PDL-1 Inhibition With Avelumab and Concurrent Second-generation ADT in African Americans With Castrate-resistant Metastatic Prostate Cancer
Phase: PHASE2
Conditions: Metastatic Castration-resistant Prostate Cancer
Sponsor: Jodi Layton, MD

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TITLE:   PDL-1 inhibition with Avelumab and concurrent second-generation ADT in 
African Americans with castrate-resistant metastatic prostate cancer. 
 
IRB Protocol #:  2018-1236 
IND #: 139559 
Version: 4  
Version Date 25 September 2018 
 
 
Principal Investigator: 
 
Jodi L. Layton, MD 
131 S. Robertson St. 
New Orleans, LA 70112 
jlayton@tulane.edu 
 
Co-Investigators: 
Pedro C. Barata, MD MSc 
Brian E. Lewis, MD MPH 
Alton O. Sartor, MD 
 
Funding and Study drug provided by EMD Serono, Inc. 
 
 
 

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TABLE OF CONTENTS 
 
1. TRIAL SUMMARY……………………………………………………………………………….Pg 4  
1.1. TRIAL DESIGN…………………………………………………………………..…………........5 
1.2. TRIAL DIAGRAM……………………………………………………………………….…........6 
2. BACKGROUND AND RATIONALE……………………………………………………………….7 
3. PATIENT POPULATION…………………………………………………………………………....8 
4. HYPOTHESIS………………………………………………………………………….......................9 
5. ENDPOINTS…………………………………………………………………………..........................9 
5.1. Primary…………………………………………………………………………............................9 
5.2. Secondary…………………………………………………………………………........................9 
5.3. Ancillary Studies………………………………………………………………………….............9 
6. METHODS…………………………………………………………………………...........................10 
6.1. Entry Criteria…………………………………………………………………………................10 
6.2. Subject Inclusion Criteria………………………………………………………………………10 
6.3. Subject Exclusion Criteria…………………………………………………………………...…11 
6.4. Trial Treatments…………………………………………………………………………...........13 
6.5. Dose Modifications…………………………………………………………………………........14 
6.6. Timing of Administration…………………………………………………………………….....21 
6.7. Concomitant Medications/Vaccinations…………………………………………………….…21 
6.8.  Supportive Care Guidelines…………………………………………………………………....22 
6.9. Infusion Reaction Treatment Guidelines……………………………………………………....22 
6.10. 
Radiotherapy…………………………………………………………………………....23 
6.11. 
Diet/Activity/Contraception ……...……………………………………………………23 
6.12. 
Subject Withdrawal/Discontinuation Criteria……………………………………..…25 
6.13. 
Safety Monitoring………………………………………………………………………26 
7. TRIAL FLOW CHART…………………………………………………………………………......28 
8. DETAILED STUDY DESIGN……………………………………………………………………...32 
8.1. Informed Consent………………………………………………………………………….........32 
8.2. Inclusion/Exclusion Criteria…………………………………………………………………....32 
8.3. Assignment of Treatment Number……………………………………………………………..32 
8.4. Medical History………………………………………………………………………….............33 
8.5. Prior and Concomitant Medications…………………………………………………………...33 
8.6. Subsequent Anti-Cancer Treatment…………………………………………………………...33 
8.7. Clinical Procedures/Assessment………………………………………………………………..33 
8.8. Withdrawal/Discontinuation …………………………………………………………………...39 
8.9. Blinding/Unblinding………………………………………………………………………….....39 
8.10. 
Post-Treatment…………………………………………………………………………39 
8.11. 
Simple Study Phase Flow Diagram …………………………………………………...39 
9. STATISTICAL JUSTIFICATION…………………………………………………………………40 
9.1. Statistical Analysis Plan Summary…...………………………………………………………..40 
9.2. Primary Endpoint…………...…………………………………………………………………..41 
9.3. Secondary Endpoints……...…………………………………………………………………….41 
10. LIST OF REFERENCES…………………………………………………………………………....43 
11. APPENDICES…………………………………………………………………………......................44 
A. RECIST v1.1…………………………………………………………..……………....................44 
B. Prostate Cancer Clinical Trials Working Group 3……………………………………………44 
C. CTCAEv4.0…….……………………………………………………………………...................44 

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D. ECOG Performance Status……………………………………………………………………..44 
E. Abiraterone…………………………………………………………………………....................45 
F. Enzalutamide………………………………………………………………………….................45 
G. Apalutimide ……………………………………………………………………………………..45 
H. Darolutimide …………………………………………………………………………………….45 
I. Avelumab Pharmacy Manual…………………………………………………………………..46 
J. Report, Assessment and Close Out of Temperature Excursion……………………………...58 
 
List of Tables 
 
Table 1: Adequate Organ Function Laboratory Values………………………………….….11 
Table 2: Management of Immune-mediated Adverse Reactions……………………….…...14 
Table 3: Treatment Modification for Symptoms of Infusion-Related Reactions…………..23 
Table 4: Imaging and Treatment after 1st Radiologic Evidence of PD……………………..36 
Table 5: Laboratory Tests……………………………………………………………………...38 
 
 
 
List of Figures 
 
Figure 1: Trial Design ………………………………………………………………………….6 
Figure 2: Study Phase Flow Diagram…………………………………………………………39  
 
 
 

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1. TRIAL SUMMARY 
Abbreviated Title 
Phase II Trial of Avelumab plus 2nd-generation ADT in AA Subjects 
with mCRPC   
Sponsor Product Identifiers 
Avelumab 
Trial Phase 
Phase II 
Clinical Indication 
Metastatic Castration-Resistant Prostate Cancer (mCRPC) 
Trial Type 
Interventional 
Type of control 
No treatment control 
Route of administration 
Intravenous 
Trial Blinding 
Unblinded Open-label 
Treatment Groups 
Avelumab 10mg/kg every 2 weeks (Q2W) + 2nd generation ADT 
Number of trial subjects 
Thirteen subjects will be enrolled in initial cohort with a potential for 
expansion to a total of 27AA patients 
Estimated time to enrollment 
The trial will require approximately 4 0 months to enrollment for initial 
cohort from the time the first subject signs the informed consent until the 
last subject’s last study-related phone call or visit. 

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Duration of Participation 
Each subject will participate in the trial from the time the subject signs 
the Informed Consent Form (ICF) through the final protocol-specified 
contact. 
After a screening phase of 21 days (with 28 days for imaging), eligible 
subjects will be enrolled into an initial cohort. Subjects will receive 
avelumab and continue with 2nd-generation ADT they had been already 
receiving.  
Treatment will continue until documented disease progression, 
unacceptable adverse events (AEs), intercurrent illness that prevents 
further administration of treatment, Investigator’s decision to 
withdraw the subject, subject withdrawal of consent, noncompliance 
with trial treatment or procedure requirements, subject receives 52 
administrations of avelumab (approximately 2 years), or administrative 
reasons requiring the cessation of treatment. Treatment may continue 
beyond progression in cases where the treating physician determines that 
clinical benefit is occurring.  
Subjects who discontinue for reasons other than disease progression 
will have post-treatment follow-up for disease status until disease 
progression, initiation of a non-study prostate cancer treatment, 
withdrawal of consent, or becoming lost to follow-up. All subjects will 
be followed by telephone for overall survival until death, withdrawal 
of consent, or study closure. 
1.1 TRIAL DESIGN 
This is a nonrandomized, open-label trial of avelumab in subjects with metastatic castration-
resistant prostate cancer (mCRPC) experiencing PSA or radiographic progression while 
receiving 2nd generation ADT (abiraterone / enzalutamide/ apalutamide or darolutamide). 
Metastases must be radiographically evident by whole body bone scintigraphy or CT/MRI 
scan.  
Progression of disease at time of enrollment with be defined as either 
1. 
PSA progression will be defined by PSA rise on 2 consecutive measurements at 
least 1 week apart with baseline PSA of > 2ng/dL.  
2. 
  And/or radiographic disease progression in soft tissue or bone with or 
without PSA progression 
 
Thirteen African American subjects will be enrolled into the initial cohort. 
If at least one positive response (PSA decrease by >50% and or radiographic per RECIST 1.1) is 
found, the study will be expanded to accrue a total of 27 patients. The trial will be conducted in 
accordance with Good Clinical Practices. 
 

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Subjects enrolled in the study will receive avelumab 10 mg/kg every 2 weeks (Q2W) and 
continue their previously started 2nd generation ADT (abiraterone or enzalutamide).  
 
All subjects will undergo radiographic imaging assessments and PSA assessments to evaluate 
response to treatment at regular intervals. On study imaging will be assessed every 12 weeks. 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be adapted per the 
consensus guidelines of the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) as 
described in Appendix A/B to account for the tumor progression patterns seen in bone 
metastases in prostate cancer. PSA will be obtained every 2 weeks with PSA progression 
assessed per PCWG3.  
Adverse events (AEs) will be monitored throughout the trial and graded in severity according to 
the guidelines outlined in the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 (see Appendix C).  
Treatment with avelumab will continue until documented confirmed disease progression, 
unacceptable AEs, intercurrent illness that prevents further administration of treatment, 
Investigator’s decision to withdraw the subject, subject discontinuation from the study, 
noncompliance with trial treatment or procedure requirements, subject receives 52 
administrations of avelumab (approximately 2 years), or administrative reasons requiring the 
cessation of treatment. 
After the end of treatment, each subject will be followed for 30 days for AE monitoring 
(serious AEs will be collected for 90 days after the end of treatment or 30 days after the end 
of treatment if the subject initiates new anticancer therapy, whichever is earlier). Subjects 
who discontinue treatment for reasons other than disease progression will remain on study 
and continue to undergo study-related disease assessments until documented disease 
progression, initiation of a n e w  non-study p ro s t at e cancer treatment, withdrawal of 
consent, or becoming lost to follow-up. All subjects will enter survival follow up, and will 
be contacted at their regularly scheduled clinic visit, or by telephone approximately 
every 6 months, until death or withdrawal of consent or end of study.  
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 7.0.  
 
1.2 TRIAL DIAGRAM 
 
African American subjects with mCRPC currently receiving either abiraterone or enzalutamide 
and documented PSA progression (on serial PSA’s at least 1 week apart) and/or worsening 
radiographic disease by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) will enroll 
into the pre-expansion Cohort. 
 
The trial design is depicted in Figure 1.  
 

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Figure 1.  
 
*Cohort will be expanded to 27 if  > 1 response via PCWG3 seen in the first 13 patients accrued.  
 
2.0 BACKGROUND AND RATIONALE 
 
PD-1 Inhibitors and Prostate Cancer 
PD-1 inhibitors have garnered considerable interest and activity in a variety of advanced cancers. 
Prostate cancer, as well as colon cancer, were initially considered to be an exception to this rule. 
Graff et al. (1) have recently publicized data demonstrating considerable effect of 
pembrolizumab in a subset of men with advanced CRPC. This data is revitalizing the field of 
PD-1 inhibition in prostate cancer. Direct personal communication with Dr. Graff (November 
2016) indicates that analysis of the tumor specimens is not yet complete but in at least one case, 
there is an underlying micro-satellite instability (MSI) suggesting the possibility of an underlying 
mismatch repair defect among some responders.  
 
Careful studies of mismatch repair defects indicate that in colon cancer individuals whose tumors 
have these mismatch repair defects can markedly benefit from PD1 inhibition (2). Merck in fact 
has now received FDA approval of pembrolizumab in MSI cancers (3).  
 
Mismatch and DNA Repair Issues in Prostate Cancer 
Studies in Lynch Syndrome and prostate cancer indicate mismatch repair alterations can clearly 
occur in prostate cancer (4,5). Some data suggest that Lynch syndrome patients have a higher 
risk of prostate cancer (5). In one study, 488 Lynch syndrome families with disease-predisposing 
germline mutations in MLH1, MSH2, MSH6 or PMS2 were identified in the national Danish 
registry. In this cohort of 1609 males (677 mutation carriers and 932 first-degree relatives), 
prostate cancer developed in 16 mutation carriers and in 12 first-degree relatives. The tumors 
were linked to disease-predisposing mutations in MSH2 (n=14), MLH1 (n=8) and MSH6 (n= 6). 
We note that the effects of PD1 inhibition in men DNA repair mutations are not yet defined but 
we believe this issue is of potential significance.  
 
In the large studies on inherited (germline) DNA in metastatic CRPC published by Pritchard et al 
(6) in 692 patients, mutations in DNA mismatch were detected as follows: MLH1 (n=0), PMS2 
(n=2), MSH2 (n=1), and MSH6 (n=1). None of these frequencies were distinct from the large 
control population. On the other hand, a variety of DNA repair mutations including: BRCA2 
(n=37), BRCA1 (n=6), ATM (n=11), GEN1 (n=2), RAD51D (n=3), CHEK2 (n=10) and PALB2 
(n=3) germline mutations were more common in CRPC patients as compared to controls. 
Notably this study used exomic sequencing and thus incomplete data are available from this data 
set. 
 

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A distinct autopsy study by Pritchard et al (7), demonstrated 12% (7 of 60) of advanced prostate 
cancers were hypermutated, and all of the hypermutated cancers had mismatch repair gene 
mutations and MSI. Quite interestingly, mutations were typically complex MSH2 or MSH6 
structural rearrangements rather than epigenetic MLH1 silencing. These assays for MSH2 and 
MSH6 alterations involved a targeted deep sequencing approach (BROCA assay) that included 
capture of both intronic and flanking DNA sequences in addition to exons.  
 
There are current collaborations between Tulane University and the Pritchard group studying 
mismatch repair and DNA repair genes in men of African-American ancestry but results are not 
yet available. We anticipate that this would be part of the correlative studies going forward with 
immune modulation.  
 
Race Differences 
The relationship between prostate cancer and race has been well studied and unequivocal data 
demonstrate African-American (AA) men are at higher risk for prostate cancer death as 
compared to other ethnic groups in the United States. In addition to having higher incidence of 
death, there’s an earlier onset of disease; considerable work has been ongoing to understand why 
these disparities exist.  
 
Provocative findings demonstrate prostate cancer to be an immune-mediated treatment 
responsive disease. In solid tumors, the very first immune mediated treatment to prolong overall 
survival (OS) in men with metastatic castrate resistant prostate cancer (CRPC) occurred after 
treatments with sipuleucel-T (8). Though the overall effects were modest, and the therapy 
expensive, the phase III IMPACT trial was pivotal for FDA approval and this agent is now used 
in the United States for CRPC therapy. 
 
While not much has been yet publicized, the effects of this immune-based therapy appear to be 
more pronounced in AA men as compared to Caucasian men. In an analysis of all randomized 
trials with sipuleucel-T, the hazard ratio of OS in AA men was a remarkable 0.288 [95% CI: 
0.125, 0.662]; p = .003 (9). AA men treated with this therapy had median overall survival benefit 
of 45.3 months versus 14.6 months in the control arm, a median survival difference of 30.7 
months.  
 
More recent data from a much larger study submitted with sipuleucel-T (10) confirm and extend 
the sipuleucel-T initial findings with a larger matched cohort. AA pts had a significantly longer 
median OS of 39.5 months vs 28.1 months for CAU pts (p<0.001; HR 0.665, 95% CI 0.530-
0.835). After univariate and multivariate analyses, six baseline characteristics were significantly 
associated with OS - including AA men. 
 
3.0 PATIENT POPULATION 
African-American men with histologically or cytologically confirmed adenocarcinoma of the 
prostate, currently undergoing treatment for castrate-resistant metastatic disease with a second-
generation androgen deprivation therapy (abiraterone/enzalutamide/apalutamide or 
darolutamide).

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4.0 HYPOTHESIS 
 
We hypothesize African-American men are responsive to inhibition of the PD-1 signaling 
pathway and propose to test this concept in a pilot clinical trial. We also propose to link these 
therapeutic responses with correlative studies on mismatch and DNA repair alterations using the 
BROCA assays. 
 
5.0  ENDPOINTS 
5.1 
Primary: to evaluate the proportion of men with PSA response >50% 
5.2 
Secondary:  to assess PSA progression-free survival (PFS); radiographic PFS, 
RECISTv1.1 response, overall survival (OS), and safety 
 
 
 
5.3 
Ancillary studies  
5.3.1 To establish the relationships between DNA based biomarkers and clinical activity 
5.3.2 Mismatch repair and DNA repair assays on germline and where feasible somatic samples 
using BROCA assays that extend beyond the exomic sequencing typically used.

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6.0 METHODS 
 
6.1 Entry Criteria 
Diagnosis/Condition for entry into trial: Male subjects at least 18 years of age with 
mCRPC whom are currently receiving treatment with second-generation androgen 
deprivation therapy (abiraterone/enzalutamide/apalutimide/darolutamide) with evidence of 
progression of disease. Patients receiving a second-generation androgen deprivation therapy 
(2nd generation ADT) for metastatic hormone sensitive prostate cancer (mHSPC), who show 
evidence of progression to mCRPC, will be allowed to participate in this study. 
 
6.2 Subject Inclusion Criteria 
To be eligible for participation in this trial, the subject must: 
 
1 
Must be of African descent; Black or African American: A person having origins in any 
of the black racial groups of Africa. Terms such as “Haitian” or “Negro” can be used in 
addition to “Black or African American.” 
2 
Be willing and able to provide written informed consent for the trial.  
3 
Be ≥18 years of age on day of signing informed consent. 
4 
Have histologically or cytologically confirmed adenocarcinoma of the prostate without 
small cell histology. Diagnosis must be stated in a pathology report. 
5 
Have evidence of metastatic disease as determined by CT/MRI scans and/or bone 
metastases by whole body bone scintigraphy.  (Use MRI if CT is contraindicated, and for 
imaging of the brain if clinically indicated).  
6 
Have documented disease progression within 3 months of screening, as determined by 
the Investigator, by means of at least one of the following: 
PSA progression as defined by a minimum of two rising PSA levels with an 
interval of ≥ 1 week between each assessment where the PSA value at 
screening should be ≥ 2 ng/mL. 
Radiographic disease progression in soft tissue or bone with or without PSA 
progression as determined by Recist 1.1 and/or PCWG3 
7 
Have ongoing androgen deprivation with serum testosterone < 50 ng/dL (< 2.0 nM). 
If the subject is currently being treated with LHRH agonists or antagonists (for 
subjects who have not undergone an orchiectomy). This treatment must be continued 
throughout the study. 
8 
Be receiving and tolerating either abiraterone acetate, enzalutamide, apalutamide or 
darolutamide for at least 8 weeks prior to documented disease progression. Note: the 2nd 
generation ADT that the patient is currently progression on needs to be the first 2nd gen 
ADT used in the CRPC setting  
9 
Have a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group 

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(ECOG) Performance Scale (Appendix D). 
10 
Male subjects of reproductive potential must agree practice abstinence from 
heterosexual activity OR use a highly effective method of contraception, starting at 
the time of informed consent and continue through 60 days after the last dose of 
study therapy (see section 6.1.1.)  
11 
Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 10 days of treatment initiation. 
 
Table 1.  Adequate Organ Function Laboratory Values 
 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
>1,500 x109/L 
Platelets 
≥100,000 x109/L 
Hemoglobina 
≥9 g/dL 
Renal 
Creatinine OR 
Measured or calculatedb creatinine clearance 
(GRF can also be used in place of creatinine or 
creatinine clearance) 
<1.5 X ULN   OR 
 
 
≥30.0 mL/min for subject with creatinine levels 
> 2X institutional ULN  
Hepatic 
Serum Total Bilirubin 
≤ 1.5 X ULN (unless patient has Gilbert’s syndrome) 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN OR 
≤5xULN for subjects with liver metastases 
a. 
Hemoglobin may reach threshold by transfusion 
b. 
Creatinine clearance should be calculated according to the Cockcroft-Gault formula or per institutional 
standard. 
 
6.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject:  
 
1 
Is currently participating and receiving study therapy in a clinical trial, or has participated 
in a study of an investigational agent (and received study therapy or used an 
investigation device) within 4 weeks of the first dose of study treatment. 
2 
No more than one line of a 2nd generation ADT (abiraterone acetate /enzalutamide/ 
apalutamide/darolutamide) for mCRPC is permitted for study entry.  
3 
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment.  

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Note: the following are allowed: a. intranasal, inhaled, topical steroids, or local 
steroid injection (e.g., intraarticular injection); b. systemic corticosteroids at 
physiological doses < 10mg/day of prednisone or equivalent; c. steroids as 
premedication for hypersensitivity reactions (e.g., CT scan premedication). 
4 
Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the 
first dose of trial treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to mAbs administered more than 4 weeks earlier.  
5 
Has had >2 prior systemic chemotherapy agents for mCRPC Note: chemotherapy in 
the mHSPC setting is allowed  
6 
Prior surgery within 4 weeks of initiating study treatment 
Note: If subjects received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to the first 
dose of trial treatment. 
7 
Has any additional malignancy that has required active treatment in the last 3 years.  
Exceptions include: basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin, or low-grade Ta or T1 urothelial carcinoma of that 
bladder that has undergone potentially curative therapy. 
8 
Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  
Note: Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least 
four weeks prior to the first dose of trial treatment and any neurologic 
symptoms have returned to baseline), have no evidence of new or enlarging 
brain metastases. This exception does not include carcinomatous meningitis 
which is excluded regardless of clinical stability. 
9 
Has an active autoimmune disease that might deteriorate when receiving an immune-
stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid 
diseases not requiring immunosuppressive treatment are eligible.  
10 
Has had prior organ transplantation including allogenic stem-cell transplantation.  
11 
Has an active infection requiring systemic therapy. 
12 
Has active, clinically significant Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies).  Patients with well controlled HIV will be allowed to be enrolled into the 
study. 
13 
Has Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive 
HBV surface antigen or HCV RNA if anti-HCV antibody screening test is positive). 
14 
Has received a live vaccine within 4 weeks of first dose of avelumab; live vaccines are 
prohibited throughout course of the trial. Inactivated vaccines are allowed.  

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15 
Has known prior severe hypersensitivity to investigational product or component in its 
formulations, including known severe hypersensitivity reactions to monoclonal 
antibodies (NCI CTCAE v4.3 Grade > 3).  
16 
Has clinically significant (i.e., active) cardiovascular disease: cerebral vascular 
accident/stroke (< 6months prior to enrollment), myocardial infarction (< 6months prior 
to enrollment), unstable angina, congestive heart failure (> New York Heart 
Association Classification Class II), or serious cardiac ventricular arrhythmia requiring 
medication.  
17 
Persisting toxicity related to prior therapy (NCI CTCAE v. 4.3 Grade > 1); however, 
alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety 
risk based on investigator’s judgment are acceptable. 
18 
Other severe acute or chronic medical conditions including colitis, inflammatory bowel 
disease, immune 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. 
 
6.4 Trial Treatment(s)  
6.4.1 Experimental treatment to be used in this trial: 
Drug 
Dose/Potency Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
avelumab 
10 mg/kg 
Q2W 
IV infusion 
Day 1 of each 
cycle 
Experimental 
Trial treatment should begin on the day 1 of cycle 1 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations. 
6.4.2 Non-experimental treatments shall be one of the following: 
Drug 
Dose/Potency Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Abiraterone 
1000 mg 
Daily 
PO on empty 
stomach 
Daily 
Standard of 
care 

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Enzalutamide 
160 mg 
Daily 
PO  
Daily 
Standard of 
care 
Darolutimide 
600 mg  
BID 
PO 
Daily 
Standard of 
care  
Apalutamide  
240 mg 
Daily 
PO 
Daily 
Standard of 
care 
Patients with dose modifications made prior to study entry may be maintained (at lower 
dose) as clinically indicated  
 
6.5 Dose Modification   
There are no dose modifications allowed for the study drug Avelumab. 
Dose modifications for non-experimental treatments will be allowed per clinical discretion. 
Adverse events (both non-serious and serious) associated with avelumab exposure may 
represent an immunological etiology. These AEs may occur shortly after the first dose or 
several months after the last dose of treatment. Avelumab should be withheld for drug-
related toxicities and severe life-threatening AEs as per Tables 2 and 3.  
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, subject vacation, 
and/or holidays). Subjects should be placed back on study therapy within 4 weeks of the 
scheduled interruption, unless otherwise discussed with the managing provider. The reason 
for interruption should be documented in the subject's study record. See below for suggested 
management of potential adverse reactions: 
 
Table 2.  Management of Immune-mediated Adverse Reactions 
Gastrointestinal irAEs 
Severity of Diarrhea/Colitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Diarrhea: < 4 stools/day over 
Baseline 
Colitis: asymptomatic  
Continue avelumab therapy 
Symptomatic treatment (e.g. 
loperamide) 
Close monitoring for worsening symptoms 
Educate subject to report worsening immediately 
If worsens: 
Treat as Grade 2, 3 or 4.  

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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  
 
Withhold avelumab therapy 
Symptomatic treatment 
If improves to Grade ≤ 1:  
Resume avelumab therapy 
 
If persists > 5-7 days or recurs: 
Treat as Grade 3 or 4. 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 stools per 
day over Baseline; incontinence; IV 
fluids ≥ 24 h; interfering with ADL 
Colitis (Grade 3):  severe abdominal 
pain, medical intervention indicated, 
peritoneal signs 
Grade 4: life-threatening, 
perforation 
Withhold avelumab for 
Grade 3. 
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3. 
 
1.0 to 2.0 mg/kg/day 
prednisone 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; resume avelumab therapy following steroids 
taper (for initial Grade 3).  
 
If worsens, persists > 3 to 5 days, or recurs after 
improvement: 
Add infliximab 5mg/kg (if no contraindication). Note: 
infliximab should not be used in cases of perforation or 
sepsis.  
Dermatological irAEs 
Grade of Rash 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 to 2  
Covering ≤ 30% body surface area  
Continue avelumab therapy 
Symptomatic therapy (for 
example, antihistamines, 
topical steroids)  
If persists > 1 to 2 weeks or recurs:  
Withhold avelumab therapy  
Consider skin biopsy  
 
Consider 0.5-1.0 mg/kg/day prednisone or equivalent. 
Once improving, taper steroids over at least 1 month, 
consider prophylactic antibiotics for opportunistic 
infections, and resume avelumab therapy following 
steroids taper. 
If worsens:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Covering > 30% body 
surface area;  
Grade 4: Life threatening 
consequences  
Withhold avelumab for 
Grade 3. 
Permanently discontinue for 
Grade 4 or recurrent Grade 3.  
Consider skin biopsy  
Dermatology consult  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month; resume avelumab 
therapy following steroids taper (for initial Grade 3). 

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1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Radiographic changes only  
Consider withholding 
avelumab therapy  
Monitor for symptoms every 
2 to 3 days  
Consider Pulmonary and 
Infectious Disease consults  
Re-assess at least every 3 weeks 
If worsens:  
Treat as Grade 2 or Grade 3 to 4.  
Grade 2 
Mild to moderate new symptoms  
Withhold avelumab therapy 
Pulmonary and Infectious 
Disease consults 
Monitor symptoms daily; 
consider hospitalization  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
Re-assess every 1 to 3 days  
If improves:  
When symptoms return to Grade ≤ 1, taper steroids over 
at least 1 month, and then resume avelumab therapy 
following steroids taper  
If not improving after 2 weeks or worsening:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Severe new symptoms; 
New/worsening hypoxia; 
Grade 4:  Life-threatening  
Permanently discontinue 
avelumab therapy. 
Hospitalize. 
Pulmonary and Infectious 
Disease consults. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent  
Add prophylactic antibiotics 
for opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month  
If not improving after 48 hours or worsening:  
Add additional immunosuppression (for example, 
infliximab, cyclophosphamide, IV immunoglobulin, or 
mycophenolate mofetil)  
Hepatic irAEs 
Grade of Liver Test Elevation 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 

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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  
Withhold avelumab therapy 
Increase frequency of 
monitoring to every 3 days. 
If returns to Grade ≤ 1: 
Resume routine monitoring; resume avelumab therapy. 
If elevation persists > 5 to 7 days or worsens:  
Treat as Grade 3 to 4. 
Grade 3 to 4 
AST or ALT > 5 x ULN and/or total 
bilirubin > 3 x ULN  
Permanently discontinue 
avelumab therapy  
Increase frequency of 
monitoring to every 1 to 
2 days  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consult gastroenterologist/ 
hepatologist 
Consider obtaining MRI/CT 
scan of liver and liver biopsy 
if clinically warranted  
If returns to Grade ≤ 1:  
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. 
Renal irAEs 
Grade of Creatinine Increased 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Creatinine increased > ULN to 1.5 x 
ULN 
Continue avelumab therapy 
Continue renal function monitoring 
If worsens: 
Treat as Grade 2 to 3 or 4. 
Grade 2 to 3 
Creatinine increased > 1.5 and ≤ 6 x 
ULN 
 
 
 
 
 
Withhold avelumab therapy 
Increase frequency of monitoring to 
every 3 days 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
If returns to Grade ≤1: 
Taper steroids over at least 1 month, and resume 
avelumab therapy following steroids taper. 
If worsens:  
Treat as Grade 4. 
Grade 4 
Creatinine increased > 6 x ULN 
 
Permanently discontinue avelumab 
therapy 
Monitor creatinine daily 
If returns to Grade ≤1: 
Taper steroids over at least 1 month. 

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1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
Nephrology consult 
Cardiac irAEs 
Myocarditis 
Initial Management 
Follow-up Management 
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 
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. 
Immune-mediated myocarditis 
Permanently discontinue avelumab. 
Guideline based supportive treatment as 
appropriate as per cardiology consult. * 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections. 
Once improving, taper steroids over at least 1 
month. 
 
If no improvement or worsening, consider 
additional immunosuppressants (e.g. 
azathioprine, cyclosporine A). 
*Local guidelines, or e.g. 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 
Endocrine irAEs 
Endocrine Disorder 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Continue avelumab therapy 
Endocrinology consult if needed 
 
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
Continue hormone replacement/suppression 
and monitoring of endocrine function as 
appropriate. 

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adrenal insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate.   
 
Rule-out secondary endocrinopathies 
(i.e. hypopituitarism / hypophysitis) 
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Withhold avelumab therapy 
Consider hospitalization 
Endocrinology consult 
 
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
type I diabetes mellitus) as 
appropriate.   
 
Rule-out secondary endocrinopathies 
(i.e. hypopituitarism / hypophysitis) 
Resume avelumab once symptoms and/or 
laboratory tests improve to Grade ≤ 1 (with or 
without hormone replacement/suppression). 
 
Continue hormone replacement/suppression 
and monitoring of endocrine function as 
appropriate.  
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies) 
If secondary thyroid and/or adrenal 
insufficiency is confirmed (i.e. 
subnormal serum FT4 with 
inappropriately low TSH and/or low 
serum cortisol with inappropriately 
low ACTH): 
• 
Refer to endocrinologist for 
dynamic testing as indicated and 
measurement of other hormones 
(FSH, LH, GH/IGF-1, PRL, 
testosterone in men, estrogens in 
women)  
• 
Hormone 
replacement/suppressive therapy 
as appropriate  
• 
Perform pituitary MRI and visual 
field examination as indicated 
 
If hypophysitis confirmed: 
• 
Continue avelumab if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month 
• 
Withhold avelumab if moderate, 
severe or life-threatening 
symptoms of hypophysitis and/or 
abnormal MRI. Consider 
Resume avelumab once symptoms and 
hormone tests improve to Grade ≤ 1 (with or 
without hormone replacement). 
 
In addition, for hypophysitis with abnormal 
MRI, resume avelumab only once shrinkage of 
the pituitary gland on MRI/CT scan is 
documented.  
 
Continue hormone replacement/suppression 
therapy as appropriate. 

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hospitalization. Initiate 
corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) 
followed by corticosteroids taper 
during at least 1 month. 
• 
Add prophylactic antibiotics for 
opportunistic infections. 
 
 
 
 
 
Other irAEs (not described above) 
Grade of other irAEs 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 2 or Grade 3 clinical signs 
or symptoms suggestive of a 
potential irAE 
Withhold avelumab therapy pending 
clinical investigation 
If irAE is ruled out, manage as appropriate 
according to the diagnosis and consider re-
starting avelumab therapy 
If irAE is confirmed, treat as Grade 2 or 3 irAE. 
Grade 2 irAE or first occurrence 
of Grade 3 irAE 
Withhold avelumab therapy 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent   
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month and resume 
avelumab therapy following steroids taper. 
Recurrence of same Grade 3 
irAEs 
Permanently discontinue avelumab 
therapy 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month. 
Grade 4  
 
Permanently discontinue avelumab 
therapy 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent and/or other 
immunosuppressant as needed 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult. 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month 
Requirement for 10 mg per day 
or greater prednisone or 
equivalent for more than 12 
Permanently discontinue avelumab 
therapy 
Specialty consult 
 

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Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine 
aminotransferase; AST=aspartate aminotransferase; BNP=B-type natriuretic peptide; CK-MB=creatine 
kinase MB;  CT= computed tomography; FSH=follicle-stimulating hormone; GH=growth hormone; IGF-
1=insulin-like growth factor 1; irAE=immune related adverse event; IV=intravenous; LH=luteinizing 
hormone; MRI=magnetic resonance imaging; NCI CTCAE=National Cancer Institute Common 
Terminology Criteria for Adverse Events; PRL=prolactin;T4=thyroxine; TSH=thyroid stimulating 
hormone; ULN=upper limit of normal. 
 
 
6.6 Timing of Administration 
The first infusion should be administered within 21 days of screening. Avelumab should be 
administered on Day 1 of each 2 week cycle after all procedures/assessments have been 
completed as detailed on the Trial Flow Chart (Section 7). 
 
6.7 Concomitant Medications/Vaccinations  
6.7.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids. If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. Subject may remain on anti- coagulation 
therapy as long as the PT or PTT is within therapeutic range of the intended use of 
anticoagulants. 
6.7.2 Prohibited Concomitant Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required. 
Subjects are prohibited from receiving the following therapies during the Screening 
and Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biologic therapy  
• GM-CSF  
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency 
 
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer 

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• Immunotherapy not specified in this protocol 
• Investigational agents other than avelumab 
• Any other second-generation androgen deprivation therapy other than the one the 
patient was enrolled into the trial on (patients cannot switch between non-
experimental therapies). 
• Systemic radiotherapy 
o Note: Palliative localized radiation therapy to a site of pre-existing 
disease may be permitted while on study. The radiation treatment field 
may not include a target or measurable lesion by RECIST 1.1. (see section 
6.10) 
• Live vaccines within 30 days prior to the first dose of trial treatment and 
while participating in the trial. Examples of live vaccines include, but are not 
limited to, the following: measles, mumps, rubella, chickenpox, yellow fever, 
rabies, Bacillus Calmette-Guerin (BCG), and oral typhoid vaccine. Seasonal 
influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however intranasal influenza vaccines (e.g., FluMist
®
) are live attenuated 
vaccines, and are not allowed. 
 
6.8 Supportive Care Guidelines 
 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  
 
6.9 Infusion Reaction Treatment Guidelines 

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Table 3. Treatment Modification for Symptoms of Infusion-Related Reactions  
NCI-CTCAE Grade  
Treatment Modification for Avelumab 
Grade 1 – mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease the avelumab infusion rate by 50% and monitor closely 
for any worsening. 
 
Grade 2 – moderate 
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (for example, 
antihistamines, NSAIDs, narcotics, IV fluids); 
prophylactic medications indicated for ≤ 24 h. 
Temporarily discontinue avelumab infusion. 
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 avelumab infusion immediately and disconnect infusion tubing 
from the subject. 
Subjects must be withdrawn immediately from study avelumab and 
must not receive any further avelumab treatment. 
- If avelumab infusion rate has been decreased by 50% or interrupted due to an infusion reaction, it must remain decreased for the next 
scheduled infusion.  If no infusion reaction is observed in the next scheduled infusion, the infusion rate may be returned to baseline at the 
subsequent infusions based on investigator’s medical judgment. - If hypersensitivity reaction occurs, the subject must be treated according to 
the best available medical practice.  
IV = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse Event; NSAIDs = nonsteroidal 
anti-inflammatory drugs. 
 
6.10 
Radiotherapy/Surgical Intervention 
The use of radiotherapy or surgical intervention while on study must be recorded in the trial 
database. 
Localized palliative radiation therapy to any site of disease may be permitted while on study. 
Patients may continue treatment on study beyond (investigator’s assessed RECIST v1.1 or 
PCWG3 defined) progression if patient is tolerating therapy and exhibiting investigator-
assessed clinical benefit (11).  
Use of surgical intervention should be completed as medically necessary.  Continuation of 
treatment on study after a surgical intervention needs to be cleared by the Principle 
Investigator.   
6.11     Diet/Activity/Contraception 
 
6.11.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting. 
 
 

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6.11.2 Contraception 
Avelumab may have adverse effects on a fetus in utero. Subjects should be informed that 
taking the study medication may involve unknown risks to the fetus (unborn baby) if 
pregnancy were to occur during the study. To participate in the study, subjects of childbearing 
potential must adhere to the contraception requirement from the time of informed consent 
throughout the study period up to 60 days after the last dose of trial therapy. If there is 
any question that a subject of childbearing potential will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study.  If a patient’s 
partner does become pregnant, the patient needs to inform the Principle Investigator 
immediately. 
For this trial, male subjects will be considered of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition). 
Male subjects of reproductive potential must agree to avoid impregnating a partner while 
receiving study drug and for 30 days after the last dose of study drug by complying with 
one of the following: 
1) practice abstinence† from heterosexual activity; 
OR 
2) use (or have their partner use) acceptable contraception during heterosexual 
activity. 
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner 
• 
contraceptive rod implanted into the skin 
Combination method (requires use two of the following):  
• 
diaphragm 
with spermicide 
(cannot 
be used in conjunction 
with 
cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only) 
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin 
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection. 
 
† Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently 
employed as the subject’s preferred and usual lifestyle and if considered acceptable by local regulatory agencies and 
ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post ovulation methods, etc.) and withdrawal 
are not acceptable methods of contraception. 

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‡ If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as an acceptable 
method of contraception for subjects participating at sites in this country/region 
6.12  Subject Withdrawal/Discontinuation Criteria 
 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the investigator should any untoward incident occur. In addition, a subject 
may be withdrawn by the investigator or the Sponsor if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety 
reasons. Specific details regarding discontinuation or withdrawal procedures; including 
specific details regarding withdrawal from Future Biomedical Research, are provided in 
Section 8. 
In this trial, a subject may discontinue from treatment but continue to participate in 
the regularly scheduled activities, as long as the subject does not withdraw consent.  
A subject must be discontinued from the trial for any of the following reasons: 
● The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• The subject is lost to follow-up. 
 
A subject must be discontinued from treatment but should continue to be monitored in 
the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) discontinues 
treatment but agrees to continue to participate in the regularly scheduled study 
activities. 
Documented disease progression as assessed by the investigator using RECIST 1.1 
guidelines or for bone disease use PCWG3 criteria (Appendix B). (Clinical deterioration 
will not be considered progression).  
• Intercurrent illness that prevents further administration of treatment. 
• Noncompliance with trial treatment or procedure requirements. 
• Administrative reasons. 
 
The End of Treatment and Follow-up visit procedures are listed in Section 7.0 (Trial Flow 
Chart). After the end of treatment, each subject will be followed for 30 days for AE 
monitoring (SAEs will be collected for 90 days after the last dose of treatment).  
Subjects who discontinue for reasons other than PD will have post-treatment follow-up for 
disease status until disease progression, initiation of a non-study prostate cancer treatment, 
withdrawal of consent or loss to follow-up.  

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After documented disease progression or the start of new antineoplastic therapy, each subject 
will be followed by telephone for overall survival until death, withdrawal of consent, or the 
end of the study, whichever occurs first. 
6.13   Safety Monitoring 
 
6.13.1 Safety relevant inclusion and exclusion criteria: (see Table 1) 
Minimum required safety-related inclusion and exclusion criteria for avelumab to be 
included in the study protocols are described in Table 1. Additional inclusion and 
exclusion criteria should be considered based on requirements related to other drugs used 
in combination treatments, target population or study objectives as well as based on 
Sponsor (investigator) judgment. 
6.13.2 Safety assessments 
• Blood chemistry and hematology assessments:  must be performed at baseline, prior 
to each avelumab dose, at end of treatment visit and at 30 days post-treatment safety 
follow-up. 
• Free T4 and TSH must be performed at baseline and at least every 8 weeks during 
treatment and at end of treatment or 30 days post-treatment safety follow-up (if not 
performed in the previous 8 weeks). 
 
6.13.3 Extended safety follow-up 
• Given the potential risk for delayed immune-related toxicities, safety follow-up for 
SAEs must be performed up to 90 days after the last dose of avelumab administration. 
• The extended safety follow-up beyond 30 days after last avelumab 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. 
 
6.13.4 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 the first 
4 infusions of avelumab is mandatory (for example, 25-50 mg diphenhydramine and 
500-650 mg paracetamol IV or oral).  Premedication should be administered for 
subsequent avelumab infusions based upon clinical judgment and presence/severity of 
prior infusion reactions. This may be modified based on local treatment standards and 
guidelines, as appropriate.  
• 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.  Steroids (dexamethasone 10 mg), epinephrine (1:1,000 dilution), allergy 
medications (IV antihistamines), bronchodilators, or equivalents, and oxygen should 
be available for immediate access. 

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• Observation period:  Following avelumab infusions, patients must be observed for 30 
minutes post-infusion for potential infusion-related reactions for the first four doses. 
6.14 Toxicity Management (see Table 2 and Table 3): 
Treatment Modification for Symptoms of Infusion-Related Reactions (Table 2) 
Management of immune-mediated adverse reactions (Table 3)  
6.15 Safety Reporting  
The Sponsor-Investigator is responsible for safety reporting and to identify and follow-up on 
Serious Adverse Events (SAEs) experienced by participants in the study and to forward the 
information to the local regulatory authorities and EMD Serono, as required by local regulations 
(for regulatory reporting) and as required by the ISS agreement (for reporting to EMD Serono).  
Additional site(s) will report directly to Tulane Caner Center Office of Clinical Research who will 
forward to the regulatory authorities and EMD Serono as necessary.   
The following reportable events must be submitted to EMD Serono within 2 business days or 3 
calendar days (whichever comes first) using the applicable safety report form provided. The 
Sponsor-Investigator Dr. Jodi Layton will assume responsibility for submitting the reportable 
event(s) to EMD Serono as well as ensuring that any local reporting requirements are 
completed in parallel. 
 
Serious Adverse Events 
o Results in death; 
o Is life threatening; 
o Results in persistent or significant disability/incapacity; 
o Results in or prolongs an existing inpatient hospitalization;  
o Is a congenital anomaly/birth defect; 
o Is another medically important event;  
o Potential drug-induced liver injury (Hy’s Law cases) 
Exposure during Pregnancy or Breastfeeding (even if not associated with an AE) 
Occupational exposure (even if not associated with an adverse event) 
 
Contact information for submission of reportable events to EMD Serono: 
Fax: +49 6151 72 6914 
OR 
E-mail: ICSR_CT_GPS@merckgroup.com)Specifying: PROTOCOL Number and/or Title, EMD 
Serono assigned Study Number SUBJECT Number, SITE Number/PI Name 
 
 
 

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7.0 TRIAL FLOW CHART 
Trial Period: 
Screening 
Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Screening 
(Visit 1) 
1 
2 
3 
4 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow- 
upb 
Follow Up 
Visitsc 
Survival 
Follow-Up 
5 
6 
7 
8 
Scheduling Window (Days): 
-21 to -1 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
from last 
dose 
(± 3 days) 
Every 12 
weeks post 
last dose (± 
7 days) 
Every 6 
months 
(± 14 days) 
Or by 
phone 
Administrative Procedures 
Informed Consent 
Xd 
Inclusion/Exclusion Criteria 
X 
Demographics and Medical History 
X 
Prior and Concomitant Medication Review 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
Trial Treatment Administration 
Xf 
X 
X 
X 
X 
X 
X 
X 
Subsequent Anticancer Therapy Status 
X 
X 
Survival Status 
X 
Clinical Procedures/Assessments 
Adverse Events Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
Xg 
Full Physical Examinationh 
X 
X 
Directed Physical Examinationh 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs and Weighti 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
 
 

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Trial Period: 
Screening 
Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Screening 
(Visit 1) 
1 
2 
3 
4 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow- 
upb 
Follow Up 
Visitsc 
Survival 
Follow-Up 
5 
6 
7 
8 
Scheduling Window (Days): 
-21 to -1 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
from last 
dose 
(± 3 days) 
Every 
12 weeks 
post last 
dose 
(± 7 days) 
Every 6 
months (± 
14 days) or 
by phone 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
Xj 
X 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
CBC with Differentiall 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
Comprehensive Chemistry Panell 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
Urinalysisl 
Xk 
 
Xn 
 
Xn 
X 
Xm 
FT4 and TSHl 
Xk 
 
 
X 
 
X 
X 
Xm 
Testosteronel 
Xk 
Xo 
Xo 
Xo 
Tumor Marker Assessment (PSA)p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Efficacy Measurements 
Tumor Imaging 
Xq 
 
Xp 
 
Xr 
Xs 
Tumor Tissue Collection/Correlative and Biomarker Studies 
Tumor Tissue Collection (Newly Obtained and 
Archival) 
Xt 
 
 
 

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a. 
All treatment cycles are 2 weeks ± 3 days. 
b. 
If a subject initiates a new anti-cancer therapy within 30 days after the last dose of trial treatment, the 30-day Safety Follow-up visit must occur before the start of the 
new therapy. Once new anti-cancer therapy has been initiated the subject will move into survival follow-up. 
c. 
Follow-up visits must occur every 12 weeks (84 days ± 7 days) from the date of last dose of study treatment for up to 1 year. In subjects who discontinue study 
therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic imaging (CT/MRI and bone 
scans) and PSA every 12 weeks until: 1) the start of new anti-cancer treatment, 2) documented disease progression, 3) death or 4) the end of the study, whichever 
occurs first. 
d. 
Written consent must be obtained prior to performing any protocol specified procedures. Results of a test performed prior to the subject signing consent are acceptable 
in lieu of new screening tests if they are a part of routine clinical management and performed within the specified timeframe. 
e. 
Prior medications: record all medications taken within 28 days prior to the first dose of trial treatment. Concomitant medications: all medications started during the trial 
and up to 30 days after last dose of trial treatment regardless of when the safety follow-up visit occurs. All medications related to reportable SAEs should be recorded. 
f. 
Trial treatment should begin on the day of treatment allocation or as close as possible to the date on which the subject is allocated. 
g. 
Record all AEs occurring up to 30 days after the last dose of trial treatment. SAEs must be recorded up to 90 days after the last dose of trial treatment or until the start 
of new anti-cancer treatment, whichever comes first. Treatment related SAEs must always be reported within 24 hours. 
h. 
A full physical exam will be performed at screening and at treatment discontinuation; all treatment visits will include a directed physical exam. 
i. 
Height will be measured at screening only. 
j. 
ECOG Performance Status will be performed on day 1 at every other cycle and at treatment discontinuation. 
k. 
Laboratory procedures at screening are to be performed within 10 days prior to the first dose of trial treatment. 
l. 
After Cycle 1, pre-infusion laboratory procedures may be conducted up to 72 hours pre-infusion, labs are specified in section 8.7; table 5. 
m. Unresolved abnormal lab results associated with drug-related AEs should be followed until resolution. 
n. 
Urinalysis and thyroid function testing are done at screening, every 4 cycles or 8 weeks, treatment discontinuation, and the safety follow-up visit. 
o. 
Testosterone will be done at screening, every fourth cycle (Cycles 4, 8, 12,…) and at treatment discontinuation 
p. 
Imaging assessments (CT/MRI and bone scans) and PSA should be performed every 12 weeks, at treatment discontinuation and during follow-up. The timing of these 
assessments should not be adjusted for dose delays or cycle starts. 
q. 
The initial tumor imaging will be performed within 28 days prior to the first dose of trial treatment. Scans performed as part of routine clinical management are acceptable 
for use as the screening scan if they are of diagnostic quality and performed within 28 days prior to the first dose of trial treatment. 
r. 
If a scan was obtained within 4 weeks prior to treatment discontinuation, then another scan at discontinuation is not mandatory. Radiological evaluation should be repeated 
Trial Period: 
Screening 
Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
 
Treatment Cycle/Title: 
Screening 
(Visit 1) 
1 
2 
3 
4 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow- 
upb 
Follow Up 
Visitsc 
Survival 
Follow-Up 
5 
6 
7 
8 
 
 
 
Scheduling Window (Days): 
-21 to -1 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
from last 
dose 
(± 3 days) 
Every 
12 weeks 
post last 
dose 
(± 7 days) 
Every 6 
months 
(± 14 days) 
or by 
phone 
Blood for Genetic Analyses 
Xu 
Tumor BROCA Testingv 
X 
 
 
 
 
Blood for ctDNA (plasma)w 
X 
 
X 
 
X 

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at treatment discontinuation in subjects discontinuing without confirmed disease progression (date of discontinuation ± 4 weeks). 
s. 
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic 
imaging (CT/MRI and bone scans) and PSA (every 12 weeks from the date of last dose of study treatment) until: 1) the start of new anti-cancer treatment, 2) documented 
disease progression, 3) death or 4) the end of the study, whichever occurs first. 
t. 
Baseline tumor tissue for biomarker analysis from an archival tissue sample and/or newly obtained core or excisional biopsy from non-radiated metastasis may be obtained 
for correlative studies for responders. Refer to Section 9. 
u. 
Blood will be collected to obtain genetic analyses at time of initial treatment and run on patients responding 
v. 
Tumor BROCA testing will be performed on all feasible samples if patient agreeable to additional testing. This is not a requirement to participate in this study. 
w. Blood for cfDNA will be obtained every 3 months IF feasible for Guardant 360 testing on responders, once confirmed  

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8.0 DETAILED STUDY DESIGN 
 
8.1 
Informed Consent 
 
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place. 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use. The subject or his/her legally acceptable 
representative should be informed in a timely manner if additional information becomes 
available that may be relevant to the subject’s willingness to continue participation in the 
trial. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the subject’s dated 
signature or by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level. 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 
8.2 Inclusion and Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial. 
 
8.3 Assignment of Treatment Number 
All eligible subjects will receive a treatment number. The treatment number identifies the 
subject for all procedures occurring after treatment allocation. Once a treatment number is 
assigned to a subject, it can never be re-assigned to another subject. Treatment numbers 
will begin with 001.  If a patient is a screen failure, they will be assigned the next number in 
sequence, and that number will not be replaced. 
A single subject cannot be assigned more than 1 treatment number. 

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8.4 Medical History 
A medical history will be obtained by the investigator or qualified designee. The medical 
history will include all active conditions and any conditions diagnosed within the prior 10 
years that are considered clinically significant by the Investigator. Details pertaining to the 
subject’s prostate cancer diagnosis will be recorded separately and not listed as medical 
history. 
8.4.1 History of Prostate Cancer 
The investigator or qualified designee will obtain information regarding the subject’s prostate 
cancer. This information will include but is not limited to the presentation at primary 
diagnosis, date and stage at primary diagnosis, date of and stage at most recent recurrence, 
and location of metastases at screening (if applicable). 
8.4.2 Prior Treatment for Prostate Cancer 
The investigator or qualified designee will review and report all prior treatments to prostate 
cancer including systemic treatments, radiation, and surgeries. 
 
8.5 Prior and Concomitant Medications  
8.5.1 Prior Medications 
The investigator or qualified designee will review and record prior medication taken by the 
subject within 28 days prior to the first dose of trial treatment. 
8.5.2 Concomitant Medications 
The investigator or qualified designee will record medications taken by the subject during the 
trial up to 30 days after the last dose of trial treatment. All medications related to reportable 
SAEs should be recorded. 
 
8.6 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-cancer therapy initiated after 
the last dose of trial treatment. If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30-day Safety Follow-up visit must occur before the 
start of the new therapy. Once new anti-cancer therapy has been initiated, the subject will 
move into survival follow-up. 
 
8.7 Clinical Procedures/Assessment

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8.7.1 
Adverse Event Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated. Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 5.0 (see Appendix C). Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment. 
All AEs of unknown etiology associated with avelumab exposure should be evaluated to 
determine if they are events with potential immunologic etiology. See Section 6.3 Table 3 
regarding the identification, evaluation, and management of AEs of a potential 
immunological etiology. 
Please refer to Section 6.11 for detailed information regarding the assessment and recording of 
AEs within 24hours. 
 
8.7.2 Physical Exam 
8.7.2.1 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period and at treatment discontinuation. Clinically significant abnormal findings at 
screening should be recorded as medical history. New clinically significant abnormal findings at 
treatment discontinuation should be recorded as AEs. 
8.7.2.2 Directed Physical Exam 
The investigator or qualified designee will perform a directed physical exam, as clinically 
indicated, prior to dosing on Day 1 of each treatment cycle. New clinically significant 
abnormal findings should be recorded as AEs. 
8.7.2.3 Vital Signs 
The investigator or qualified designee will assess vital signs at screening, prior to dosing on 
Day 1 of each treatment cycle and at treatment discontinuation. Vital signs include 
temperature, heart rate, respiratory rate, weight and blood pressure. Height will be measured at 
screening only 
8.7.3 12-Lead ECG 
A standard 12-lead ECG will be performed once at the screening visit using local standard 
procedures. Clinically significant abnormal findings should be recorded as medical history. 
8.7.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG Performance Status at screening 
and prior to dosing on Day 1 of each treatment cycle, and at treatment discontinuation.  
This scale can be found for reference in appendix D. 

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8.7.5 
TUMOR IMAGING AND ASSESSMENT OF DISEASE 
Tumor imaging should be acquired by computed tomography (CT, strongly preferred) and 
radionuclide bone scan. Magnetic resonance imaging (MRI) should be used where CT is 
contraindicated or for imaging in the brain. The same imaging technique regarding modality 
and use of contrast should be used in a subject throughout the trial to optimize the 
visualization of existing and new tumor burden. Tumor imaging by both CT (or MRI) and 
radionuclide bone scan is required at every scheduled imaging time point. 
8.7.5.1 Initial Tumor Imaging 
Initial tumor imaging at screening must be performed within 28 days prior to the date of first 
dose of trial treatment. Tumor imaging by both CT (or MRI) and radionuclide bone scan is 
required at screening. 
Scans performed as part of routine clinical management are acceptable for use as the screening 
scans if they are of diagnostic quality, performed within 28 days prior to the date of first 
dose of trial treatment. 
At screening, all lesions seen by CT (or MRI) and radionuclide bone scan will be 
documented. In determining response to treatment or progression, investigators must evaluate 
all target and non-target lesions and search for new lesions at each imaging time point. 
8.7.5.2 Tumor Imaging During Trial 
On study imaging assessments must be performed every 12 weeks (± 7 days). Imaging timing 
should follow calendar days from date of allocation and should not be adjusted for delays in 
cycle starts. 
1. RESPONSE 
Per RECIST 1.1, response should be confirmed by a repeat radiographic assessment not 
less than 4 weeks from the date response was first documented. The scan for 
confirmation of response may be performed ≥ 4 weeks after the first indication of 
response or at the next scheduled scan, whichever is clinically indicated. Subjects who 
obtain a repeat scan do not need to undergo the next scheduled imaging if it is < 4 weeks 
after the confirmation scan. Subjects will return to their regular imaging schedule starting 
with the next time point. 
2. PROGRESSION 
Radiographic progression for soft tissue lesions will be determined according to RECIST 
1.1 (see appendix A). Disease progression in soft tissue lesions should be confirmed by the 
site ≥ 4 weeks after the first radiologic evidence of PD. Subjects who have unconfirmed 
disease progression and are clinically stable may continue treatment at the discretion of 
the investigator until progression is confirmed by the site. Subjects who obtain a repeat 
scan do not need to undergo the next scheduled imaging if it is < 4 weeks after the 
confirmation scan. Subjects will return to their regular imaging schedule starting with the 

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next time point. Subjects who have confirmed disease progression, as assessed by the 
site, will discontinue treatment. 
Radiographic progression for bone lesions will be determined as described in the 
consensus guidelines of the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) 
(see appendix B).  
If a subject with confirmed radiographic progression is clinically stable or clinically 
improved, and there is no further increase in the tumor dimensions at the confirmatory 
scan, an exception may be considered to continue treatment.  
Imaging should continue to be performed until documented disease progression, the start 
of new anti-cancer treatment, withdrawal of consent or death, whichever occurs first. 
 
Table 4.  Imaging and Treatment after 1st Radiologic Evidence of PD 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD 
Repeat imaging 
at  > 4 weeks to 
confirm PD 
(soft-tissue 
progression) 
Repeat bone 
scan at > 6 
weeks to 
confirm PD 
(bone 
progression) 
May continue 
study treatment 
at the 
Investigator’s 
discretion while 
awaiting 
confirmatory 
scan 
Repeat imaging 
at  > 4 weeks to 
confirm PD if 
possible (soft- 
tissue 
progression) 
Repeat bone 
scan at > 6 
weeks to 
confirm PD if 
possible (bone 
progression) 
Discontinue 
treatment 
Repeat scan 
confirms PD 
No additional 
imaging required 
Discontinue 
treatment 
No additional 
imaging required 
N/A 
Repeat scan 
shows SD, PR 
or CR 
Continue 
regularly 
scheduled 
imaging 
assessments 
every 12 
weeks 
Continue study 
treatment at the 
Investigator’s 
discretion 
Continue 
regularly 
scheduled 
imaging 
assessments 
every 12 
weeks 
 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per Investigator’s 
discretion 
*clinically stable subjects should have repeat imaging and may stay on treatment at the discretion of the 
investigator 
8.7.6 End of Treatment and Follow-up Tumor Imaging 
 

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In subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation (± 4 week window). If a previous scan was obtained within 4 
weeks prior to the date of discontinuation another scan at treatment discontinuation isn’t 
mandatory. In subjects who discontinue trial treatment due to documented disease 
progression, this is the final required tumor imaging. 
In subjects who discontinue trial treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by tumor imaging using the 
same imaging schedule the subject was on during treatment (every 12 weeks after the date 
of last dose) until: 1) the start of new anti-cancer treatment, 2) disease progression, 3) 
death or 4) the end of the study, whichever occurs first. 
8.7.7 Treatment Beyond Progression 
 
When feasible, subjects should not be discontinued until progression is confirmed by the 
local site investigator/radiology assessment. This allowance to continue treatment despite 
initial radiologic PD takes into account the observation that some subjects can have a transient 
tumor flare in the first few months after the start of immunotherapy and then experience 
subsequent disease response and/or may have radiographic progression that is not 
clinically significant. Subjects that are deemed clinically unstable are not required to have 
repeat tumor imaging for confirmation of PD.  
In subjects who have shown initial evidence of radiological PD by RECIST 1.1, it is at the 
discretion of the PI whether to continue a subject on study treatment until repeat imaging is 
obtained. This clinical judgment decision by the site investigator should be based on the 
subject’s overall clinical condition, including performance status, clinical symptoms, and 
laboratory data. Subjects who are clinically stable may continue receiving study therapy. 
Clinically stable subjects should also have at the confirmatory scan no further increase in the 
target lesions, no unequivocal increase in non-target lesions and no additional new lesions 
develop (non-worsening PD) to continue study treatment. 
8.7.8 Tumor Marker Assessment (PSA) 
 
The initial Prostate-Specific Antigen (PSA) biomarker assessment at screening must be 
performed within 10 days prior to the date of initiation of treatment. 
On study PSA biomarker assessments must be performed every 2 weeks from the date of 
initiation of treatment and for as long as subject remains on treatment. PSA should be 
measured on day 1 of each cycle regardless of cycle delays.  
In subjects who discontinue trial treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by PSA biomarker 
assessments using the same schedule the subject was on during treatment (every 12 weeks 
from the date of last dose) until: 1) the start of new anti-cancer treatment, 2) disease 
progression, 3) death or 4) the end of the study, whichever occurs first 
 

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PSA progression will be defined as follows: 
1. For those with no PSA decrease from baseline, a rise in PSA of 25% or more (of at 
least 2ng/mL or more) construes progression at a time point 6 or more weeks after 
therapy initiation (and/or at least 3 treatment administrations of avelumab) 
For those with a PSA decrease after starting therapy, the PSA should rise 25% from the nadir (at 
least 2 ng/mL increase) with a confirmed increase 2 or more weeks later. 8.7.9 Sample testing 
for Ancillary studies 
8.7.9.1 Tissue for BROCA testing 
If tissue samples available, testing for BROCA will be performed in coordination with   
University of Washington Genetics and Solid Tumors Laboratory on all patients with response 
to treatment. If no tissue available, additional biopsy of new/viable progressing tumor will be 
considered but is not a requirement for study enrollment.  
8.7.9.2 ctDNA Sample testing for ancillary studies 
ctDNA will be obtained at time of enrollment or within 4 weeks of screening visit and then 
every 12 weeks +/- 2 weeks.  These samples will be stored on site as designated. Guardant 360 
test will be performed with each sample on those found to be responding to treatment at 8-12 
weeks.  
 
8.7.10 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)  
Table 5. Laboratory Tests  
Hematology 
Chemistry 
Urinalysis 
Other 
Platelet Count 
Alanine Aminotransferase 
(ALT) 
Protein 
Free Thyroxine (FT4) 
WBC (Total and 
Differential) 
Aspartate Aminotransferase 
(AST) 
Specific Gravity 
Thyroid Stimulating 
Hormone (TSH) 
Red Blood Cell 
Count 
Lactate Dehydrogenase 
(LDH) 
Microscopic Exam 
(If abnormal results are 
noted) 
Blood for Genetic 
Analysis 
Absolute Neutrophil 
Count 
Carbon Dioxidea 
(CO2 or bicarbonate) 
Testosterone 
Absolute 
Lymphocyte Count 
Calcium 
Prostate-Specific 
Antigen (PSA) 
Chloride 
BROCA testing 
(tissue) 
Glucose 
ctDNA testing 
Potassium 
 
Sodium 
 
Total Bilirubin 
Direct Bilirubin (If total 
Total protein 
Blood Urea Nitrogen 

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Creatinine 
Creatinine 
Creatinine 
Creatinine 
 
After Cycle 1, pre-dose laboratory procedures may be conducted up to 72 hours prior to 
dosing. Results of scheduled laboratory tests must be reviewed by the investigator or qualified 
designee and found to be acceptable prior to each dose of trial treatment. Any results 
found to be clinically unacceptable may be repeated, abnormal lab values should be recorded as 
AE and treated if necessary, and followed until resolution. 
 
8.8 Withdrawal/Discontinuation 
 
Subjects who discontinue/withdraw from treatment prior to completion of the treatment 
regimen should be encouraged to continue to be followed for all remaining study visits. 
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the End-of-Treatment visit should be performed at the time of discontinuation. 
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 6.7 – Safety 
Monitoring. 
 
8.9 Blinding/Unblinding 
This is an open label trial; there is no blinding for this trial. 
 
8.10 Post-Treatment 
Subjects will be required to return to clinic approximately 30 days after the last dose of trial 
drug for the post-treatment visit. If the post-treatment visit occurs less than 30 days after the 
last dose of trial drug, a subsequent follow-up phone call should be made at 30 days post the 
last dose of trial drug to determine if any adverse events have occurred since the post-trial 
clinic visit. 
8.10.1 Follow Up 
After the 30-day safety follow up, patients will enter the follow up phase of the study.  Follow-
up visits must occur every 12 weeks (84 days ± 7 days) from the date of last dose of study 
treatment for up to 1 year. In subjects who discontinue study therapy without documented 
disease progression, every effort should be made to continue monitoring their disease status by 
radiologic imaging (CT/MRI and bone scans) and PSA every 12 weeks until: 1) the start of 
new anti-cancer treatment, 2) documented disease progression, 3) death or 4) the end of the 

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study, whichever occurs first.  Once that patient experiences progression, they move into 
typical follow up procedures which will occur every 12 weeks.  
8.10.2 Survival Follow-up 
After completion of one year of follow up, all patients will move into survival follow up, 
where they will be contacted in clinic, or by telephone, every 6 months (+/- 14 days) to assess 
subsequent cancer therapies and survival.  This phase will continue until death, withdrawal of 
consent or end of study, whichever comes last.  
8.11  Simple Study Phase Flow Diagram 
Figure 2: 
 
9.0 STATISTICAL JUSTIFICATION 
 
9.1 Statistical Analysis Plan Summary  
 
The primary efficacy variable is the proportion of successes, where success for a patient is a 
decrease in PSA of at least 50% from baseline and/or a radiographic response using RECIST 1.1 
criteria. In the pre-expansion cohort, further development would not be indicated if certain 
thresholds are not met on at least two occasions. We expect that the response rate is at least 10-
20% in the general population based on prior PD-1 inhibitor data, and potentially higher in the 
AA population. Of note, we anticipate the majority of responses will occur within 8-12 weeks of 
treatment initiation.  
 
This trial will test the hypothesis using a two-stage minimax plan with a desirable response 
probability of  ≥ 20% in AA with a goal of 80% power and an undesirable response probability 
of  ≤ 5% with an alpha = 0.05.  
 
The pre-expansion cohort will enroll 13 patients to be treated with the trial drug for an 
anticipated 8-12 weeks. This study will be terminated if 0 subjects respond and further study will 
be deemed of little interest. If there are 1 or more responses in the pre-expansion cohort, the 
study will be expanded to a second stage, with a total of 27 evaluable African American patients 
enrolled. If the total number responding ≤ 3, that cohort will be terminated given further study 
will be deemed of little interest.  Evaluable patients are all those that have at least one PSA value 
Screening  
21 days (28 days 
for imaging) 
Enrollment     
 all screening 
procedures 
complete and all 
inclusion/exclusion 
criteria met 
 
Off Study- 
EOT 
At time of 
progression  
Treatment 
Per section 7.0, 
continues until 
confirmed 
disease 
progression (can 
continue past 
per PI decision)    
30 Day 
Safety 
F/U 
From date 
of last 
treatment 
 
Follow up 
Every 12 
weeks from 
last 
treatment, 
continues 
for 1 year.  
 
Survival 
Every 6 
months, in 
clinic or by 
phone until 
death  
 
 

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or radiographic assessment 8 or more weeks post initiation of treatment with avelumab; patients 
that progress or die earlier than 8 weeks are considered non-responders. 
 
Using this design, if the trial drug is ineffective, there will be a 0.0416 probability of concluding 
that it is effective (the target value is 0.050). If the trial drug is effective at the proposed response 
rate of at least 20%, there is a 0.1989 probability of concluding that it is not effective (the target 
value is 0.200).  
 
 
Study Design Overview 
Phase II Trial of Avelumab plus 2nd-generation ADT in AA 
Subjects with mCRPC   
Treatment Assignment 
All subjects will receive avelumab 10mg/kg mg administered 
intravenously (IV) every 2 weeks (Q2W). 
Statistical Justification 
No response in 13 patients in pre-expansion cohort excludes the 
possibility of a clinically relevant response rate of > 20%. 
Primary Endpoint(s) 
   PSA response > 50% at ≥ 8 weeks 
Secondary Endpoints 
PSA progression-free survival using PCWG3 criteria; radiographic PFS 
by PCWG3 criteria, OS, and safety as determined by CTCAE v4.0 
criteria 
Correlative studies 
We propose cfDNA, germline, and BROCA testing of tumors when 
feasible using either non-radiated primary or metastatic lesions for all 
responders.  
 
9.2 Primary Endpoint 
The primary endpoint is a PSA response at 8 weeks or greater from starting study treatment and 
with a minimum of 3 treatments administered. 
• A PSA response is defined as a ≥50% PSA decline at 8 weeks or greater from the 
time of starting study treatment. The two-stage minimax design of the study will 
be utilized to determine whether further investigation of the study drug is 
warranted.  
9.3 Secondary Endpoints 
The secondary endpoints are: 
• 
PSA progression-free survival (pPFS) defined as the time from enrollment until PSA 
progression by PCWG3 or death, whichever occurs earlier. Subjects without pPFS at the 
time of data cut-off will be censored at the date of last adequate cancer assessment. PSA 
progression-free survival will be reported using Kaplan-Meier estimates, with 95% CI for 
median time-to-event. 

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• 
Radiographic progression-free survival (rPFS) defined as the time from enrollment until 
radiographic progression by PCWG3 or death, whichever occurs earlier. Subjects without 
rPFS at the time of data cut-off will be censored at the date of last known to be alive. 
Radiographic progression-free survival will be reported using Kaplan-Meier estimates, 
with 95% CI for median time-to-event. 
• 
Overall survival (OS) defined as the time from enrollment until death on study.  Subjects 
who are alive at the time of data cut-off will be censored at the date of last known to be 
alive. OS will be reported using Kaplan-Meier estimates, with 95% CI for median time-
to-event. 
• 
Safety will be summarized by nature, severity, and frequency utilizing CTCAE version 
4.03. 

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10.0 REFERENCES 
 
1. Graff J et al. Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. 
Oncotarget, Vol. 7, No. 33; July 2016. 
 
2. Le DT et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 
372:2509, 2015. 
 
3. http://www.esmo.org/Oncology-News/Pembrolizumab-Receives-FDA-Breakthrough-
Therapy-Designation-in-Advanced-Colorectal-Cancer 
 
4. Dominguez-Valentin M et al. Frequent mismatch-repair defects link prostate cancer and 
Lynch syndrome. BMC Urology, 16:15, 2016. 
 
5. Raymond VM et al. Elevated risk of prostate cancer among men with Lynch syndrome. J Clin 
Oncol. 31:1713, 2013. 
 
6. Pritchard C et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate 
Cancer, NEJM, 375:443-53, 2016. 
 
7. Pritchard C et al. Complex MSH2 and MSH6 mutations in hypermutated microsatellite 
unstable advanced prostate cancer. Nature Communications, 5:4988, 2012.   
 
8. Kantoff PW et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl 
J Med 363: 411, 2010. 
 
9. McLeod et al. Abstract #953: Sipuleucel-T in African Americans: A subgroup Analysis of 
Three Phase 3 Trials of Sipuleucel-T in Metastatic Castrate Resistant Prostate Cancer; AUA 
Annual Meeting May 2012 
 
10. Sartor et al. Overall Survival Analysis of African American and Caucasian Patients 
Receiving Sipuleucel-T: Preliminary Data from the Proceed Registry. J Urol, Vol 197: 4, April 
2017. 
 
11. Escudier et al. Treatment Beyond Progression in Patients with Advanced Renal Cell 
Carcinoma Treated with Nivolumab in CheckMate 025. J Eur Uro 7319, April 2017. 
 
12. E.A. Eisenhauer et al. New Response evaluation criteria in solid tumors: Revised RECIST 
Guideline (version 1.1). EJC 45: 228-247, 2009.  
 
13. Scher et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated 
Recommendations from the Prostate Cancer Clinical Trials Working Group 3. JCO 34:12, 1402-
1418, 2016. 
 

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11. Appendices 
 
A. RECIST v1.1 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either CT or 
MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this study. 
As published in the European Journal of Cancer [12]. 
 
B.  Prostate Cancer Clinical Trials Working Group 3 
PCWG3 will be used in this study to assess PSA response.  
 
As published in Journal of Clinical Oncology (13) 
 
C. CTCAE v.0 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version .0 will be utilized for adverse event reporting. 
(https://evs.nci.nih.gov/ftp1/CTCAE/About.html) 
 
D. ECOG Performance Status 
 
GRADE ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
*Oken  M,  Creech  R,  Tormey  D,  et  al.  Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655 

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http://ecog-acrin.org/resources/ecog-performance-status 
 
E. Abiraterone 
 
Dosing and dose modifications will be up to prescriber’s discretion. Monitoring and 
modifications shall follow standard manufacturer’s recommendations which can be found at the 
following: 
 
https://www.zytiga.com/shared/product/zytiga/zytiga-prescribing-information.pdf 
 
F. Enzalutamide 
 
Dosing and dose modifications will be up to prescriber’s discretion. Monitoring and 
modifications shall follow standard manufacturer’s recommendations which can be found at the 
following: 
 
https://www.astellas.us/docs/us/12A005-ENZ-WPI.pdf 
 
G. Apalutamide 
 
 This section will be updated upon approval of commercial drug  
 
H. Darolutimide  
 
This section will be updated upon approval of commercial drug  
 

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I. Avelumab Pharmacy Manual 
 
Product Information 
Product name: 
Avelumab (MSB0010718C) 
Dosage/Strength:  
20mg/ml 
Purpose: 
Investigator Sponsored 
Study 
Administration Route: 
IV 
 
 
 
Pharmacy Manual  
Investigator Sponsored Study Use of Avelumab 
 
 
 
 
 
PDL-1 inhibition with Avelumab and concurrent second-
generation ADT in African Americans with castrate-resistant 
metastatic prostate cancer. 
 
MS100070-0011 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PURPOSE OF THE PHARMACY MANUAL  
The Pharmacy Manual summarizes the information collected during the Clinical Administration Study1 in order to 
support the preparation of the investigational medicinal product for use in an Investigator Sponsored Study setting by 
giving indication on handling instruction, approved ancillaries and in use stability. 
 
1.0 
DESCRIPTION OF THE INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
1.1 
General information:  
Avelumab drug product is a fully human antibody of the IgG1 isotype that specifically targets 
and blocks the ligand (PD-L1) for PD-1. 
Merck KGaA will package and distribute the IMP to sites via their distribution vendor - Fisher 
Clinical Services.  The IMP will be shipped in transport cool containers (2oC to 8oC) that are 
monitored with temperature control devices.  
1.2 
Pharmaceutical formulation:  
Avelumab is a sterile solution intended for intravenous (IV) infusion. 
1.3 
Description of the formulation: 
The investigational product avelumab is a sterile, clear, colorless and non-pyrogenic solution for 
intravenous infusion. 
It is presented in Type I glass vials filled with 10 mL of liquid (200 mg/vial), closed with a rubber 
septum and sealed with an aluminum flip off seal. 
Each single-use vial contains 200 mg of avelumab, formulated as a 20 mg/mL preservative-free 
acetate buffered solution at pH 5.2 in presence of Polysorbate 20 and Mannitol.  
This product requires further dilution prior to IV infusion.   
 
1.4 
Description of the infusion solution: 
Avelumab infusion solution should be prepared by dilution in 0.9% Sodium Chloride (Normal 
Saline) (or in 0.45% Sodium Chloride, only if the first option is not applicable). The verified 
avelumab concentration range in the infusion solution is 0.016 mg/mL to 8 mg/mL. 
 
 
 
 
 
 
 
                                                     
1 Study N° 60259: Clinical Administration Study of Anti PDL1 200mg/vial presentation for PhII/III  

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2.0  
DETERMINATION OF SUBJECT DOSE (see Annex 4 for worksheet) 
Dosing calculation: 
The required dose (mg) is based on the patient’s bodyweight (kg) at each visit, unless otherwise indicated in the study 
protocol. 
 
Step 1:  Calculation of Dose 
Equation 1:  Required dose (mg) = 10 (mg/kg) x patient weight (kg) 
 
For example:  For a patient weighing 75 kg: 
Required dose (mg) = 10 mg/kg x 75 kg = 750 mg 
 
Step 2: Calculation of Number of Vials 
Calculate the required number of avelumab drug product (DP) vials.  Round up to the next whole number of vials.   
 
 
Equation 2: 
# of assigned vials for DP =   
Required dose from 𝐄𝐄𝐄𝐄𝐄𝐄𝐄𝐄𝐄𝐄𝐄𝐄𝐄𝐄𝐄𝐄 𝟏𝟏 (𝐦𝐦𝐦𝐦)
200 (mg/vial)
 
 
For example:  
# of assigned vials for DP =  
750 mg
200 mg/vial = 3.75 vials 
 
 
Rounded up to the next whole number = 4 vials 
 

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3.0 
PREPARATION FOR USE 
3.1 
General Instructions: 
 
To prepare the dilutions, subsequent preparation steps must be accomplished by adequate trained 
personnel to guarantee the sterility of the product to be injected. 
Preferred method is to prepare the solution under laminar flow box using aseptic techniques. If a 
laminar flow box is unavailable, alternative procedures and aseptic handling techniques in place that 
prevent microbiological contamination may be used. 
Only the necessary materials should be present in the working area during each preparation step.   
Only clinical site personnel who are appropriately trained on the procedure detailed in this document 
may perform the preparation and administration procedures specified in this manual. Clinical site 
personnel involved in these procedures must comply with all applicable regulations and standards.   
Utilize local site procedures as appropriate.   
 
Safety Precautions: 
 
Handling Information:  Recommendation in the Safety Data Sheet (SDS) should be followed.  The 
SDS will be provided separately.   
 
Safety Equipment Used:  Appropriate gowning and footwear as per local site procedures. 
 
3.2 
Calculation of Volume of Avelumab and Normal Saline Required 
Based on a total infusion volume of 250 mL, calculate the volume of avelumab and Normal Saline 
required to prepare the infusion bag: 
 
 
Equation 3: 
Volume of avelumab(mL) =  
Required dose from 𝐄𝐄𝐄𝐄𝐄𝐄𝐄𝐄𝐄𝐄𝐄𝐄𝐄𝐄𝐄𝐄 𝟏𝟏 (mg) 
20mg
 mL
 
 
Equation 4: 
Volume of Normal Saline (mL) = 250 mL – Volume of avelumab (from Equation 3) 
 
For example: 
Using the same examples as above: 
Volume of avelumab (mL) =  
750 mg 
20mg
 mL
  =  37.5 mL (Round to the nearest tenth place #.X) 
 
Volume of Normal Saline (mL) = 250 mL – 37.5 mL = 212.5 mL (Round to the nearest whole number) 
 

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3.3 
Preparation of Dosing Solution 
A. Ensure that all materials (see Annex 2 for list of approved ancillary materials) and equipment 
required are available before starting the dose preparation 
B. Remove the vial(s) required for the dose to be prepared and allow the vial(s) to reach room 
temperature prior to preparing dose for 30 (+20) minutes 
C. Gently invert the vial(s) several times before use.  Do NOT shake or agitate vigorously.   
D. Follow the preparation steps below according to the type of IV infusion bag used for dose 
preparation.  Refer to Annex 3 for additional examples.   
 
If using an empty IV infusion bag: 
1. Add the volume of Normal Saline* calculated in Equation 4 to the appropriate sized 
empty bag using appropriately sized syringes with 18-22G needle(s) (preferably 18G 
needles). 
2. Add the volume of avelumab (mL) calculated in Equation 3 to the bag containing 
Normal Saline* using a new appropriately sized syringe(s) with 18-22G needle(s) 
(preferably 18G needles).   
 
If using a pre-filled Normal Saline* IV infusion bag§: 
1. Remove a volume corresponding to the volume of avelumab (mL) calculated in 
Equation 3 from the pre-filled bag containing Normal Saline using an appropriately 
sized syringe with 18-22G needles (preferably 18G needles). 
2. Add the calculated volume of avelumab (mL) from Equation 3 to the pre-filled bag 
containing Normal Saline* using a new appropriately sized syringe with an 18-22G 
needle(s) (preferably 18G needles).  
 
* Note: The standard solution to be used for the dilution is 0.9% saline solution. Only if this solution is not 
available, 0.45% saline solution may be used. 
 
§ Note: if the bag is pre-filled with more than 250 mL (for example, 500 mL), discard the excess volume of saline 
solution.  This option should be considered only if 250 mL bags are not available.   
 
E. Gently invert the prepared IV bag 10 times to mix.  Do NOT shake. 
F.  Attach appropriate label to the IV infusion bag. 
 
For any site whose local/institutional guidelines require the use of an over-fill infusion preparation 
procedure, the local/institutional guidelines may be used provided the following requirements are 
fulfilled: 
o 
An infusion bag large enough to hold the final volume of prepared product is used  
o 
The dose calculation performed to determine the concentration of avelumab drug product is 
to be based on the total volume of the preparation specified in this manual. The over-fill has 
to be calculated using the same concentration  
o 
A copy of the protocol used for over-fill infusion preparation will be maintained in the 
pharmacy records 
Document the actual dose administered and amount of required over-fill in the pharmacy records. 
 
 

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4.0 
ADMINISTRATION INSTRUCTIONS 
The administration must be performed by adequately trained personnel.  Prior to dosing the subject, adhere to 
normal standard of care and aseptic techniques.   
 
The prepared avelumab dosing solution for infusion is connected to the infusion set equipped with a 0.2 micron PES 
(or PSU but only if PES membrane is not available) in-line filter and an appropriate gauge standard venous catheter 
for the subject. Alternatively, a permanent venous catheter or implantable port may be used. Prior to infusion, prime 
the assembly with the dosing solution. 
 
Set the infusion pump to deliver the entire infusion volume over 1 hour (-10/+20 minutes).   A constant infusion rate 
is achieved by using a microprocessor-controlled infusion pump. 
Immediately following the infusion of avelumab, it is recommended (but not mandatory) to conduct a normal saline 
flush using the same tubing and 25-100 mL normal saline infused at the same rate to clear the infusion set of residual 
drug. 
 
Document administration details in the pharmacy records.  
 
 
5.0 
STORAGE AND IN-USE STABILITY 
Drug Product Vials 
 
Storage conditions:  
MSB0010718C drug product must be stored in the original packaging at refrigerated conditions (2- 8°C, 36-46°F) 
until use with a temperature log maintained daily. The storage condition is based on data from ongoing long term 
stability studies with avelumab.  
 
Avelumab drug product stored at room temperature (15-25°C, 59-77°F) or higher temperatures for extended periods 
of time might be subject to degradation.  
 
Avelumab drug product must not be frozen. 
 
In the event of a temperature excursion: 
 
• 
Inform Fisher Clinical Services immediately by sending a Temperature Excursion Form (provided separately) 
to  AvelumabTemperatureExcursion@thermofisher.com  
 
And 
 
• 
Quarantine vials until further approval for use is received     
 

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Handling conditions:  
Prior to the preparation of the dilution for final infusion, allow each vial to equilibrate to room temperature (15-
25°C, 59-77°F) preferably for 30-50 min. 
 
Rough shaking of the solution must be avoided. Addition of other medication to the infusion containers containing 
avelumab must be avoided.  
 
Retention of Drug Product Vials: 
All opened vials (full, partially full, and empty) may be destroyed at the site by the appropriate site personnel (e.g., 
pharmacist, study nurse/coordinator) following local environmental requirements and institutional policies.  All 
destruction must be fully documented at the time of destruction on the investigational product accountability log, or 
equivalent document at the time of destruction. 
 
If opened vials are not destroyed immediately following drug preparation, opened vials must be stored in sealed, 
clear plastic bags until destruction.   
 
All unopened vials must be destroyed at the end of the treatment period unless Merck KGaA provides 
separate instructions for return. 
 
Prepared Dosing Solution ready to be injected 
Avelumab drug product must be diluted with a Normal Saline solution (Sodium Chloride for injection). 
 
Immediate administration of the prepared dosing solution is preferred. 
 
In case prepared dosing solution cannot be administered immediately after preparation, the acceptable holding time 
is: no more than 8 hours at room temperature (15-25°C, 59-77°F), including infusion time, or no more than 24 
hours under refrigerated conditions (2-8°C, 36-46°F), including infusion time.  
 
If stored under refrigerated conditions, allow each bag to equilibrate to room temperature (15-25°C, 
59-77°F), preferably for one hour before administration.  
 
If not used following the indications reported in this Pharmacy Manual, in-use storage times and conditions prior 
to administration are the responsibility of the user.   
 
Vehicular Transport of Prepared Dosing Solution ready to be injected 
Vehicular transport of the prepared avelumab diluted solution from a compounding facility to a clinical centre is 
not recommended: it could cause a non-controlled rough shaking of the solution, that can induce aggregation of the 
medication. 
 
In case remote preparation of the dosing solution and transport by vehicle cannot be avoided, certain requirements 
must be followed: 
 
• 
Transportation transit time of prepared infusion bag cannot be more than 22 hours, 
 
• 
Dosing solution must be controlled at refrigerated conditions (2- 8°C, 36-46°F) during transport. The time 
required to reach the target temperature (from 2-8°C to 25°C) may not be more than 3 hours 
 
• 
Dosing solution must be allowed to equilibrate to room temperature (15-25°C, 59-77°F), prior to 
administration, preferably for one hour before administration 
 

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6.0 
HISTORY OF CHANGES  
 
Document History 
Version 
Reason for Versioning 
Date 
V 1.0 
Issuing of new document (based on MOP v4.0) 
10 Jun 2016 
V 2.0 
Updated to align with v6 of the avelumab Manual of 
Preparation: 
 
MSB0010718C substituted with avelumab throughout 
document 
 
Par 2.0: update sentence linked to “dosing calculation” 
 
Par.5.0: Change in the holding time conditions for prepared 
solution for dosing based on new data from microbial 
challenge study. Update sentence linked to the “prepared 
dosing solution ready to be injected”.  Introduction of 
instruction for vehicular transport of 
prepared dosing solution ready to be injected 
09 May 2017 
 
 
 
 
 
 
• 
Transportation documentation, including transit time and temperature control, must be maintained in the 
pharmacy files. 
 
Retention of supplies: 
Normal saline solution may be disposed of according to local site procedures.  Other items used in the dose 
preparation and administration should be disposed of according to local site procedures.   

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ANNEX 1 
Glossary 
DP          
Drug Product 
EVA         Ethylene Vinyl Acetate 
IV             Intravenous 
PB            Polybutadiene 
PE            Polyethylene 
PES          Polyethersulfone 
PP            Polypropylene 
PSU 
 Polysulfone 
PUR 
Polyurethane  
PVC         Polyvinylchloride 
 
ANNEX 2 
Approved materials 
All ancillaries made of the materials included in the following list, DEHP, latex free, FDA approved can be used. 
 
The use of 0.2 µm PES (polyethersulfone) in-line filters is mandatory. Alternatively, 0.2 µm PSU (polysulfone) in-
line filters can be used (PES to be preferred). 
List of approved materials: 
 
acronym  
material 
EVA  
ethylene vinyl acetate 
PB  
polybutadiene 
PE  
polyethylene 
PES  
polyethersulfone 
PP  
polypropylene 
PSU  
polysulfone 
PUR  
polyurethane 
PVC  
polyvinyl chloride  
Silicone 
silicone 
Titanium 
titanium 

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ANNEX 3 
Examples for target dose calculation (pre-filled 250 mL bags)* 
Dose 
level 
(mg/kg) 
Patient´s 
bodyweight 
(kg) 
Target dose for 
administration 
(mg) 
Volume of 
0.9% sodium 
chloride 
solution to be 
withdrawn 
from infusion 
bag  
(mL)  
Volume of 
avelumab drug 
product to be added 
to the infusion bag  
(mL) 
Final nominal 
volume for 
administration 
(mL) 
Final 
nominal 
avelumab 
concentration 
in the 
infusion 
solution 
(mg/mL) 
Number of 
DP vials 
required for 
preparation 
10 
40 
400 
20 
20 
250 
1.6 
2 
10 
120 
1200 
60 
60 
250 
4.8 
6 
10 
200 
2000 
100 
100 
250 
8.0 
10 
0.1 
40 
4 
0.2 
0.2 
250 
0.0016 
1 
 * Round to the nearest tenth place for DP volume to be added 
 
Examples for target dose calculation (empty 250 mL bags)* 
Dose 
level 
(mg/kg) 
Patient´s 
bodyweight 
(kg) 
Target dose for 
administration 
(mg) 
Volume of 
0.9% sodium 
chloride 
solution to be 
added to the 
empty 
infusion bag 
(mL)  
Volume of 
avelumab drug 
product to be added 
to the infusion bag 
 (mL) 
Final nominal 
volume for 
administration 
(mL) 
Final nominal 
avelumab 
concentration in 
the infusion 
solution 
(mg/mL) 
Number of 
DP vials 
required for 
preparation 
10 
40 
400 
230 
20 
250 
1.6 
2 
10 
120 
1200 
190 
60 
250 
4.8 
6 
10 
200 
2000 
150 
100 
250 
8.0 
10 
0.1 
40 
4 
249.8 
0.2 
250 
0.0016 
1 
 * Round to the nearest tenth place for DP volume to be added 

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ANNEX 4 
MSB0010718C (Avelumab) Intravenous Administration – Investigator Sponsored Study 
The appropriate details should be filled in here prior to dose preparation (or documented otherwise in the 
pharmacy files). 
 
Patient Name: ______________  Patient Date of Birth:  _______________  Patient Weight: ________ kg 
 
Equation 1:  Dose (mg) =      Subject Weight (kg)      x _____ mg/kg  =         Dose (mg)     mg 
 
Equation 2: Number of avelumab Vials =       Dose (mg)      /  200 mg/vial = _________ vial(s) 
 
Equation 3: Volume of avelumab (mL) =       Dose (mg)      /  20 mg/mL  = (Round to the nearest tenth place)  mL 
 
Equation 4: Volume of Normal Saline (mL) = 250 mL -  (from Equation 3)    = (Round to the nearest whole number) mL 
 
Date of dose preparation: ___________________ (dd-mmm-yyyy)  
 
Time at start of dose preparation: _____________(hh:mm)   □ AM □ PM 
 
Expiry Date and Time of Prepared Dose: 
 
Expiry Date: __________________ (dd-mmm-yyyy)   Expiry Time: _____________(hh:mm)   □ AM □ PM 
The expiry time is 24 hours from the time the vials were removed from the refrigerator and allowed to reach room temperature 
 
Calculation by (Print Name and initials): ________________________ Date: __________(dd-mmm-yyyy)  
Verified by (Print Name and initials): ________________________ Date: __________(dd-mmm-yyyy)  
 
Instructions for Preparation 
Data 
Indicated type and volume of bag used for dose preparation 
□ Empty: _______ mL Bag 
□ Pre-filled: 0.9% NaCl _______mL Bag 
Volume of Normal Saline 
• Removed from a pre-filled bag (volume from Equation 3), OR 
• Added to an empty IV bag (volume from Equation 4  
 
___________ mL 
□  Removed       □  Added 
Volume of avelumab added to prepared IV bag (from Equation 3) 
___________ mL 
 
Prepared by (Print Name and initials): ________________________ Date: __________(dd-mmm-yyyy)  
Verified by (Print Name and initials): ________________________ Date: __________(dd-mmm-yyyy)  
 

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Contact the responsible Treating Physician immediately to report any                                                               
dose preparation and administration deviations. 
Comments on dose preparation (record any deviations from Pharmacy Manual instructions; storage time, conditions, 
etc.): 
 
 
 

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J. Reporting, Assessment And Close Out of Temperature Excursion  
REPORTING, ASSESSMENT AND CLOSE OUT OF TEMPERATURE 
EXCURSIONS - Avelumab Investigator Sponsored Study 
Please complete Section 1, print, sign and scan, then send to:  AvelumabTemperatureExcursion@thermofisher.com 
Section 1 : Report (ALL excursions) 
Protocol N°/Trial No ( as applicable/if applicable): 
Reporting Unit/Site/Depot/CMO: Site 
(include Site Name/Country as applicable / if applicable):       
Product (DS/DP/IMP/NIMP):       
Batch N°:       
Presentation:       
Kit or patient N° (only IMP):       
Quantity of product affected:       
Excursion occurred during: 
 Transport  
 Storage (CMO/Warehouse)  
 Storage (CMO/Depot)  
 Storage (CRO/ Site) 
Apparent Cause: 
 Temperature deviation during storage/transport 
 Refrigerator, cold room, air-conditioning problems 
 Power failure 
 Other 
Description of Excursion :  
Date :       
Temperature :       
Duration :       
Documentation Attached  
 No, justification………………………. 
 Yes  (please list) 
Comments / Emergency Action Taken:       
 
 
 
Datalogger nr.:       
Person reporting the temperature excursion event  
Name/Function/Site:       
                                             
Signature : 
                                             
Date : 
 

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Section 2 – ASSESSMENT (All excursions) 
Assessment Visual Appearance: 
  Container contents 
  Primary packaging 
  Secondary packaging 
Data Assessment : 
  Complies with Transport and Storage Conditions  
  Data shows allowable excursion only  
Result of Assessment by QP/Authorised/Delegate/QC:  
 Allowable Temperature Excursion – material can be confirmed for intended use, e.g. clinical use 
(Section 3 and 4 are not applicable) 
 Critical Temperature Excursion - requires Assessment/Investigation and decision by QP  
(See Page 2 of 2).  
EMD Serono Trackwise reference:       
(for critical deviations only, not relevant for Trial Sites/CROs) 
Comments:  
QP/Authorised/Delegated/QC:  
Name & Function :       
                           Signature : 
                                                    Date 
 
If assessed as allowable excursion, please send the close out to fax n° :       
 
Section 3 – Investigation 
(Critical Temperature Excursions only) 
EMD Serono Trackwise Deviation Reference (not relevant for site/CROs):  
 
Excursion Report Reference :  
Documentation Reviewed:  
      
 
Record of storage history:  YES 
 
NO 
 
Data to support the deviation:  
 
 
 
 

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SECTION 4 - CLOSE OUT (Critical Temperature Excursions only) 
Final Conclusion:  
      
 
The product involved in the deviation can be used: YES 
 NO 
 (Tick the relevant box ) 
Comment:  
      
 
 
Qualified Person Close Out: 
Name :          
 
Signature: 
 
 
 
Date(data): 
 
PDL-1 inhibition with Avelumab and concurrent second-generation ADT in African Americans 
with castrate-resistant metastatic prostate cancer.