tumours in an analysis based on a 1% cut-off for tumour cell staining (hazard 
ratio for progressive disease, 0.45; 95% CI: 0.27, 0.75). 
 
The ovarian cancer expansion cohort had a data cutoff of 23 October 2015. This cohort enrolled and 
treated a total of 124 subjects. The ORR based on confirmed and unconfirmed responses for subjects 
treated in the ovarian cancer expansion cohort was 9.7% (12 of 124 subjects). In 6 of the 12 
responders (50.0%), the responses were ongoing at the time of the data cutoff. The median PFS for 
the ovarian cancer expansion cohort was 11.3 weeks (95% CI: 6.1 to 12.0 weeks).  
 
The gastric cancer expansion cohort in the ongoing Phase I Trial EMR100070-002 had a data 
cut off of 11 March 2015 for 20 subjects being treated with 10 mg/kg of avelumab once every 
2 weeks. As of the data cutoff, 3 of 20 subjects responded to study treatment (all responses were 
PRs and all responses were confirmed responses), and the BOR was 15.0% (95% CI: 3.2% to 37.9%). 
Two of the responders had the first response at around Week 6 and 1 responder had the first 
response at around Week 18. Two of the 3 responders had their response continued at the time of 
the data cutoff. The median PFS of this group according to RECIST 1.1 was 11.9 weeks (95% CI: 6.0 
to 12.3 weeks). The Kaplan-Meier estimates predicted a PFS rate of 43.3% at 12 weeks. 
 
The Phase II EMR 100070-003 Trial in Merkel Cell carcinoma gave avelumab to 88 patients and 
resulted in an objective response in 28 patients (31.8% [95.9% CI 21.9-43.1]), including 8 complete 
responses.27 Responses were ongoing in 23 (82%) of 29 at the time of data cut off 03 March 2016. 
Median PFS was 2.7 months (95% CI: 1.4, 6.9), and the proportion of subjects who were progression-
free at 6 months was 40% (95% CI: 29, 50). 
 
For further data, please refer to the current Investigator’s Brochure for avelumab. 
 
3.4 
Purpose and Rationale 
 
Data supporting PD-L1 inhibition in prostate cancer was found when enzalutamide resistant cell lines 
and xenografts on mice had increased PD-L1.28 Our own cell lines established at Duke that are 
enzalutamide resistant also demonstrate upregulation of PD-L1 at the protein and RNA level as 
compared with the parental cell lines, suggesting that PD-L1 is an adaptive response to stress and is 
highly dynamic (data unpublished). Further, we have also looked at a cohort of patients with 
NEPC/SCPC using a tissue microarray for PD-L1 expression by immunohistochemistry and have found 
that a small subset (~20% small cell, ~10% adenocarcinoma) of these cases express high levels of PD-
L1 (data unpublished). Further still is evidence showing that there is a high burden of genetic 
mutations in NEPC15 which has been seen in other cancers to confer susceptibility to 
immunotherapy. 
 
Given the emerging role of immunotherapy across multiple tumor types to produce durable 
responses, and given the similarity of small cell by both histology and its response to current 
chemotherapy, we hypothesize that avelumab will produce a clinical and radiographic response in 
NEPC that will be durable in a subset of patients. In this study, we are defining the NEPC “phenotype” 

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based on clinical poor risk features of AR-independence or based on histologic evidence of NEPC in 
tissue or serum. 
4 OBJECTIVES AND ENDPOINTS 
4.1 
Primary Endpoint 
 
To determine the efficacy of PD-L1 inhibition with avelumab as measured by a modified PCWG3, 
where RECIST 1.1 is replaced with iRECIST, a modified RECIST 1.1 for immune-based therapeutics, 
radiographic response rate in men with metastatic neuroendocrine-like prostate cancer.  
 
4.2 
Secondary Endpoints 
 
1. To describe the efficacy of PD-L1 inhibition with avelumab as measured by PCWG3 using 
RECIST1.1 
2. To describe the radiographic progression free survival (rPFS) of PD-L1 inhibition with 
avelumab using modified PCWG3 with both RECIST 1.1 and iRECIST criteria in this setting. 
3. To describe the overall survival of PD-L1 inhibition in this setting. 
4. To described the toxicities and safety of PD-L1 inhibition with avelumab in men with 
metastatic neuroendocrine-like prostate cancer. 
4.3 
Exploratory Endpoints 
 
1. To describe the impact of PD-L1 inhibition with avelumab on blood-based biomarker changes 
over time, including PSA, chromogranin-A, cell free DNA, LDH, and alkaline phosphatase. 
2. To determine if levels of circulating biomarkers secreted by neuroendocrine-like prostate 
cancers correlate with clinical and radiographic treatment response 
3. To determine if the presence of different immunohistochemical markers on the pre-biopsy 
specimens prognosticates clinical and radiographic treatment response 
4. To determine if the level of different circulating immune cells correlate with both progressive 
addition of immunotherapy as well as clinical and radiographic treatment response or disease 
progression 
5. To determine if levels of cell free DNA correlate with clinical and radiographic treatment 
response 
6. To isolate prostate neuroendocrine-like CTCs for ex vivo growth and culture and characterization 
studies. 
5 INVESTIGATIONAL PLAN 
5.1 
Study Design 
 
This is an open label, single arm, phase 2 study of men with neuroendocrine phenotype prostate 
cancer to assess the safety and efficacy of avelumab 10 mg/kg IV every 2 weeks until progression or 
intolerable side effects. Cycles will be 4 weeks long and thus include 2 doses of avelumab. This study 
will be at multiple centers with the Duke Cancer Institute as the lead site. For stage 1, Duke will serve 
as the single site for this study.  For stage 2, the study would be expanded to include additional sites 

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through the Department of Defense Prostate Cancer Clinical Trials Consortium (DOD PCCTC). All 
subjects will be followed for disease progression and death from the date that the subjects were 
registered to the protocol. 
 
At radiologic progression a standard of care post-treatment progression biopsy will be collected at 
the discretion of the treating provider, and if proper consent is obtained, additional tissue will be 
collected for research tests including assessments of resistance mechanisms and immune checkpoint 
status.  The additional research tissue will be banked in the Biospecimen Repository & Processing 
Core (BRPC) under Pro00080869. The study team will also pursue dual consent to BRPC Pro00035974 
for future unspecified research. 
 
Men will continue on their ADT used at entry into study per investigator with subsequent changes 
made per investigator. Men not on ADT at time of entry due to being purely SCPC can remain off 
ADT. Men with SCPC on ADT at study entry can remain on ADT per investigator while all men with 
mixed histologies should remain on active ADT during trial participation.  
 
Men will be allowed to receive palliative radiation to any disease site indicated by the treating 
physician at any time before or during the study, provided that another untreated site of 
measureable disease is present at baseline. 
5.2 
Drug Discontinuation Criteria 
 
All subjects will be monitored for adverse events (AEs) on treatment using NCI CTCAE v4.0 or the 
most current version.  Stopping rules based on unacceptable toxicities will be used in this study.  
Avelumab will be discontinued in the patient if there is unacceptable toxicity defined as:  
• 
Any grade 5 treatment-related death 
• 
Any Grade 4 AE except for single laboratory values out of normal range that are unlikely related 
to study treatment as assessed by the Investigator, do not have any clinical correlate, and resolve 
within 7 days with adequate medical management 
• 
Any Grade 3 AE except for any of the following:  
o Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with 
medical management 
o Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that 
resolves to Grade ≤ 1  
o Single laboratory values out of normal range (excluding Grade ≥ 3 liver function test 
increase) that are unlikely related to study treatment according to the Investigator, do 
not have any clinical correlate, and resolve to Grade ≤ 1 or baseline within 7 days or by 
the next visit with adequate medical management 
o Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor 
o Change in Karnofsky Performance Status to ≤ 40 that does not resolve to ≥ 50 within 14 
days (infusions should not be given on the following cycle, if the Karnofsky Performance 
Status  is ≤ 40  on the day of study drug administration) 
 
Grade 2 immune-related AEs should be managed as follows: 
• 
If a Grade 2 ADR resolves to Grade ≤ 1 by the last day of the current cycle, treatment may 
continue. 

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• 
If a Grade 2 ADR does not resolve to Grade ≤ 1 by the last day of the current cycle, infusions 
should not be given on the following cycle.  If at the end of the following cycle the event has 
not resolved to Grade 1, the subject should permanently discontinue treatment with a 
avelumab ADR (except for hormone insufficiencies and conditions that are adequately 
treated with medical management, that can be managed by replacement therapy; for these 
hormone insufficiencies, up to 2 subsequent doses may be omitted). Patients with transient, 
minor Grade 2 ADRs, may be permitted to continue therapy with permission of the study PI 
provided the patient is adequately managed medically.  
• 
Upon the second occurrence of the same Grade 2 ADR (except for hormone insufficiencies 
that can be managed by replacement therapy) in the same subject, treatment with 
avelumab has to be permanently discontinued 
 
There will be no dose modifications for avelumab in this study. Dose interruptions for reasons other 
than toxicity (e.g., surgical procedures) may be allowed with PI approval. The investigator and the PI 
will determine the acceptable length of treatment interruption. If avelumab is withheld for > 8 weeks 
then study treatment will be permanently discontinued. 
 
If the investigator believes the patient is likely to derive clinical benefit, avelumab treatment can be 
resumed after being withheld for > 8 weeks. If a patient must be tapered off corticosteroids used to 
treat adverse events, study treatment may be withheld for > 8 weeks with PI approval. 
 
5.3 
Trial Stopping Rules 
 
If at any time after the first 12 subjects are enrolled, the observed proportion of unacceptable 
treatment-related toxicity exceeds 25% by at least one standard error, accrual will be immediately 
suspended to the trial.  Unacceptable toxicity will be defined as grade 3 or higher treatment related 
adverse events.  Each patient will be categorized according to their most severe toxicity using NCI 
CTC v4.0 or the most current version. 
5.4 
Treatment Modification Guidelines for Infusion-Related Reactions 
 
Please see the below table for suggested treatment modification for symptoms of infusion related 
reactions 
 
NCI-CTCAE Grade (modified) 
Treatment Modification for Study Drug 
Grade 1 – mild 
Mild transient reaction; 
(based on combination of signs and 
symptoms which may include mild pruritus, 
flushing, rhinitis, rash, fever, and chills) 
Stop study drug infusion and provide 
supportive care in accordance with local 
institutional  hypersensitivity protocol. 
Resume infusion at 50% of previous rate 
once acute infusion-related reaction has 
resolved and monitor closely for any 
worsening.  
Grade 2 – moderate 
Therapy or infusion interruption indicated 
but responds promptly to symptomatic 
treatment (for example, antihistamines, 
Stop study drug infusion and provide 
supportive care in accordance with local 
institutional  hypersensitivity protocol. 

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NSAIDs, narcotics, IV fluids); prophylactic 
medications indicated for ≤ 24 h. 
Resume infusion at 50% of previous rate 
once infusion-related reaction has resolved 
or decreased to at least Grade 1 in severity, 
and monitor closely for any worsening. 
 
Grade 3 or Grade 4 – severe or 
life-threatening 
Grade 3: Prolonged (for example, not 
rapidly responsive to symptomatic 
medication and/or brief interruption of 
infusion); recurrence of symptoms following 
initial improvement; hospitalization 
indicated for clinical sequelae. 
Grade 4: Life-threatening consequences; 
urgent intervention indicated. 
Stop the study drug infusion immediately 
and disconnect infusion tubing from the 
subject. 
Subjects have to be withdrawn immediately 
from study drug treatment and must not 
receive any further study drug treatment. 
• 
If hypersensitivity reaction occurs, the subject must be treated according to the best 
available medical practice.  
• 
Once the avelumab infusion rate has been decreased by 50% or interrupted due to an 
infusion-related reaction (grade 1 or 2), the infusion rate may be increased back to the 
initial rate during that same infusion or during subsequent infusions at the discretion of 
the provider. Subjects may also be pre-medicated with steroids and/or oral or inhaled 
cromolyn sodium at the discretion of the provider. 
• 
For subsequent infusions after a grade 1 or 2 reaction, at least 1 modification must be 
made to the infusion parameters: rate can be decreased (to a 3 or 4 hour infusion) and/or 
additional pre-medications can be administered at the discretion of the provider.  
• 
The starting infusion rate for the study drug should not exceed 4 hours. 
• 
If the avelumab is given over 4 hours, the options for optimization of pre-medications 
have been exhausted, and the patient continues to experience a grade 1 or 2 reaction, 
then the study drug must be discontinued permanently.   
 
5.5 
Management of Immune-mediated Adverse Reactions 
 
Please see the table below for management of immune-mediated adverse reactions 
 
Since inhibition of PD-L1 stimulates the immune system, immune-related AEs (irAEs) may occur.  
Treatment of irAEs is mainly dependent upon severity (NCI-CTCAE grade): 
Grade 1 to 2:  treat symptomatically or with moderate dose steroids, more frequent monitoring 
Grade 1 to 2 (persistent):  manage similar to high grade AE (Grade 3 to 4) 
Grade 3 to 4:  treat with high dose corticosteroids 
Treatment of gastrointestinal, dermatological, pulmonary, hepatic and endocrine irAEs should 
follow guidelines set forth in the table below. 
Gastrointestinal irAEs 
Severity of Diarrhea / 
Colitis (NCI-CTCAE v4.03) 
Management 
Follow-up 

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Grade 1 
Diarrhea: < 4 stools/day 
over Baseline 
Colitis: asymptomatic  
Continue avelumab 
therapy 
Symptomatic 
treatment (for 
example, 
loperamide) 
Close monitoring for worsening 
symptoms 
Educate subject to report 
worsening immediately 
If worsens: 
Treat as Grade 2 or 3/4  
Grade 2 
Diarrhea:  4 to 6 stools per 
day over Baseline; IV fluids 
indicated < 24 hours; not 
interfering with ADL 
Colitis:  abdominal pain; 
blood in stool  
Delay avelumab 
therapy 
Symptomatic 
treatment 
If improves to Grade 1:  
Resume avelumab therapy 
If persists > 5 to 7 days or recur: 
0.5 to 1.0 mg/kg/day 
methylprednisolone or equivalent  
When symptoms improve to Grade 
1, taper steroids over at least 1 
month, consider prophylactic 
antibiotics for opportunistic 
infections, and resume avelumab 
therapy per protocol (if reduced to 
10 mg/day or less of prednisone 
equivalent). 
If worsens or persists > 3 to 5 days 
with oral steroids: 
Treat as Grade 3 to 4 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 
stools per day over 
Baseline; incontinence; IV 
fluids ≥ 24 hrs.; interfering 
with ADL 
Colitis (Grade 3):  severe 
abdominal pain, medical 
intervention indicated, 
peritoneal signs 
Grade 4:  life-threatening, 
perforation 
Discontinue 
avelumab therapy 
per protocol 
1.0 to 2.0 mg/kg/day 
methylprednisolone 
IV or equivalent 
Add prophylactic 
antibiotics for 
opportunistic 
infections  
Consider lower 
endoscopy  
If improves:  
Continue steroids until Grade 1, 
then taper over at least 1 month 
If persists > 3 to 5 days, or recurs 
after improvement: 
Add infliximab 5 mg/kg (if no 
contraindication), Note: Infliximab 
should not be used in cases of 
perforation or sepsis  
Dermatological irAEs 
Grade of Rash 
(NCI-CTCAE v4) 
Management 
Follow-up 

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Grade 1 to 2  
Covering ≤ 30% body 
surface area  
Symptomatic 
therapy (for 
example, 
antihistamines, 
topical steroids)  
Continue avelumab 
therapy 
If persists > 1 to 2 weeks or recurs:  
Consider skin biopsy  
Delay avelumab therapy 
Consider 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent. Once improving, taper 
steroids over at least 1 month, 
consider prophylactic antibiotics 
for opportunistic infections, and 
resume avelumab therapy once 
patient has reached prednisone 
equivalent of 10 mg/d and 
improving. 
If worsens:  
Treat as Grade 3 to 4  
Grade 3 to 4 
Covering > 30% body 
surface area; life 
threatening consequences  
Delay or discontinue 
avelumab therapy 
Consider skin biopsy  
Dermatology consult  
1.0 to 2.0 mg/kg/day 
methylprednisolone 
IV or IV equivalent  
If improves to Grade 1:  
Taper steroids over at least 1 
month and add prophylactic 
antibiotics for opportunistic 
infections  
Resume avelumab therapy 
Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v4) 
Management 
Follow-up 
Grade 1 
Radiographic changes only  
Consider delay of 
avelumab therapy  
Monitor for 
symptoms every 2 to 
3 days  
Consider Pulmonary 
and Infectious 
Disease consults  
Re-image at least every 3 weeks 
If worsens:  
Treat as Grade 2 or Grade 3 to 4  

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Grade 2 
Mild to moderate new 
symptoms  
Delay avelumab 
therapy 
Pulmonary and 
Infectious Disease 
consults 
Monitor symptoms 
daily, consider 
hospitalization  
1.0 mg/kg/day 
methyl-prednisolone 
IV or oral equivalent  
Consider 
bronchoscopy, lung 
biopsy  
Re-image every 1 to 3 days  
If improves:  
When symptoms return to near 
Baseline, taper steroids over at 
least 1 month and then resume 
avelumab therapy and consider 
prophylactic antibiotics 
If not improving after 2 weeks or 
worsening:  
Treat as Grade 3 to 4  
Grade 3 to 4 
Severe new symptoms; 
New / worsening hypoxia; 
life-threatening  
Discontinue 
avelumab therapy 
Hospitalize  
Pulmonary and 
Infectious Disease 
consults 
2 to 4 mg/kg/day 
methylprednisolone 
IV or IV equivalent  
Add prophylactic 
antibiotics for 
opportunistic 
infections  
Consider 
bronchoscopy, lung 
biopsy  
If improves to Baseline:  
Taper steroids over at least 6 
weeks  
If not improving after 48 hours or 
worsening:  
Add additional immunosuppression 
(for example, infliximab, 
cyclophosphamide, IV 
immunoglobulin, or 
mycophenolate mofetil)  
Hepatic irAEs (reportable per section 9.3) 
Grade of Liver Test 
Elevation 
(NCI-CTCAE v4) 
Management 
Follow-up 
Grade 1 
Grade 1 AST or ALT > ULN 
to 3.0 x ULN and / or total 
bilirubin > ULN to 1.5 x ULN  
Continue avelumab 
therapy 
Continue liver function monitoring  
If worsens:  
Treat as Grade 2 or 3 to 4  
Grade 2 
AST or ALT > 3.0 to ≤ 5 x 
ULN and / or total bilirubin 
> 1.5 to ≤ 3 x ULN  
Delay avelumab 
therapy 
Increase frequency 
of monitoring to 
every 3 days  
If returns to Baseline:  
Resume routine monitoring, 
resume avelumab therapy 
If elevations persist > 5 to 7 days or 
worsen:  

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Report per section 
9.3 
 
 0.5 to 1 mg/kg/day 
methylprednisolone or oral 
equivalent and when LFT returns to 
Grade 1 or Baseline, taper steroids 
over at least 1 month, consider 
prophylactic antibiotics for 
opportunistic infections, and 
resume avelumab therapy 
Grade 3 to 4 
AST or ALT > 5 x ULN and / 
or total bilirubin > 3 x ULN  
Discontinue 
avelumab therapy  
Increase frequency 
of monitoring to 
every 1 to 2 days  
1.0 to 2.0 mg/kg/day 
methylprednisolone 
IV or IV equivalent 
Add prophylactic 
antibiotics for 
opportunistic 
infections  
Consult 
gastroenterologist 
Consider obtaining 
MRI/CT scan of liver 
and liver biopsy if 
clinically warranted  
Report per section 
9.3 
 
If returns to Grade 2:  
Taper steroids over at least 1 
month  
If does not improve in > 3 to 5 
days, worsens or rebounds:  
Add mycophenolate mofetil 1 gram 
(g) twice daily  
If no response within an additional 
3 to 5 days, consider other 
immunosuppressants per local 
guidelines  
Endocrine irAEs 
Endocrine Disorder 
Management 
Follow-up 
Asymptomatic TSH 
abnormality  
Continue avelumab therapy   
 If TSH < 0.5 x LLN, or TSH > 2 x ULN, or consistently out of 
range in 2 subsequent measurements: include T4 at 
subsequent cycles as clinically indicated; consider 
endocrinology consult  
Symptomatic 
endocrinopathy  
Evaluate endocrine 
function  
Consider pituitary 
scan  
Symptomatic with 
abnormal lab / 
pituitary scan:  
If improves (with or without 
hormone replacement):  
Taper steroids over at least 1 
month and consider prophylactic 
antibiotics for opportunistic 
infections  
Resume avelumab therapy  

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Delay avelumab 
therapy 
1 to 2 mg/kg/day 
methylprednisolone 
IV or by mouth 
equivalent  
Initiate appropriate 
hormone therapy  
No abnormal lab / 
pituitary MRI scan 
but symptoms 
persist:  
Repeat labs in 1 to 3 
weeks / MRI in 1 
month  
Subjects with adrenal insufficiency 
may need to continue steroids with 
mineralocorticoid component  
Suspicion of adrenal crisis 
(for example, severe 
dehydration, hypotension, 
shock out of proportion to 
current illness)  
Delay or discontinue avelumab therapy  
Rule out sepsis  
Stress dose of IV steroids with mineralocorticoid activity  
IV fluids  
Consult endocrinologist  
If adrenal crisis ruled out, then treat as above for symptomatic 
endocrinopathy  
Cardiac irAEs 
Myocarditis 
Management 
Follow-up 
New onset of cardiac signs 
or symptoms and / or new 
laboratory cardiac 
biomarker elevations (e.g. 
troponin, CK-MB, BNP) or 
cardiac imaging 
abnormalities suggestive of 
myocarditis.  
Withhold avelumab therapy 
Hospitalize. In the presence of 
life 
threatening 
cardiac 
decompensation, 
consider 
transfer 
to 
a 
facility 
experienced 
in 
advanced 
heart failure and arrhythmia 
management.     
Cardiology 
consult 
to 
establish etiology and rule-
out 
immune-mediated 
myocarditis.  
Guideline based supportive 
treatment as appropriate per 
cardiology consult.* 
Consider myocardial biopsy if 
recommended per cardiology 
consult. 
If symptoms improve and 
immune-mediated etiology is 
ruled out, re-start avelumab 
therapy. 
  
If symptoms do not 
improve/worsen, viral 
myocarditis is excluded, and 
immune-mediated etiology is 
suspected or confirmed 
following cardiology consult, 
manage as immune-mediated 
myocarditis. 

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Immune-mediated 
myocarditis 
Permanently 
discontinue 
avelumab. 
Guideline based supportive 
treatment as appropriate per 
cardiology consult.* 
Methylprednisolone 1-2 
mg/kg/day.  
Once 
improving, 
taper 
steroids over at least 1 month 
and 
add 
prophylactic 
antibiotics for opportunistic 
infections. 
If no improvement or 
worsening, consider 
additional 
immunosuppressions (e.g. 
azathioprine, cyclosporine A) 
*Local guidelines, or eg. ESC or AHA guidelines  
ESC guidelines website:  
https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 
 
 
5.6 
Concomitant Medications 
 
Concomitant medication will be evaluated at each study visit during study treatment.  Concomitant 
medications include all vitamins, herbal remedies, over the counter, and prescription medications.  
Bone anti-resorptive therapy (denosumab, zoledronic acid) is permitted concurrently.  ADT in the 
form of GnRH agonists or antagonists is permitted as part of the study as per standard of care 
practice. For patients on enzalutamide during screening, enzalutamide is permitted to be continued 
on study following progression per eligibility criteria.  Enzalutamide will be able to be restarted 
during screening prior to study entry in patients who have had prior progression on enzalutamide 
per the discretion of the treating physician.  
 
The following medications are prohibited within 2 weeks of enrollment and while on study drug, 
unless otherwise indicated below:  
• 
Flutamide, bicalutamide or nilutamide;  
• 
5 α-reductase inhibitors (finasteride, dutasteride) are permitted concurrently;  
• 
Estrogens;  
• 
Abiraterone acetate  
• 
Systemic glucocorticoids greater than the equivalent of 10 mg per day of prednisone unless 
required to treat an immune related ADR or needed as pre-treatment for an allergy to contrast; 
• 
Androgens (testosterone, dihydroepiandrosterone [DHEA], etc.);  
• 
All other investigational, chemotherapeutic, biologic, and radiopharmaceutical anti-cancer 
agents are prohibited within 4 weeks of enrollment and for the duration of study treatment 
• 
Any herbal or complementary treatments that, in the opinion of the treating physician may 
increase the risk to the patient, are prohibited. 
 
The following treatments do not require study discontinuation: 
 
• 
Blood transfusions and growth factor support per standard of care and institutional guidelines;  

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• 
Steroids given at a maximum equivalent daily dose of 10 mg of prednisone;  
• 
Pain therapy per standard of care and institutional guidelines 
5.7 
Study Drug Blinding 
 
Not applicable, this is an open-label study 
5.8 
Randomization 
 
Not applicable, this is a non-randomized study 
5.9 
Rationale for Selection of Dose, Regimen, and Treatment Duration 
 
The dosing used for both the GnRH agonist and avelumab (10 mg/kg IV every 2 weeks) is derived 
from earlier studies described in Section 3.3.2.1. 
5.10 
Definition of Evaluable Subjects, On Study, and End of Study 
 
Patients who consent but do not receive a dose of study drug will be replaced and will not be 
considered evaluable.   
 
All subjects enrolled onto the study who receive at least one dose of avelumab will be included in 
the intention-to-treat analysis for the primary endpoint.   
 
All subjects enrolled onto the study who receive at least one dose of avelumab will be evaluable for 
the secondary and exploratory endpoints. 
 
Given the potential risk for delayed immune-related toxicities, safety follow-up must be performed 
28 days after the last dose of avelumab administration. 
 
The extended safety follow-up beyond 28 days after last study drug administration may be 
performed either via a site visit or via a telephone call with subsequent site visit requested in case 
any concerns noted during the telephone call. 
5.11 
Early Study Termination 
 
This study can be terminated at any time for any reason by the PI-sponsor.  If this occurs, all subjects 
on study will be notified as soon as possible.  Additional procedures and/or follow up should occur 
in accordance with Section 8.8, which describes procedures and process for prematurely withdrawn 
subjects 
 
6 STUDY DRUG 
6.1 
Names, Classification, and Mechanism of Action 
 
Avelumab (MSB0010718C) is a fully human antibody of the immunoglobulin G (IgG) 1 isotype that 

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specifically targets and blocks PD-L1, the ligand for PD-1, thus removing the suppressive effects of 
PD-L1 on the anti-tumor CD8+ T cells. Pfizer is developing avelumab for the treatment of cancer. 
Avelumab is FDA-approved for treatment of adults and pediatric patients 12 years and older with 
metastatic Merkel cell carcinoma in the United States.  
6.2 
Packaging and Labeling 
 
Avelumab drug product is a sterile, clear, and colorless concentrate for solution intended for 
intravenous (IV) infusion. The drug is presented at a concentration of 20 mg/mL in single-use glass 
vial containing 200 mg of avelumab.  
6.3 
Supply, Receipt, and Storage 
 
Avelumab drug product must be stored at 2°C to 8°C until use, and it must not be frozen. Rough 
shaking of avelumab product must be avoided. Avelumab drug product must be diluted with 0.9% 
saline solution; alternatively a 0.45% saline solution can be used if needed. It is recommended that 
the diluted avelumab solution is used immediately. For further data on avelumab please refer to the 
Investigator’s Brochure.  
 
It is given as an IV in an approved chemotherapy infusion center by certified chemotherapy nurses.  
6.4 
Special Precautions for Administration 
 
Premedication: In order to mitigate infusion-related reactions, a premedication with an 
antihistamine and with paracetamol (acetaminophen) 30 to 60 minutes prior to each dose of 
avelumab is mandatory (for example, 25-50 mg diphenhydramine and 500-650 mg paracetamol IV 
or oral).  This may be modified based on local treatment standards and guidelines, as appropriate. 
Subjects may also be pre-medicated with steroids and/or oral or inhaled cromolyn sodium at the 
discretion of the provider. 
 
Setting: Avelumab should be administered in a setting that allows for immediate access to an 
intensive care unit or equivalent environment and administration of therapy for anaphylaxis, such 
as the ability to implement immediate resuscitation measures. Avelumab should be given over 2 
hours (-10 min/+20min).  Steroids (dexamethasone 10 mg), epinephrine (1:1,000 dilution), allergy 
medications (IV antihistamines), bronchodilators, or equivalents, and oxygen should be available for 
immediate access.  
 
Observation period:  Following avelumab infusions, subjects must be observed for 30 minutes 
post-infusion for potential infusion-related reactions.   
 
7 SUBJECT ELIGIBILITY 
 
7.1 
Inclusion Criteria 
 

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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 (Dr. Jiaoti Huang). Central Duke pathologic review is not 
required for screening but rather for confirmation of histologic subtype. Local pathologic review 
is sufficient for eligibility determination. 
a. 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. 
b. 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:    
 
a. 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. 
b. Soft-tissue progression based on new lesions or growth of existing soft tissue metastases.  
c. 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. 
 

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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. 
7.2 
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 

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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. 
 

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8 SCREENING AND ON-STUDY TESTS AND PROCEDURES 
 
≤35 Days 
Prior to 
Dosing 
Cycle  Duration = 28 days  
(+/- 3 day window of allowance) (2) 
 
Post Treatment (+/- 7 days) 
Activity 
Screening
/ baseline 
Day 1 of every 
cycle(1, 2, 10, 16, 17) 
Day 15 of 
every cycle(2) 
EOT / 
Progression/
Withdrawal(3) 
Safety follow up 
(28 days post 
treatment) 
Long Term 
Follow-Up 
(every 3 
months) 
Baseline Documentation 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
Central histology review of tumor 
tissue, Duke pathology 
X 
 
 
 
 
 
Medical/Oncological History(4) 
X 
X 
X 
X 
X 
X 
Laboratory Studies 
 
 
 
 
 
 
Hematology(5) 
X 
X 
X 
X 
X 
 
Blood Chemistry(5) 
X 
X 
X 
X 
X 
 
Urinalysis(6) 
X 
 
 
 
 
 
PSA 
X 
X 
 
X 
X 
 
Testosterone 
X 
X 
 
X 
 
 
Thyroid Studies(5) 
X 
X 
 
X 
X 
 
Tumor Markers(7) 
X 
X 
 
X 
 
 
Study Treatment 
 
 
 
 
 
 
Study Treatment – ADT +/- 
enzalutamide (SOC)(8) 
X 
X 
X 
X 
 
 
Study Treatment – Avelumab(9) 
 
X 
X 
 
 
 
Tumor Assessments 
 
 
 
 
 
 
Tumor Imaging(10) 
X 
X 
 
X 
 
 
Post-Progression Biopsy(11) 
 
 
 
X 
 
 
Clinical Assessments 
 
 
 
 
 
 
Physical Examination(12) 
X 
X 
X 
X 
X 
 

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KPS, Weight, Vitals 
X 
X 
X 
X 
X 
 
Adverse Events(13) 
 
X 
X 
X 
X 
 
Conmed/Treatment(14) 
X 
X 
X 
X 
X 
 
Survival Follow-up(15) 
 
 
 
 
 
X 
Research Laboratory Studies 
(Cycle 1 day 1, Cycle 3 day 1 and EOT)(3) 
 
 
 
 
 
 
Immune cell monitoring(16) 
 
X 
 
X 
 
 
Cell Free DNA(16) 
 
X 
 
X 
 
 
CTCs for culture (17) 
 
X 
 
X 
 
 
Patient Reported Outcomes 
 
 
 
 
 
 
FACT-P(18) 
 
X 
 
X 
 
 
Footnotes: 
1. Day 1 Cycle 1 Assessments: Hematology, blood chemistry, PSA, testosterone, and PSA need not be obtained on day 1 if a screening 
sample has been performed within 14 days. Baseline Signs/symptoms are only needed on Cycle 1 Day 1. Thyroid studies do not need to 
be repeated on Day 1 of Cycle 1 if obtained within the screening window.  
2. Cycle 1 Day 15+: Avelumab can be given up to 3 days before or after the expected start date of each infusion/treatment day after Cycle 
1 Day 1. Cycles are continued until progression or until significant adverse event. 
3. End of Treatment/Progression/Withdrawal: To occur at time of decision to end treatment.   These assessments do not need to be 
completed if they have been performed within 7 days of study withdrawal (within the last 6 weeks for tumor assessments). +/- 7 day 
window of allowance. Treatment beyond radiologic or PSA progression is permitted if there is potential for clinical benefit with continued 
therapy. Research blood samples will be collected at iRECIST-defined progression or at the EOT visit, whichever comes first.  
4. Medical/Oncological History: Includes oncologic history, demographics, history of other disease processes  and concomitant illnesses. 
Central review of pathology at Duke is required at baseline. 
5. Samples for hematology, blood chemistry, and thyroid studies: CBC w/ differential, CMP (including AST, ALT, Alkaline Phosphatase), 
LDH, phosphorus, TSH, free T4. Thyroid studies must  be performed at least every 8 weeks starting after cycle 1 and at end of 
treatment/safety follow-up (if not performed in the previous 8 weeks). PSA and testosterone should be performed at least every 4 weeks. 
6. Urinalysis: Tests will be done at screening, then as clinically indicated thereafter; tests to be performed at the local laboratory.  Urinalysis 
should also include a urine spot protein at baseline. A 24 hour urine analysis is required if urine protein is > 1+. 
7. Tumor Markers: CEA and chromogranin A will be measured at baseline and those that are elevated will be measured every 4 weeks 
thereafter. (Standard of care) 
8. Standard of Care Treatment (Androgen Deprivation Therapy (ADT), +/- enzalutamide): Patients already on ADT at study entry should 
continue with dosing and administration is to be determined by the treating provider but can include gonadotropin releasing hormone 

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agonists or antagonists. ADT will continue throughout all cycles. If patient has pure SCPC they do not need to be started on ADT but are 
allowed to continue per treating provider if already on ADT. Concurrent enzalutamide is permitted. 
9. Study Treatment (Avelumab):  Avelumab will be administered at 10 mg/kg IV every 2 weeks. One cycle is 2 infusions (4 weeks). 
10. Tumor imaging:  Bone scan, and either CT or MRI scans of the chest, abdomen, and pelvis will be performed to assess disease status at 
baseline as well as every 8 weeks or at treatment discontinuation (if  imaging did not occur within 6 weeks of visit ) as well as whenever 
disease progression is suspected, to confirm partial or complete response. NaF-PET/CT may be used in place of bone scan and CT in select 
cases.  In all cases, the same imaging modality should be used throughout the study on individual subjects.  Baseline tumor imaging must 
be performed within 35 days of cycle 1 day 1. MRI brain should be done in all subjects at baseline if indicated clinically and should be 
followed every 8 weeks with the other scans if metastasis(es) are found or if disease progression is suspected. Allowable window for 
tumor assessment imaging studies is +/- 7 days. Subjects removed from therapy for any reason other than disease progression will 
continue to be followed for radiographic progression until additional treatments are started, when available.  
11. Post-Progression Biopsy: An optional standard of care post-treatment progression biopsy will also be collected and additional tissue for 
research will be banked in the Biospecimen Repository & Processing Core (BRPC) under Pro00080869 for future research on resistance 
mechanisms including assessment of immune checkpoint status. 
12. Physical Examination: Examination of major body systems.  It does not need to be done cycle 1, day 1 if performed within the last 7 days. 
13. Adverse Events: Subjects must be followed for adverse events from the first day of study treatment until 28 days after the last dose of 
study treatment, or until all serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable”, 
whichever is earlier.  Serious adverse events should be monitored and reported from the time the patient starts study drug treatment  
as described in the protocol. 
14. Concomitant medications/treatments: Concomitant medications and treatments will be recorded from up to 35 days prior to the start 
of study treatment, during the study, and through the safety follow up visit. 
15. Survival Follow up: After the EOT/Withdrawal of treatment, subjects will be surveyed for their survival status by either a direct phone 
call or through the chart review. A clinic visit on study is not needed. The subjects will be surveyed every 3 months for up to 3 years, 
unless the subject has requested otherwise.  
16. Immune Cell Monitoring and Cell Free DNA: Research blood samples will be collected at 3 time points during the course of therapy. At 
initiation (Cycle 1 Day 1), on Cycle 3 Day 1, and at progression. A total of four blood tubes will be collected at each interval. Three tubes 
will be processed for the immune cells. Plasma samples (single EDTA tube) will also be collected and processed at each time point.  (see 
laboratory manual for details on shipping and handling) 
17. CTCs for culture: Research blood will be collected on cycle 1 day 1 and at progression for circulating tumor cell enrichment and cell 
culture. 
18. PROs: Patient reported outcomes will be assessed using the Functional Assessment of Cancer Therapy – Prostate (FACT-P).  Subjects will 
first complete the questionnaire in clinic prior to administration of study medication. Subjects will then be asked to complete a follow up 
FACT-P on day 1 of cycles 1, 4, 7 and every 3 subsequent cycles, and at End of Treatment/Withdrawal 
 

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8.1 
Screening Examination 
The screening examination will take place within 35 days of initiation of therapy.  An informed 
consent form must be signed by the subject before any screening procedure takes place.  
 
Subject data to be collected at the Screening Examination includes:   
 
• 
Informed consent process utilizing a signed and dated IRB-approved ICF  
• 
Confirmation of inclusion/exclusion criteria 
• 
Medical history including demographics, concomitant illnesses and oncologic history.  Oncologic 
history must include specific documentation of prostate cancer histologic diagnosis. 
• 
Prior and concomitant medications and non-pharmacologic treatments taken within 4 weeks of 
screening will be recorded.  In addition, all prior treatments including surgery and radiotherapy 
for prostate cancer will be recorded, regardless of when administered. 
• 
Standard of Care tumor imaging within 35 days of Cycle 1, Day 1 must include:   
o CT of the chest, abdomen, and pelvis for tumor assessment And 
o Whole body bone scan (99-Technetium), standard-of-care 
o Note:  NaF-PET/CT may be used in place of bone scan and CT in select cases 
o MRI Brain should be performed if clinically indicated based on symptoms of CNS 
metastases 
• 
Sample collection for the following laboratory evaluations (all standard-of-care): 
o Complete blood count (CBC) with differential:   WBC count with differential, platelet 
count, hemoglobin, and hematocrit. 
o Serum chemistries:   Sodium, potassium, chloride, blood urea nitrogen (BUN) or urea, 
creatinine, glucose, carbon dioxide (CO2) or bicarbonate, calcium, total protein, 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, total 
bilirubin, and alkaline phosphatase, thyroid stimulating hormone (TSH), free thyroxine 
(fT4).   
o Urinalysis 
o Testosterone   
o PSA levels.   
o Tumor markers (CEA and chromogranin A) 
• 
Physical examination to be conducted and height (cm), weight (kg), and vital signs (including 
temperature [°C], blood pressure [mmHg], heart rate [beats per minute], and respiratory rate 
[breaths per minute]) to be measured and recorded 
• 
Karnofsky performance status 
• 
Pathology review 
8.2 
Subject Registration and Enrollment 
 
8.2.1 Informed Consent 
Authorized study personnel should fully explain the scope of the study to each subject before 
obtaining informed consent.  Consent should occur prior to any research procedures and before 
formal screening procedures.  Subjects should be advised of any known risks inherent in the planned 

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procedures, of any alternative treatment options, of their right to withdraw from the study at any 
time for any reason, and of their right to privacy.  
 
When obtaining informed consent, study personnel should: 
First: Confirm that the subject is a potential candidate for study participation. 
Next: Obtain dated and signed informed consent. 
Finally: Confirm that the subject is eligible as defined in Section 7.0 (Inclusion/Exclusion Criteria).  A 
record of subjects who fail to meet entry criteria (i.e., screening failures) will be maintained. 
 
Subjects will be entered into the Duke clinical trial subject registry per institutional policy.  
8.2.2 Registration 
Subject registration at each study site/institution will be conducted according to the institution’s 
established policies and all sites will be overseen by the Duke University Medical Center 
Genitourinary Oncology Group. Prior to registration, subjects will be asked to sign and date an 
Institutional Review Board (IRB)-approved consent form.  After obtaining informed consent, the 
consent document and any registration documents will be submitted for review and registration of 
the subject by the lead site (Duke). All consented subjects will be registered and assigned a unique 
study ID. A record of subjects who fail to meet entry criteria (i.e., screen failures) will be maintained.   
 
Refer to Subject Registration Instructions in the Coordinator Manual for details. 
8.2.3 Enrollment 
 
Subjects will be enrolled only after all pre-treatment screening evaluations are completed and all 
eligibility criteria are met. Once the subject has been registered and found to meet all eligibility 
criteria, the subject will be approved for enrollment. Study treatment must not commence until the 
subject has received his/her identification number and enrollment approval from the lead site. 
8.3 
Run-In Period 
 
Not applicable 
8.4 
Treatment Period 
 
Treatment will be administered on an outpatient basis.  Avelumab will be given every 2 weeks 
according to the calendar of events.  On study procedures are detailed in the schedule of events 
including blood tests, imaging, medical history and concomitant medications, toxicity assessments, 
FACT-P assessments, and correlative biomarkers.  
8.5 
End of Treatment 
 
In the event of disease progression, unacceptable toxicity, or withdrawal of consent, study treatment 
is to be stopped and an end-of-treatment visit is to be conducted within 7 days.   
The following procedures are to be conducted at the end-of-treatment visit: 
• 
Concomitant medications and non-pharmacologic treatments to be reviewed and recorded. 
• 
Sample collection for the following laboratory evaluations (all standard-of-care): 

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o CBC:  WBC with differential, platelet count, hemoglobin, and hematocrit. 
o Chemistries:  sodium, potassium, chloride, blood urea nitrogen (BUN) or urea, creatinine, 
glucose, carbon dioxide (CO2) or bicarbonate, calcium, total protein, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), albumin, total bilirubin, and 
alkaline phosphatase, thyroid stimulating hormone (TSH), free thyroxine (fT4).   
o Testosterone 
o PSA  
o Tumor markers (CEA and chromogranin A) 
o Progression biopsy of metastatic site (optional) and research blood samples (see laboratory 
manual). 
• 
Research blood sample collection will occur at this visit or iRECIST defined progression, 
whichever comes first 
• 
Tumor imaging as per standard of care practices to document progression 
• 
Physical examination to be conducted, including weight (kg) and vital signs (including 
temperature [°C], blood pressure [mmHg], heart rate [beats per minute], and respiratory rate 
[breaths per minute]). 
• 
Karnofsky performance status. 
• 
Functional Assessment of Cancer Therapy – Prostate (FACT-P) will be administered 
8.6 
Follow up period 
8.6.1 Safety Follow-up visit 
The safety follow-up visit is to occur 28 days (+/- 7 days) after the last dose of study agent.  
Subjects that discontinue treatment due to reasons other than progressive disease will be 
followed until progression through Standard of Care scans. 
8.6.2 Extended safety follow-up 
Given the potential risk for delayed immune-related toxicities, extended safety follow-up must be 
performed up to 90 days after the last dose of avelumab administration for all serious or study drug-
related toxicities were not resolved or not determined to be “chronic” or “stable” within 28 days 
after the last dose of avelumab. The extended safety follow-up beyond 28 days after last study drug 
administration may be performed either via a site visit or via a telephone call with subsequent site 
visit requested in case any concerns noted during the telephone call. 
8.6.3 Survival Follow-up Period 
 
Subjects will be followed for disease progression and death for a maximum period of 3 years from 
the date that the Subjects were enrolled to the protocol. Imaging studies and clinical visits will be 
performed as per standard-of-care.  
 
 
8.7 
End of Study 
 
After progression or withdrawal from treatment, each subject will be followed every 3 months 
following their end-of-treatment visit for a total of 3 years from study enrollment for survival follow 

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up.  The overall end of study will occur when the last enrolled subject has completed his 3 year 
follow-up visit or death.   
 
8.8 
Early Withdrawal of Subjects(s) 
 
8.8.1 Criteria for Early Withdrawal 
 
Subjects may voluntarily withdraw from the study at any time.  The PI may also withdraw a subject 
from the study at any time based on his/her discretion.   
 
       Reasons for PI-initiated withdrawal may include the following: 
• 
Symptomatic disease progression or objective radiologic progression that is not consistent 
with iRECIST 
• 
Unacceptable toxicity, intercurrent illness, or changes in the patient’s condition (at the 
discretion of the treating physician) — Reason(s) for removal must be clearly documented 
in the physician progress note 
• 
The patient may withdraw from study treatment at any time for any reason and still be 
followed per protocol. 
• 
Provider decision that the subject is no longer clinically benefiting from avelumab 
8.8.2 Follow-up Requirements for Early Withdrawal 
 
Upon early withdrawal from study treatment, an end of treatment visit should be conducted within 
7 days as described above.  At withdrawal, all on-going study-related toxicities and SAEs should be 
followed until resolution, unless in the investigator’s opinion, the condition is unlikely to resolve due 
to the subject’s underlying disease.  Subjects should be followed up for new AEs for 90 calendar days 
after the last dose of avelumab.  All new AEs possibly related to study treatment occurring during 
that period should be collected. 
 
8.8.3 Replacement of Early Withdrawal(s) 
 
Patients who consent but do not receive a dose of study drug will be replaced and will not be 
considered evaluable.    Subjects who prematurely withdraw but received a dose of study drug will 
not be replaced. 
 
8.9 
Study Assessments  and Definitions 
8.9.1 Medical History 
 
At the initial visit, the detailed medical history will include concomitant illnesses and oncologic 
history. All prior treatments including surgery, chemotherapy, hormonal therapy, and radiotherapy 
for prostate cancer will be recorded, regardless of when administered.  This medical history will be 

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updated at subsequent visits.  Concomitant medications and non-pharmacologic treatments taken 
will be recorded at each visit. 
8.9.2 Physical Exam 
 
 
Physical examination should include:  height (cm – screening visit only), weight (kg), physical exam 
findings, and vital signs.  Vital signs include temperature [°C], blood pressure [mmHg], heart rate 
[beats per minute], and respiratory rate [breaths per minute].   Karnofsky performance status will 
be assessed and recorded at each visit.  All additional elements of the physical exam will be 
documented per the provider’s discretion. 
8.9.3 Correlative Exploratory Biomarker Studies 
 
1. To describe the impact of PD-L1 inhibition with avelumab on blood-based biomarker changes 
over time, including PSA, chromogranin-A, cell free DNA, LDH, and alkaline phosphatase.  For 
Objective 1, Subjects will have standard of care serum CEA and chromogranin A, LDH, PSA, and 
alkaline phosphatase drawn per the protocol. Samples will be drawn on Day 1 of every cycle. Cell 
free tumor DNA from plasma (research) will be collected and analyzed at baseline, cycle 3 day 1, and 
at progression.  Changes in these biomarkers over time will be described using descriptive statistics 
only without formal testing.  Please see the lab manual for associated details. Given that these are 
standard of care measures for NEPC patients and may be clinically useful in monitoring response to 
treatment, these are not considered research tests.  
 
2. To determine if levels of circulating biomarkers secreted by neuroendocrine-like prostate 
cancers correlate with clinical and radiographic treatment response.  For this objective, baseline 
and longitudinal levels of the biomarkers described in objective 1 will be associated with 
radiographic and clinical response to avelumab as well as duration of response, PFS, and survival.  
These are considered exploratory analyses.   
 
3.  To determine if the presence of different immunohistochemical markers on the pre-treatment 
biopsy specimens prognosticates clinical and radiographic treatment response.  For Objective 3, all 
Subjects will have already submitted a sample of tumor tissue for central review at Duke University 
Department of Pathology. Acceptable tissues include local prostate biopsies, surgical specimens, or 
metastatic biopsies.  Outside slides or recuts of outside tissue is required for histologic review prior 
to enrollment as part of the screening process.  Additional formalin fixed tissue (block, biopsy, or 
slides) may be kept for biomarker studies specific to this trial.  These samples will then be assessed 
for immune checkpoint biomarker expression (PD-1, PD-L1, CD8, and CTLA4 among others) as well 
as other expression of other tumor specific proteins (PD-L1, PD-L2, AR, PSA, FOXA2, p53, Rb, Cyclin 
D1, Chromogranin A, synaptophysin, p38 activity, SNAIL, among others).   Associations of pre-
treatment biopsies with primary and secondary outcomes will be described in an exploratory 
fashion. 
 
For subjects that opt-in for the post-progression biopsy, additional tissue will also be collected and 
banked in the Biospecimen Repository & Processing Core (BRPC) under Pro00080869 for future 
research to identify resistance mechanisms and immune checkpoint status. 
 

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4. To determine if the level of different circulating immune cells correlate with both progressive 
addition of immunotherapy as well as clinical and radiographic treatment response or disease 
progression.  For Objective 4, peripheral blood for immune subset phenotyping will be collected 
from subjects at baseline (Cycle 1 Day 1), at Cycle 3 Day 1, and at disease progression. These will 
then be processed by the Duke Substrate Services Core & Research Support (SSCRS) laboratory and 
analyzed in the Duke Immune Profiling Core Laboratory (DIPC) (Kent Weinhold) at Duke University. 
Changes in immune cell phenotypes over time will be described during avelumab therapy, as will 
associations with clinical/radiographic responses and duration of response, PFS.  Please see the lab 
manual for specific details about tube types, processing, collection and storage.  
 
5. To determine if levels of cell free DNA correlate with clinical and radiographic treatment 
response. For objective 5, peripheral blood and plasma will be drawn to collect cell free DNA for 
analysis.  We will measure and characterize cell free DNA at baseline (Cycle 1 Day 1), at Cycle 3 Day 
1, and at disease progression. Cell free DNA will be analyzed using whole exome sequencing.  Please 
see the lab manual for further details of plasma processing and collection/storage.  
 
6.    To isolate prostate neuroendocrine-like CTCs for ex vivo culture and characterization studies.  
 One 7.5 mL EDTA tube of research blood will be collected on cycle 1 day 1 and at progression for 
circulating tumor cell enrichment, cell culture and serial passaging ex vivo as cell lines for 
characterization and long-term studies of prostate cancer biology. Please see the lab manual for 
further details of collection and processing samples for CTCs. 
8.9.4 Imaging Assessments  
 
All baseline evaluations will be performed as closely as possible to the beginning of treatment (<35 
days). For subsequent evaluations, the method of assessment and techniques will be the same as 
those used at baseline. 
 
To assess the antitumor effect of a treatment, imaging-based evaluation is preferable to evaluation 
by clinical examination. CT and MRI should be performed using contiguous slices of 10 mm or less. 
Spiral CT should be performed using a 5-mm contiguous reconstruction algorithm (interval). If a 5-
mm contiguous reconstruction algorithm (interval) is not used, as a general rule, the lesion diameter 
should be no less than double the reconstruction algorithm (interval) and must be at least 20 mm 
for nonspiral CT or at least 10 mm for spiral CT. (If available, spiral CT is preferred in all instances.) 
This applies to tumors of the chest, abdomen, and pelvis. Head and neck tumors and those of the 
extremities typically require specific protocols. Sodium Fluoride PET-CT +/- IV contrast may be used 
as an alternative to CT/bone scan if available.  Brain MRI should be ordered as per standard of care 
practice in symptomatic or small cell carcinoma patients.  
8.9.5 PSA 
 
PSA testing should be performed at each cycle (every 4 weeks). To report PSA-based outcomes, 
PCWG3 recommends that the percent of change in PSA from baseline to 8 and 12 weeks depending 
on trial design (or earlier for those who discontinue therapy) and the maximum decline in PSA that 
occurs at any point after treatment be reported for each patient using a waterfall plot.  

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8.9.6 Non-PSA Tumor markers (Standard of care) 
 
Chromogranin-A levels will be measured at baseline and on day 1 of each cycle if elevated.  CEA 
should be assessed at baseline and if elevated, followed on day 1 of each cycle. 
8.9.7 Measurable disease 
 
According to iRECIST32, measurable disease is defined as at least 1 lesion ≥ 10 mm in its longest 
diameter as measured with computerized tomography (CT) with slice thickness no greater than 5 
mm;  ≥ 10 mm as measured with calipers on clinical exam; or >15 mm for nodal metastases using 
the shortest diameter. All tumor measurements will be taken using a ruler or calipers and recorded 
in millimeters (or decimal fractions of centimeters). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Only tumor lesions that have not been previously irradiated will be considered measurable.   
8.9.8 Nonmeasurable disease 
 
Following iRECIST, all other lesions (or sites of disease) will be considered nonmeasurable disease. 
This includes small lesions (longest diameter < 20 mm with conventional techniques or < 10 mm 
using spiral CT scan) and any of the following: 
• 
bone lesions 
• 
ascites 
• 
pleural or pericardial effusion 
• 
lymphangitis cutis or pulmonis 
• 
abdominal masses that are not confirmed and followed by imaging techniques 
• 
cystic lesions 
• 
lesions occurring within a previously irradiated area unless they are documented as new 
lesions since the completion of radiation therapy 
8.9.9 Target (nodal and visceral) lesions 
 
Following iRECIST, progression in a nodal or visceral site (i.e., liver and lung) is sufficient to 
document disease progression. The presence or absence of nodal and visceral disease before and 
after treatment should be recorded separately. 
 
All measurable lesions (up to a maximum of 5 lesions per organ and 10 lesions in total) will be 
identified as target lesions to be measured and recorded at baseline. The target lesions should be 
representative of all involved organs. Target lesions will be selected on the basis of size (i.e., the 
largest area) and suitability for accurate, repeated measurements (either by imaging techniques or 
clinically). The sum of the longest diameter (LD) of all target lesions will be calculated and reported 
as the baseline sum LD. The baseline sum LD will be used as a reference by which to characterize the 
objective tumor response. 
 

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Because small lymph nodes are difficult to measure accurately and may not be malignant, a lymph 
node must measure at least 1.5 cm by short axis by spiral CT to be considered a target lesion.30  
8.9.10 Bone lesions 
 
When the bone scan is the sole indicator of progression at baseline, disease progression in bone is 
defined as 2 or more new lesions seen on bone scan compared with a prior scan used for trial 
entry.30 In situations where scan findings suggest a flare reaction or where new lesion(s) may 
represent trauma, confirm these results with other imaging modalities (e.g., MRI or fine-cut CT). If 
many new areas of uptake are observed, confirmation is generally not necessary. 
8.9.11 Nontarget lesions 
 
All other lesions (or sites of disease) will be identified as nontarget lesions and recorded at baseline. 
Nontarget lesions will include measurable lesions that exceed the maximum number per organ (5) 
or total of all involved organs (10), as well as nonmeasurable lesions. The presence or absence of 
these lesions will be recorded on the CRF and should be evaluated at the same assessment time 
points as all target lesions. 
8.9.12 New lesions 
 
The appearance of up to 10 new measurable lesions should be recorded. Each new lesion should be 
reassessed using the same imaging modality at each time point. If measurable, the LD of each new 
lesion (including lymph nodes) should be recorded in the CRF and the sum LD of new and old lesions 
should be calculated. See Table 1 for a description of the determination of progression based on the 
presence of new lesions. 
Note: The appearance of a new lesion does not by itself satisfy the criteria for confirmed progressive 
disease. Rather, the tumor burden imposed by the new lesions must be evaluated within the 
context of the total tumor burden (i.e., preexisting plus new lesions). Confirming progression in 
target lesions, nontarget (i.e., other than bone) lesions, and bone lesions requires 2 assessment time 
points. The first must occur at Week 8 (or later) and the second occurring at least 6 weeks after the 
first. Progression declared at the first time point remains unconfirmed unless assessments at the 
second time point demonstrate continuing or worsening progression as described in section 8.10.
8.10 
Response Criteria  
 
Response and progression will be evaluated in this study using a modified PCWG3 where RECIST 1.1 
is replaced with iRECIST31 criteria and the guidelines for prostate cancer endpoints developed by the 
Prostate Cancer Clinical Trials Working Group (PCWG3).30 In brief, iRECIST defines an immune 
unconfirmed progressive disease (UPD) on the basis of RECIST 1.1 principles and now requires 
confirmation of progression. Confirmation is done by observing either a further increase in size or 
number of new lesions identified (target, non-target) or progression by RECIST 1.1. However if 
progression is not confirmed but instead shrinkage occurs, compared to baseline, which meets 
RECIST 1.1 criteria of complete response, partial response, or stable disease; then the bar is reset so 
that UPD needs to occur again, compared with nadir values, and then be confirmed again. 
 

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Trial objectives are defined based on controlling, relieving, or eliminating disease manifestations 
that are present when treatment is initiated, or preventing or delaying the development of disease 
manifestations that are expected to occur (or in some cases both). Traditional measures of response 
reflect when a treatment is working and measures of progression indicate when a drug should be 
stopped. Because assessing response in bone (the most common site of prostate cancer spread) is 
uncertain and the clinical significance of PSA changes in response to therapy is not a reliable 
predictor of response, measures of response have been expanded in consortium trials to include 
measures of progression. 
 
Subjects will need to be reevaluated for response every 2 cycles (or more frequently if indicated), 
according to the guidelines below.
8.10.1 Measurable soft-tissue lesions 
 
When evaluating soft-tissue lesions, the definitions in Table 1 apply. 
Table 1. RECIST 1.1 response criteria for target (soft-tissue) lesions 
Response 
Evaluation of Soft-Tissue Lesions 
Complete response (CR) 
the disappearance of clinical and radiological evidence of all target 
lesions and normalization of tumor marker levels 
Partial response (PR) 
a decrease from baseline ≥ 30% in the sum of the LD of all target 
lesions 
Progressive disease (PD)  an increase ≥ 20% in the sum of the LD of all target lesions based 
on the smallest sum LD since treatment started or the appearance 
of one or more new lesions or the appearance of new lesions 
Stable disease (SD) 
neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD based on the smallest sum LD recorded since 
treatment started  
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. When 
the evaluation of complete response depends on this determination, it is recommended that the 
residual lesion be investigated (e.g., fine needle aspirate or biopsy) before confirming the complete 
response status. 
8.10.2 PSA 
 
As long as patient safety is the primary concern, in the absence of other indicators of disease 
progression, therapy should not be discontinued solely on the basis of a rise in PSA. 
PSA progression is defined as the date that a 25% or greater increase and an absolute increase of 
2.0 ng/mL or more from the nadir is documented and confirmed by a second value obtained 3 or 
more weeks later. Where no decline from baseline is documented, PSA progression is defined as a 
25% increase from the baseline value along with an increase in absolute value of 2.0 ng/mL or more 
after 8 weeks. 
8.10.3 Bone 
 

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Record post-treatment changes as either “no new lesions” or “new lesions.” 
 
In the absence of clearly worsening soft-tissue (nodal and visceral) disease or disease-related 
symptoms, progression at the first scheduled assessment should be confirmed on a second scan 
performed 6 or more weeks later. In the rare case where visible lesions disappear, this too should be 
confirmed. 
 
Progressing disease on bone scan is considered when at least 2 new lesions are observed. Yet, 
progression remains unconfirmed unless at least 2 additional new lesions appear at a subsequent 
time point. 
 
Unless clinically indicated, there is no need to perform a follow-up bone scan before 12 weeks of 
treatment. To define disease progression requires a confirmatory scan (which shows additional new 
lesions compared with the first follow-up scan) performed 6 or more weeks later. When further 
progression is documented on the confirmatory scan, the date of progression recorded for the trial 
is the date of the first scan that shows the change. 
8.10.4 Nontarget lesions 
 
When assessing nontarget lesions, the definitions in Table 2 will apply. The overall assessment of 
preexisting plus new lesions at the first time point must show unequivocal progression. Progression 
at the first time point remains unconfirmed unless progression is confirmed to the same or greater 
extent at a subsequent time point. 
Table 2. RECIST response criteria for nontarget lesions 
Response 
Evaluation of Nontarget Lesions 
Complete response (CR) 
the disappearance of all nontarget lesions and normalization of 
tumor marker levels 
Incomplete response/ 
stable disease (SD) 
the persistence of one or more nontarget lesions and/or 
maintenance of tumor marker levels above the normal limits 
Progressive disease 
(PD) 
the appearance of one or more new lesions and/or unequivocal 
progression of existing nontarget lesions 
 
8.10.5 Patient-reported outcomes 
 
FACT-P scores will be collected and described over time for this study to assess quality of life 
changes.  No formal statistics will be applied to this exploratory endpoint. 
 
Transient increases in pain may occur before improvement, and those occurring in the first 12 weeks 
should not affect the course of treatment in the absence of other compelling evidence of disease 
progression. Changes in symptoms should be confirmed as for other outcome measures. Monitor 
other domains that may help determine whether the disease is progressing, including worsening in 
global quality of life, developing urinary or bowel compromise, or needing to change anticancer 
therapy. 

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8.10.6 Evaluating best overall response 
 
The best overall response is the best response recorded from the start of treatment until either 
disease progression or recurrence. The investigator’s determination of best overall response will be 
based both on response criteria and on confirmation criteria. To be assigned a status of confirmed 
partial response or complete response, changes in tumor measurements must be confirmed by 
repeat assessment performed at least 4 weeks after the criteria for response are first met. To 
confirm stable disease, follow-up measurements must meet SD criteria at a minimum interval of 4 
weeks after SD was first documented. Table 3 can be used as an assessment tool. 
Note: If unconfirmed progression noted at the first time point is not confirmed at a second time 
point, the next assessment time point after the first that meets the criteria for progression will be 
treated as time point 1. 
 
Table 3. Assessing Overall Response 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease. 
 
Subjects with global deterioration of health status who require treatment to be discontinued 
without objective evidence of disease progression should be classified as having symptomatic 
deterioration. Every effort should be made to document their objective progression, even after 
discontinuing treatment. 
 
Subjects who do not have tumor response assessment due to rapid progression or toxicity will be 
considered nonresponders, will be included in the denominator for the response rate, and will be 
classified into one of the categories listed below: 
• 
death attributed to disease progression 
• 
early discontinuation attributed to disease progression 
• 
death attributed to drug toxicity 
• 
early discontinuation attributed to drug toxicity 
Note: If a subject receives subsequent therapy before tumor progression is documented, the reason 
for changing therapy must be reported. Reasons include clinical progression, drug toxicity, or 
secondary therapy for maintaining tumor response. 
 
For immunotherapies, atypical patterns of response, including delayed responses, new lesions with 
mixed patterns of response, pseudoprogression due to immune infiltration (transient), and 
prolonged stable or partially responsive disease.  In this study, we will describe the immune-

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modified responses using the following table 440  PCWG3-modified RECIST 1.1 and immune-modified 
response and progression will be reported separately in this study. 
 
Table 4. Immune modified RECIST criteria.

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8.11 
Confirmatory Measures/Duration of Response 
8.11.1 Confirming time-to-event outcomes 
 
Any post-treatment change in disease status (imaging, biomarker studies), be it favorable or 
unfavorable, should be confirmed using a second assessment at a later time point 4 or more weeks 
later.  Unconfirmed results will be reported as such. 
8.11.2 Duration of overall response 
 
Duration of overall response is measured from the time when partial response or complete 
response is first noted until the date when recurrent or progressive disease is objectively 
documented. Duration of overall complete response is measured from the time the criteria for 
complete response are first met until the first date that recurrent disease is objectively 
documented. Duration of stable disease is measured from the start of treatment until the criteria for 
progression are met. 
8.11.3 Progression-free survival 
 
Progression-free survival (PFS) is a composite endpoint defined as the time from study entry or 
random assignment to radiographic disease progression in bone or soft-tissue, symptoms (clinical 
deterioration), or death. PSA changes will not be used to define PFS in this study.  A PFS estimate 
using both conventional PCWG3-modified RECIST 1.1 criteria and immune-modified RECIST criteria 
(Table 4) will be reported. Use an interval-censored approach in which all assessments of the 
composite PFS endpoint (i.e.bone, CT scans, and symptom assessments) are performed at the 
same time points. All assessments of disease should be collected at the same time interval every  8 
weeks. 
8.11.4 Response review 
 
All subjects who meet eligibility criteria and receive at least 1 dose of study medication/undergo 1 
scan or procedure will be included in the main analysis of the response rate, even if there are major 
protocol deviations (e.g., incorrect treatment schedule or drug administration). Each subject will be 
assigned to one of the following categories: 
 
Table 5. Categories for Response to Treatment 
Category 
Response 
1 
Complete response 
2 
Partial response 
3 
Stable disease 
4 
Progressive disease 
5 
Early death from malignant disease 
6 
Early death from toxicity 
7 
Early death from other causes 

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9 
Unknown (not assessable/insufficient data) 
NOTE: By arbitrary convention, category 9 designates unknown status in a clinical database. Subjects in 
response categories 4 to 9 will be considered to have treatment failure (disease progression). 
 
Conclusions are to be based on the population of all eligible subjects. Subanalyses may be 
performed on various subsets of subjects, such as those with no major protocol deviations or those 
who continued in the study for the entire treatment period (i.e., did not withdraw prematurely). 
Subanalyses will not serve as the basis for drawing conclusions concerning treatment efficacy. 
9 SAFETY MONITORING AND REPORTING 
The PI is responsible for the identification and documentation of adverse events and serious adverse 
events, as defined below.  At each study visit, the PI or designee must assess, through non-suggestive 
inquiries of the subject or evaluation of study assessments, whether an AE or SAE has occurred. 
9.1 
Adverse Events 
 
An adverse event (AE) is defined as any untoward medical occurrence in a subject administered a 
study drug and which does not necessarily have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a study drug, whether or not related to 
the study drug. 
 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG data, 
physical exam) should be defined as an AE only if the abnormality meets one of the following criteria: 
• 
Induces clinical signs or symptoms. 
• 
Requires active intervention. 
• 
Requires interruption or discontinuation of study medication. 
• 
The abnormality or investigational value is clinically significant in the opinion of the investigator. 
 
All adverse events, whether or not related to the study drug, must be fully and completely 
documented. 
 
From the first dose of avelumab until 28 days after the last dose of avelumab, or until all serious or 
study drug-related toxicities have resolved or are determined to be “chronic” or “stable”, whichever 
is earlier, all AEs must be recorded in the subject medical record and adverse events case report 
form. 
 
AEs will be assessed according to the CTCAE version 4.0 or the most current version.  If CTCAE grading 
does not exist for an AE, the severity of the AE will be graded as mild (1), moderate (2), severe (3), 
life-threatening (4), or fatal (5). 
 
Attribution of AEs will be indicated as follows: 
- 
Definite:  The AE is clearly related to the study drug 
- 
Probably:  The AE is likely related to the study drug 
- 
Possible:  The AE may be related to the study drug 
- 
Unlikely:  The AE is doubtfully related to the study drug 
- 
Unrelated:  The AE is clearly NOT related to the study drug 

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9.2 
Serious Adverse Events 
 
An AE is considered “serious” if, in the view of either the investigator or sponsor, it results in any of 
the following outcomes:  
• 
Results in death, 
• 
Is life threatening (an AE is considered “life-threatening” if, in the view of either the investigator 
or sponsor, its occurrence places the subject at immediate risk of death. It does not include an 
AE that, had it occurred in a more severe form, might have caused death.) 
• 
Results in persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions,  
• 
Results in congenital anomaly, or birth defect, 
• 
Requires inpatient hospitalization or leads to prolongation of hospitalization (hospitalization for 
treatment/observation/examination caused by AE is to be considered as serious), 
• 
Other medically important events. 
9.3 
Reporting of SAEs 
 
Serious adverse events, whether or not considered drug related, should be reported to the lead 
site/sponsor (Duke) within 24 hours of becoming aware of the event, using the provided DCI SAE 
Report Form and the SAE Review Form (Site Assessment). These documents should be sent to: 
 
The DCI Safety Desk – fax: (919)681-9357; phone: (919)681-9538; email: dcccsafe@dm.duke.edu  
 
If the safety desk cannot be reached within 24 hours, the Principal Investigator should be contacted: 
Dr. 
Andrew 
Armstrong 
(phone: 
(919) 
668-4615; 
pager: 
(919) 
684-8111; 
email: 
andrew.armstrong@dm.duke.edu).  
 
The initial report for each SAE or death should include at minimum the following information: 
• 
Protocol # and title 
• 
Patient initials, study identification number, sex, age 
• 
Date the event occurred (onset) 
• 
Description of the SAE 
• 
Dose level and cycle number at the time the SAE occurred 
• 
Description of the patient’s condition 
• 
Indication whether the patient remains on study 
• 
Causality 
 
Follow-up information including severity, action taken, concomitant medications, and outcome 
should be communicated to Duke as soon as possible. 
 
Upon receipt of the Serious Adverse Event Reporting form by the DCI Safety Desk, the PI will be 
notified and be required to complete the PI assessment of the DCI Safety SAE Report Review Form.  
The DCI safety desk will, in turn, submit the SAE to the DUHS IRB if deemed reportable by the PI 
assessment. The DCI safety desk will also report the event to Pfizer as described below. 
 

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The following reportable events must be submitted to Pfizer within 24 hours (or immediately for 
death or life-threatening events) using the DCI SAE Report Form with the Pfizer Reportable Events 
Fax Cover Sheet with each SAE submission. 
 
• 
Serious Adverse Events 
• 
Exposure during Pregnancy or Breastfeeding (even if not associated with an adverse event) 
• 
Occupational exposure (even if not associated with an adverse event) 
• 
Potential drug-induced liver injury (Hy’s Law cases):  These events are considered important 
medical events and should be reported as SAEs. 
 
The DCI SAE Report Form with the Pfizer Reportable Events Fax Cover Sheet should be emailed or 
faxed to: 
 
Pfizer U.S. Clincal Trial Department 
Email: USA.AEReporting@pfizer.com 
Fax number: (866) 997-8322 
 The following minimum information is required: 
• 
Protocol  
• 
Site / PI 
• 
Subject number, sex and age 
• 
The date of report 
• 
A description of the SAE (event, seriousness of the event) 
 
Follow-up information for the event should be sent within promptly (within 7 days) as necessary.  
 
In addition, if Principal Investigator becomes aware of an SAE occurring any time after the 
administration of the last dose of the Pfizer Product, Principal Investigator should report that SAE to 
Pfizer if the Principal Investigator suspects a causal relationship between the Pfizer Product and the 
SAE.   
 
Reporting to the FDA 
The Sponsor-Investigator (Duke) is responsible for reporting the serious adverse event to the FDA in 
accordance with 21CFR 312.32.  Any SAE that is possibly related and unexpected must be submitted 
to the FDA attached to the IND.   
 
9.4 
Emergency Unblinding of Investigational Treatment 
 
Not applicable 
9.5 
Procedure in case of pregnancy 
 
Not applicable, only men will be enrolled in this study. 
9.6 
Safety Oversight Committee (SOC) 
 

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The Duke Cancer Institute SOC is responsible for annual data and safety monitoring of DUHS sponsor-
investigator phase I and II, therapeutic interventional studies that do not have an independent Data 
Safety Monitoring Board (DSMB).  The primary focus of the SOC is review of safety data, toxicities and 
new information that may affect subject safety or efficacy.  Annual safety reviews includes but may 
not be limited to review of safety data, enrollment status, stopping rules if applicable, accrual, 
toxicities, reference literature, and interim analyses as provided by the sponsor-investigator.  The SOC 
in concert with the DCI Monitoring Team oversees the conduct of DUHS cancer-related, sponsor-
investigator therapeutic intervention and prevention intervention studies that do not have an 
external monitoring plan, ensuring subject safety and that the protocol is conducted, recorded and 
reported in accordance with the protocol, standing operating procedures (SOPs), Good Clinical 
Practice (GCP), and applicable regulatory requirements. 
10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 
Monitoring 
 
This clinical research study will be monitored both internally by the PI and institutionally by the Duke 
Cancer Institute (DCI).  In terms of internal review the PI will continuously monitor and tabulate 
adverse events.  Appropriate reporting to the Duke University Medical Center IRB will be made.  If an 
unexpected frequency of Grade III or IV events occur, depending on their nature, action appropriate 
to the nature and frequency of these adverse events will be taken.  This may require a protocol 
amendment, dose de-escalation, or potentially closure of the study.  The PI of this study will also 
continuously monitor the conduct, data, and safety of this study to ensure that: 
• 
Interim analyses occur as scheduled; 
• 
Stopping rules for toxicity and/or response are met; 
• 
Risk/benefit ratio is not altered to the detriment of the subjects; 
• 
Appropriate internal monitoring of AEs and outcomes is done; 
• 
Over-accrual does not occur; 
• 
Under-accrual is addressed with appropriate amendments or actions; 
• 
Data are being appropriately collected in a reasonably timely manner. 
 
DCI review and monitoring of this protocol occurs in accordance with the NCI-approved Data and Safety 
Monitoring Plan.  Briefly, protocol review begins with an initial review by the Cancer Protocol Committee 
(CPC), which assesses the ethics and safety of the protocol.  Documentation of these assessments will 
be maintained.  Formal, independent monitoring will be conducted by the DCI Monitoring Team after 
the first 3 subjects are enrolled, followed by annual monitoring of 1-3 subjects until the study is closed 
to enrollment and subjects are no longer receiving study interventions that are more than minimal risk.  
DCI Monitoring Team reports and additional data/safety/toxicity reports submitted by the PI will be 
reviewed by the Safety Oversight Committee (SOC) on an annual basis.  Additional monitoring may be 
prompted by findings from monitoring visits, unexpected frequency of serious and/or unexpected 
toxicities, or other concerns.  Monitoring visits may also be initiated upon request by DUHS and DCI 
Leadership, CPC, SOC, the Duke Office of Audit, Risk and Compliance, a sponsor, an investigator, or the 
IRB.   All study documents must be made available upon request to the DCI Monitoring Team and other 
authorized regulatory authorities, including but not limited to the National Institute of Health, National 
Cancer Institute, and the FDA.  Every reasonable effort will be made to maintain confidentiality during 
study monitoring. 
 

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10.2 
Data Management and Processing 
10.2.1 Study Documentation 
 
Study documentation includes but is not limited to source documents, case report forms, monitoring 
logs, appointment schedules, study team correspondence with sponsors or regulatory 
bodies/committees, and regulatory documents that can be found in the DCI-mandated “Regulatory 
Binder”, which includes but is not limited to signed protocol and amendments, approved and signed 
informed consent forms, FDA Form 1572, CAP and CLIA laboratory certifications, and clinical supplies 
receipts and distribution records. 
 
Source documents are original records that contain source data, which is all information in original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents include but are not limited to hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at 
the laboratories and at medico-technical departments involved in the clinical trial.  When possible, 
the original record should be retained as the source document.  However, a photocopy is acceptable 
provided that it is a clear, legible, and an exact duplication of the original document. 
10.2.2 Case Report Forms (CRFs) 
 
The electronic CRF will be the primary data collection document for the study.  The CRFs will be 
updated in a timely manner following acquisition of new source data.  Only the key personnel 
delegated on the delegation of authority log are permitted to make entries, changes, or corrections 
in the CRF. 
 
An audit trail will be maintained automatically by the electronic CRF management system.  All users 
of this system will complete user training, as required or appropriate per regulations. 
 
10.2.3 Data Management Procedures and Data Verification 
 
Users of the electronic CRF will have access based on their specific roles in the protocol.   
 
Completeness of entered data will be checked automatically by the eCRF system, and users will be 
alerted to the presence of data inconsistencies.  Additionally, the data manager and project manager 
will cross-reference the data to verify accuracy.  Missing or implausible data will be highlighted for 
the PI requiring appropriate responses (i.e. confirmation of data, correction of data, completion or 
confirmation that data is not available, etc.). 
 
The database will be reviewed and discussed prior to database closure, and will be closed only after 
resolution of all remaining queries.  An audit trail will be kept of all subsequent changes to the data. 
 

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10.2.4 Study Closure 
 
Following completion of the studies, the PI will be responsible for ensuring the following activities: 
- 
Data clarification and/or resolution 
- 
Accounting, reconciliation, and destruction/return of used and unused study drugs 
- 
Review of site study records for completeness 
- 
Shipment of all remaining laboratory samples to the designated laboratories 
11 STATISTICAL METHODS AND DATA ANALYSIS 
 
All statistical analysis will be performed under the direction of the statistician designated in key 
personnel.  Any data analysis carried out independently by the investigator must be approved by the 
statistician before publication or presentation. 
 
11.1 
Sample Size Estimation 
 
This study will use the optimal two-stage design of Simon to test a hypothesis about response rate in 
subjects with NEPC treated with avelumab. Response will be defined as a complete (CR) or partial 
response (PR).  Assuming that the response rate among subjects treated is 5%, the trial is designed to 
have 88% power with a one-sided type I error rate=5% to reject the null hypothesis of response rate 
of 5% when the true response rate was 20%. In the first stage, 18 subjects will be enrolled and if one 
or fewer responses are observed the trial will be terminated. However, if two or more responses are 
observed, an additional 26 subjects will be enrolled at the second stage for a total of 44 subjects. If 
five or more subjects respond, this new agent would be declared to have promising activity. This 
design has 88% power to conclude an agent is promising if its true objective response proportion is 
20%; Type 1 error rate (one-sided) is 0.05 (this is the probability to conclude that a given agent is 
promising if its true objective response proportion is 5%).The probability of early termination under 
the null hypothesis is 0.77.  These operating characteristics were selected to represent a reasonable 
compromise between high power, low false positive rates, and desire for small sample sizes, 
especially in the first stage. Allowing for 10% unevaluable rate, the target sample size is 49 subjects.   
 
11.2 
Analysis Sets 
 
This is a non-blinded single arm-arm phase II study of approximately 49 subjects, to assess the safety 
and efficacy of avelumab in patients with mCRPC 
11.3 
Patient Demographics and Other Baseline Characteristics 
 
Eligible men will have metastatic CRPC with NEPC phenotype with measureable disease at baseline.  
11.4 
Treatments 
 
Avelumab with ADT (unless pure SCPC present) will start on cycle 1 day 1 and continue every 2 weeks 
until progression or unacceptable toxicity.  

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11.5 
Primary Objective 
 
To estimate the overall response rate of men with NEPC treated with avelumab as determined by 
modified PCWG3 using iRECIST radiographic response.  
11.5.1 Variable 
 
Overall response rate (ORR) which is defined as either complete response (CR) or partial response 
(PR). 
11.5.2 Statistical Hypothesis, Model, Method of Analysis 
 
The null hypothesis is that the ORR is less than 5%. The trial is designed to have 88% power with a 
one-sided type I error rate=5% to reject the null hypothesis when the true response rate was 20%. 
The objective response rate will be estimated with a standard error no greater than 10.7 percentage 
points. 
11.5.3 Handling of Missing values, censoring, and discontinuations 
 
Ineligible subjects and subjects who cancel registration before receiving any therapy will not be 
included in the analyses. We will follow each patient long enough to avoid censoring due to end of 
study. The binomial test assumes that other censoring than due to end of study is rare. The study 
results are just important reference and more studies are necessary for medical decision making. 
11.6 
Secondary Objectives 
 
1. To describe the efficacy of PD-L1 inhibition with avelumab as measured by PCWG3 using 
RECIST1.1 
2. To describe the radiographic progression free survival (rPFS) of PD-L1 inhibition with avelumab 
using immune modified and PCWG3-modified RECIST 1.1 criteria in this setting. 
3. To describe the overall survival of PD-L1 inhibition in this setting. 
4. To described the toxicities and safety of PD-L1 inhibition with avelumab in men with metastatic 
neuroendocrine-like prostate cancer. 
11.6.1 Key Secondary Objectives – analysis plan 
 
The Kaplan-Meier method will be used to estimate both forms of progression-free survival as well as 
the overall survival distributions. Summary statistic will be computed for the duration of time on 
treatment distribution. The correlative science analyses will be considered exploratory and 
interpreted as such and reported using descriptive statistics and associations with clinical outcomes 
including response (radiographic) and progression free and overall survival.  
11.6.2 Other Secondary Objectives – Analysis Plan 
 
In addition, descriptive statistics will be calculated for secondary endpoints of safety profile and 
quality-of-life (QOL) endpoints, the continuous safety and QOL endpoints will be summarized as the 

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patient counts, mean, standard deviation, median, 25thand 75th percentiles, minimum and 
maximum.  The categorical safety and QOL endpoints will be categorized using frequencies and 
percentages. 
11.7 
Exploratory Objectives 
 
1. To describe the impact of PD-L1 inhibition with avelumab on blood-based biomarker changes 
over time, including PSA, chromogranin-A, cell free DNA, LDH, and alkaline phosphatase. 
2. To determine if levels of circulating biomarkers secreted by neuroendocrine-like prostate 
cancers correlate with clinical and radiographic treatment response 
3. To determine if the presence of different immunohistochemical markers on the pre-biopsy 
specimens prognosticates clinical and radiographic treatment response 
4. To determine if the level of different circulating immune cells correlate with both progressive 
addition of immunotherapy as well as clinical and radiographic treatment response or disease 
progression 
5. To determine if levels of cell free DNA correlate with clinical and radiographic treatment 
response 
6. To isolate prostate neuroendocrine-like CTCs for ex vivo growth and culture and characterization 
studies. 
 
11.8 
Interim Analysis 
 
Not applicable 
11.9 
Accrual and Follow-Up 
 
The target sample size is 18 subjects in stage 1, and 49 subjects overall if stage 1 is successful. Accrual 
is expected to be completed within 12-18 months after study activation for each stage. Stage 2 would 
require expansion to additional sites (2-3 additional sites) for accrual.  All subjects will be followed for 
disease progression and mortality from the date that the subjects were enrolled to the protocol. 
 
12 ADMINISTRATIVE AND ETHICAL CONSIDERATION 
12.1 
Regulatory and Ethical Compliance 
 
This protocol was designed and will be conducted and reported in accordance with the International 
Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice, the 
Declaration of Helsinki, and applicable federal, state, and local regulations. 
12.2 
DUHS Institutional Review Board and DCI Cancer Protocol Committee 
 
The protocol, informed consent form, advertising material, and additional protocol-related 
documents must be submitted to the DUHS Institutional Review Board (IRB) and DCI Cancer Protocol 
Committee (CPC) for review.  The study may be initiated only after the Principal Investigator has 
received written and dated approval from the CPC and IRB. 

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The Principal Investigator must submit and obtain approval from the IRB for all subsequent protocol 
amendments and changes to the informed consent form.  The CPC should be informed about any 
protocol amendments that potentially affect research design or data analysis (i.e. amendments 
affecting subject population, inclusion/exclusion criteria, agent administration, statistical analysis, 
etc.). 
 
The Principal Investigator must obtain protocol re-approval from the IRB within 1 year of the most 
recent IRB approval.  The Principal Investigator must also obtain protocol re-approval from the CPC 
within 1 year of the most recent IRB approval, for as long as the protocol remains open to subject 
enrollment. 
12.3 
Informed Consent 
 
The informed consent form must be written in a manner that is understandable to the subject 
population.  Prior to its use, the informed consent form must be approved by the IRB. 
 
The Principal Investigator or authorized key personnel will discuss with the potential subject the 
purpose of the research, methods, potential risks and benefits, subject concerns, and other study-
related matters.  This discussion will occur in a location that ensures subject privacy and in a manner 
that minimizes the possibility of coercion.  Appropriate accommodations will be made available for 
potential subjects who cannot read or understand English or are visually impaired.  Potential subjects 
will have the opportunity to contact the Principal investigator or authorized key personnel with 
questions, and will be given as much time as needed to make an informed decision about participation 
in the study. 
 
Before conducting any study-specific procedures, the Principal Investigator or designee must obtain 
written informed consent from the subject or a legally acceptable representative.  The original 
informed consent form will be stored with the subject’s study records, and a copy of the informed 
consent form will be provided to the subject. 
12.4 
Study Documentation 
 
Study documentation includes but is not limited to source documents, case report forms (CRFs), 
monitoring logs, appointment schedules, study team correspondence with sponsors or regulatory 
bodies/committees, and regulatory documents that can be found in the DCI-mandated “Regulatory 
Binder”, which includes but is not limited to signed protocol and amendments, approved and signed 
informed consent forms, FDA Form 1572, CAP and CLIA laboratory certifications, and clinical supplies 
receipts and distribution records. 
 
Source documents are original records that contain source data, which is all information in original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents include but are not limited to hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at 

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the laboratories and at medico-technical departments involved in the clinical trial.  When possible, 
the original record should be retained as the source document.  However, a photocopy is acceptable 
provided that it is a clear, legible, and an exact duplication of the original document. 
 
A case report form (CRF) (please indicate whether a paper or electronic CRF will be used) will be the 
primary data collection document for the study.  Only the key personnel delegated on the delegation 
of authority log are permitted to make entries, changes, or corrections in the CRF.  For electronic 
CRFs, an audit trail will be maintained by the electronic CRF management system. 
12.5 
Privacy, Confidentiality, and Data Storage 
 
The Principal Investigator will ensure that subject privacy and confidentiality of the subject’s data will 
be maintained.   
 
To protect privacy, every reasonable effort will be made to prevent undue access to subjects during 
the course of the study.  All research related interactions with the participant will be conducted by 
qualified research staff who are directly involved in the conduct of the research study. 
 
To protect confidentiality, subject files in paper format will be stored in secure cabinets under lock 
and key accessible only by the research staff. Electronic records of subject data will be maintained 
using a dedicated web-access secure database , which is housed in an encrypted and password-
protected server behind the Duke firewall. Access to electronic databases will be limited to delegated 
personnel.  The security and viability of the IT infrastructure will be managed by the DCI and/or Duke 
Medicine.   
 
Upon completion of the study, research records will be archived and handled per institutional policy.     
 
Subject names or identifiers will not be used in reports, presentations at scientific meetings, or 
publications in scientific journals 
12.6 
Data and Safety Monitoring 
 
Data and Safety Monitoring will be performed in accordance with the external site Data and Safety 
Monitoring Plan, provided under separate cover. 
12.7 
Protocol Amendments 
 
All protocol amendments must be initiated by the Principal Investigator and approved by the IRB prior 
to implementation.  IRB approval is not required for protocol changes that occur to protect the safety 
of a subject from an immediate hazard.  However, the Principal Investigator must inform the IRB and 
all other applicable regulatory agencies of such action immediately. 
 
Though not yet required, the CPC should be informed about any protocol amendments that 
potentially affect research design or data analysis (i.e. amendments affecting subject population, 
inclusion/exclusion criteria, agent administration, etc.). 
12.8 
Records Retention 
 

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The Principal Investigator will maintain study-related records for a period of at least six years after 
study completion per Duke policy.   
12.9 
Conflict of Interest 
 
The Principal Investigator and Sub-Investigators must comply with applicable federal, state, and local 
regulations regarding reporting and disclosure of conflict of interest.  Conflicts of interest may arise 
from situations in which financial or other personal considerations have the potential to compromise 
or bias professional judgment and objectivity.  Conflicts of interest include but are not limited to 
royalty or consulting fees, speaking honoraria, advisory board appointments, publicly-traded or 
privately-held equities, stock options, intellectual property, and gifts. 
 
The Duke University School of Medicine’s Research Integrity Office (RIO) reviews and manages 
research-related conflicts of interest.  The Principal Investigator and Sub-Investigators must report 
conflicts of interest annually and within 10 days of a change in status, and when applicable, must have 
a documented management plan that is developed in conjunction with the Duke RIO and approved 
by the IRB/IEC. 
 
 

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13 REFERENCES 
 
1. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: a cancer journal for clinicians 2016;66:7-
30. 
2. 
Marcus DM, Goodman M, Jani AB, Osunkoya AO, Rossi PJ. A comprehensive review of incidence 
and survival in patients with rare histological variants of prostate cancer in the United States from 1973 
to 2008. Prostate cancer and prostatic diseases 2012;15:283-8. 
3. 
Wang HT, Yao YH, Li BG, Tang Y, Chang JW, Zhang J. Neuroendocrine Prostate Cancer (NEPC) 
progressing from conventional prostatic adenocarcinoma: factors associated with time to development 
of NEPC and survival from NEPC diagnosis-a systematic review and pooled analysis. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 2014;32:3383-90. 
4. 
Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus 
prednisone for advanced prostate cancer. The New England journal of medicine 2004;351:1502-12. 
5. 
de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for 
metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised 
open-label trial. Lancet 2010;376:1147-54. 
6. 
de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic 
prostate cancer. The New England journal of medicine 2011;364:1995-2005. 
7. 
Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous 
chemotherapy. The New England journal of medicine 2013;368:138-48. 
8. 
Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before 
chemotherapy. The New England journal of medicine 2014;371:424-33. 
9. 
Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after 
chemotherapy. The New England journal of medicine 2012;367:1187-97. 
10. 
Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic 
prostate cancer. The New England journal of medicine 2013;369:213-23. 
11. 
Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant 
prostate cancer. The New England journal of medicine 2010;363:411-22. 
12. 
Aggarwal R, Zhang T, Small EJ, Armstrong AJ. Neuroendocrine prostate cancer: subtypes, biology, 
and clinical outcomes. Journal of the National Comprehensive Cancer Network : JNCCN 2014;12:719-26. 
13. 
Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate 
cancer. Cell 2015;161:1215-28. 
14. 
Aparicio AM, Harzstark AL, Corn PG, et al. Platinum-based chemotherapy for variant castrate-
resistant prostate cancer. Clinical cancer research : an official journal of the American Association for 
Cancer Research 2013;19:3621-30. 
15. 
Beltran H, Prandi D, Mosquera JM, et al. Divergent clonal evolution of castration-resistant 
neuroendocrine prostate cancer. Nature medicine 2016;22:298-305. 
16. 
Spiess PE, Pettaway CA, Vakar-Lopez F, et al. Treatment outcomes of small cell carcinoma of the 
prostate: a single-center study. Cancer 2007;110:1729-37. 
17. 
Steineck G, Reuter V, Kelly WK, Frank R, Schwartz L, Scher HI. Cytotoxic treatment of aggressive 
prostate tumors with or without neuroendocrine elements. Acta oncologica 2002;41:668-74. 
18. 
Nadal R, Schweizer M, Kryvenko ON, Epstein JI, Eisenberger MA. Small cell carcinoma of the 
prostate. Nature reviews Urology 2014;11:213-9. 
19. 
Hager S, Ackermann CJ, Joerger M, Gillessen S, Omlin A. Anti-tumour activity of platinum 
compounds in advanced prostate cancer-a systematic literature review. Annals of oncology : official 
journal of the European Society for Medical Oncology 2016;27:975-84. 

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20. 
Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-Repair Gene Mutations in Men with 
Metastatic Prostate Cancer. The New England journal of medicine 2016;375:443-53. 
21. 
Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate 
Cancer. The New England journal of medicine 2015;373:1697-708. 
22. 
Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF 
mutation. The New England journal of medicine 2015;372:320-30. 
23. 
Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with 
metastatic melanoma. The New England journal of medicine 2010;363:711-23. 
24. 
Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in 
recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. The Lancet 
Oncology 2016;17:883-95. 
25. 
Gulley JL, Spigel D, Kelly K, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in advanced 
NSCLC patients: A phase 1b, open-label expansion trial in patients progressing after platinum-based 
chemotherapy. Journal of Clinical Oncology 2015;33. 
26. 
Disis ML, Patel MR, Pant S, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients 
with previously treated, recurrent or refractory ovarian cancer: A phase Ib, open-label expansion trial. 
Journal of Clinical Oncology 2015;33. 
27. 
Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory 
metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. The Lancet 
Oncology 2016. 
28. 
Bishop JL, Sio A, Angeles A, et al. PD-L1 is highly expressed in Enzalutamide resistant prostate 
cancer. Oncotarget 2015;6:234-42. 
29. 
Beltran H, Rickman DS, Park K, et al. Molecular characterization of neuroendocrine prostate 
cancer and identification of new drug targets. Cancer discovery 2011;1:487-95. 
30. 
Scher HI, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-Resistant 
Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2016;34:1402-
18. 
31. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). European journal of cancer 2009;45:228-47. 
32. 
Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use in trials 
testing immunotherapeutics. The Lancet Oncology 2017;18:e143-e52. 
33. 
Beltran H, Jendrisak A, Landers M, et al. The Initial Detection and Partial Characterization of 
Circulating Tumor Cells in Neuroendocrine Prostate Cancer. Clinical cancer research : an official journal 
of the American Association for Cancer Research 2016;22:1510-9. 
34. 
Corn PG, Tu SM, Zurita AJ, et al. A multi-institutional randomized phase II study (NCT01505868) 
of cabazitaxel (CAB) plus or minus carboplatin (CARB) in men with metastatic castration-resistant 
prostate cancer (mCRPC). Journal of Clinical Oncology 2015;33. 
35. 
Lee JL, Ahn JH, Choi MK, et al. Gemcitabine-oxaliplatin plus prednisolone is active in patients 
with castration-resistant prostate cancer for whom docetaxel-based chemotherapy failed. British journal 
of cancer 2014;110:2472-8. 
36. 
Weber JS, D'Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with 
advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, 
controlled, open-label, phase 3 trial. The Lancet Oncology 2015;16:375-84. 
37. 
Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in 
untreated melanoma. The New England journal of medicine 2015;372:2006-17. 

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38. 
Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients 
with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy 
(CA184-043): a multicentre, randomised, double-blind, phase 3 trial. The Lancet Oncology 2014;15:700-
12. 
39. 
Graff JN, Alumkal JJ, Drake CG, et al. Early evidence of anti-PD-1 activity in enzalutamide-
resistant prostate cancer. Oncotarget 2016. 
40. 
Hoos A, Eggermont AM, Janetzki S, et al. Improved endpoints for cancer immunotherapy trials. 
Journal of the National Cancer Institute 2010;102:1388-97. 
 
 
 

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14 Appendix A: Performance Status Criteria 
Karnofsky Performance Scale 
% 
Description 
100 
Normal, no complaints, no evidence of disease 
90 
Able to carry on normal activity, minor signs or symptoms of disease 
80 
Normal activity with effort, some signs or symptoms of disease 
70 
Cares for self, unable to carry on normal activity or to do active work 
60 
Requires occasional assistance but is able to care for most needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled, requires special care and assistance 
30 
Severely disabled, hospitalization indicated. Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly 
0 
Dead 
 
 
 

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15 Appendix B: FACT-P (version 4) 
Below is a list of statements that other people with your illness have said are important.  
Please circle or mark one number per line to indicate your response as it applies to the 
past 7 days. 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GP1 
I have a lack of energy  
0 
1 
2 
3 
4 
GP2 
I have nausea 
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family 
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment 
0 
1 
2 
3 
4 
GP6 
I feel ill 
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed 
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GS1 
I feel close to my friends 
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family 
0 
1 
2 
3 
4 
GS3 
I get support from my friends 
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness 
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness 
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support) 
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life 
0 
1 
2 
3 
4 

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Please circle or mark one number per line to indicate your response as it applies to the past 
7 days. 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GE1 
I feel sad ..............................................................................
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness .........
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness .................
0 
1 
2 
3 
4 
GE4 
I feel nervous ......................................................................
0 
1 
2 
3 
4 
GE5 
I worry about dying ............................................................
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse............................
0 
1 
2 
3 
4 
 
 
 
FUNCTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) ..........................
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling ....................
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life .........................................................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness ..................................................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ...............................................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun......................
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now .............
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 

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Please circle or mark one number per line to indicate your response as it applies to the 
past 7 days. 
 
 
ADDITIONAL CONCERNS 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
C2 
I am losing weight 
0 
1 
2 
3 
4 
C6 
I have a good appetite 
0 
1 
2 
3 
4 
P1 
I have aches and pains that bother me 
0 
1 
2 
3 
4 
P2 
I have certain parts of my body where I experience pain 
0 
1 
2 
3 
4 
P3 
My pain keeps me from doing things I want to do 
0 
1 
2 
3 
4 
P4 
I am satisfied with my present comfort level 
0 
1 
2 
3 
4 
P5 
I am able to feel like a man 
0 
1 
2 
3 
4 
P6 
I have trouble moving my bowels 
0 
1 
2 
3 
4 
P7 
I have difficulty urinating 
0 
1 
2 
3 
4 
BL2 
I urinate more frequently than usual 
0 
1 
2 
3 
4 
P8 
My problems with urinating limit my activities 
0 
1 
2 
3 
4 
BL5 
I am able to have and maintain an erection 
0 
1 
2 
3 
4