Conditions: Prostate Cancer Recurrent Prostate Carcinoma Stage IV Prostate Adenocarcinoma
Keywords: Hormone-Resistant Prostate Cancer Prostate Carcinoma Metastatic in the Bone
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

Brief summary:
This phase II trial studies how well nivolumab and ipilimumab work in treating patients with hormone-resistant prostate cancer that has spread to other places in the body and express androgen receptor-variant-7 (AR-V7). Tumor cells expressing AR-V7 has been shown to be resistant to hormone therapy and some chemotherapy in patients with prostate cancer. Biomarker-driven therapy, such as nivolumab and ipilimumab, may work by blocking key biomarkers or proteins that help tumor cells to escape the immune system surveillance and this may help the immune system to kill tumor cells that express AR-V7.

Detailed description:

Arms:
arm 1: Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every 3 weeks for 12 weeks. Patients then receive nivolumab IV over 60 minutes every 2 weeks for 36 weeks in the absence of disease progression or unacceptable toxicity. arm 2: Patients will continue on standard of care enzalutamide, with the addition of nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every 3 weeks for 12 weeks. Patients then receive nivolumab IV over 60 minutes every 2 weeks for 36 weeks in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Ipilimumab intervention 2: Nivolumab intervention 3: Enzalutamide
Intervention descriptions: intervention 1: Given 1 mg/kg IV intervention 2: Given 3 mg/kg IV intervention 3: given orally per standard of care

Protocol document:
Prot_SAP_000.pdf: 
STARVE-PC 
Protocol Version 7 (Amendment 1) date: September 26, 2017 
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Biomarker-Driven Phase-2 Study of Combined Immune Checkpoint Blockade for AR-V7–
Expressing Metastatic Castration-Resistant Prostate Cancer (STARVE-PC) 
Johns Hopkins Kimmel Cancer Center 
IRB #: IRB00070748 
SKCCC Protocol #: J15119 
IND Sponsor-Investigator: Emmanuel Antonarakis 
IND number: 126838 
Principal Investigator 
Emmanuel Antonarakis, MD 
Johns Hopkins Kimmel Cancer Center 
Email: eantona1@jhmi.edu 
Drew Pardoll, MD PhD 
Johns Hopkins Kimmel Cancer Center 
email: dpardoll1@jhmi.edu 
 
Eugene Shenderov, MD PhD 
Johns Hopkins Kimmel Cancer Center 
Email: Eugene.Shenderov@jhmi.edu 
 
Valsamo Anagnostou, MD PhD 
Johns Hopkins Kimmel Cancer Center 
Email: vanagno1@jhmi.edu 
Statistician 
Brandon Luber, MS 
Hao Wang, PhD 
Johns Hopkins Kimmel Cancer Center 
Email: 
bluber1@jhmi.eduhwang76@jhmi.edu 
 
Project Manager 
Ting Wang, MS, MHS 
Johns Hopkins Kimmel Cancer Center 
Email: twang2@jhmi.edu 
Lead Study Coordinator: 
Rana Harb, MS 
Johns Hopkins Kimmel Cancer Center 
Email: rharb1@jhmi.edu 
 
 
 
 
 
 
 
 
Protocol Date: 9/26/17 
Amended Version Date:      CONFIDENTIALITY STATEMENT 
The information in this document is provided to you as an investigator, potential investigator, 
consultant, or contractor, for review by you, your staff, and the appropriate Institutional Review 
Board or Ethics Committee. By accepting this document, you agree that the information 
contained herein will not be disclosed to others without written authorization from the lead 
site/sponsor, except to the extent necessary to initiate the study or conduct study-related 
activities. 
NCT02601014


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SYNOPSIS 
Title 
Biomarker-Driven Phase-2 Study of Combined Immune Checkpoint Blockade 
for AR-V7–Expressing Metastatic Castration-Resistant Prostate Cancer 
(STARVE-PC) 
Lead site 
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center 
Collaborating 
sites 
Single-center study 
IRB # 
IRB00070748 
Investigational 
agents 
Ipilimumab 
Nivolumab 
Phase 
II 
Target 
population 
Men with progressive metastatic castration-resistant prostate cancer (CRPC) with 
detectable AR-V7 in CTCs 
 
Study centers 
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center 
Start 
date/Duration 
The start date for the study (first patient first visit) is anticipated to be September 
2015. 
The total duration of the study is expected to be approximately 24 months. All 
subjects will be followed up for 12 months after start of study treatment.  
Expected 
enrollment 
The study will enroll 15 evaluable patients, i.e. those positive for CTCs with 
detectable AR-V7. 
 
In cohort 2 (Amendment 1): The study will enroll 15 evaluable patients whose most 
recent therapy must be enzalutamide with progressive disease and enzalutamide 
will be continued.  
 
Rationale 
Escape from immune surveillance is a recognized feature of cancer growth and 
progression, and the clinical success of immune checkpoint blockade using 
monoclonal antibodies against CTLA-4 and PD-1 has been demonstrated in patients 
with melanoma, kidney cancer and lung cancer. It is now understood that CTLA-4 and 
PD-1 have complementary and non-overlapping roles in regulating adaptive immune 
responses. While PD-1 contributes mainly to T-cell exhaustion at peripheral sites, 
CTLA-4 inhibits T-cells at an earlier point in their maturation cycle. In preclinical 
models, combined blockade of both CTLA-4 and PD-1 resulted in more pronounced 
antitumor activity than blockade of either pathway alone. This principal has been 
exemplified in a clinical study of advanced melanoma patients, where the combination 
of ipilimumab (anti–CTLA-4) plus nivolumab (anti–PD-1) resulted in rapid and deep 
tumor regressions above and beyond those reported in prior trials of ipilimumab or 
nivolumab monotherapy. Promising results have also been seen with this combination 


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in kidney cancer. Importantly, the combination of ipilimumab and nivolumab is 
relatively safe, and immune-related adverse events are qualitatively similar to 
monotherapy treatments, and are generally reversible with steroid use. 
Biomarker-driven trials are sorely lacking in prostate cancer. AR-V7 is an androgen 
receptor splice variant that is missing the ligand-binding domain of AR (the target of 
androgens and antiandrogens) and remains constitutively active as a transcription 
factor in a ligand-independent fashion. We have recently shown that AR-V7 can be 
reliably detected at the mRNA level from circulating tumor cells (CTCs) in patients 
with metastatic CRPC, that AR-V7 is present in ~30% of men with mCRPC, and that 
AR-V7 expression is associated with primary and acquired resistance to both 
abiraterone and enzalutamide (Antonarakis et al. NEJM 2014). To this end, men with 
AR-V7–expressing mCRPC did not achieve biochemical or radiographic responses to 
abiraterone/enzalutamide, and had markedly inferior PFS and OS with 
abiraterone/enzalutamide compared to AR-V7–negative patients. In addition, 
emerging data suggest that expression of AR-V7 is also associated with resistance to 
taxane-based chemotherapy (Thadani-Mulero et al. Cancer Res 2014).  Therefore, 
developing effective treatments for AR-V7–associated mCRPC represents an urgent 
unmet medical need. In this regard, combined immune checkpoint blockade may be 
one such therapeutic approach for these patients. 
The potential clinical utility of immune checkpoint blockade in prostate cancer is 
exemplified by the use of ipilimumab in men with mCRPC (Kwon et al. Lancet Oncol 
2014). The collective aggregate of phase-2 and -3 data with ipilimumab monotherapy 
suggest a PS
 responserate (≥50% PSA reduction) of approximately 15%, and a 
radiographic response rate of about 5% among men with measurable soft-tissue 
disease. These results are distinct from those seen with active immunotherapies (e.g. 
sipuleucel-T, ProstVac-VF) in men with mCRPC, where PSA or tumor responses are 
only observed in <1% of patients. Furthermore, the clinical application of PD-1/PD-
L1–blocking antibodies in men with mCRPC is supported by data from our group and 
others showing that 1) prostate cancer cell lines can significantly up-regulate PD-L1 
expression when treated with IFN-γ in vitro; 2) treatment of the same cell lines with 
anti-androgens (including enzalutamide) can induce or increase PD-L1 expression; 
and 3) that enzalutamide-resistant prostate cancer cell lines demonstrate striking 
expression of PD-L1 (Bishop et al. Oncotarget 2004). Taken together, these data 
support a clinical paradigm in which combination immune checkpoint blockade with 
ipilimumab plus nivolumab is utilized in men with AR-V7–positive mCRPC. This study 
is driven by our novel data on AR-V7: we can use expression of this splice variant as 
evidence that these patients will not have any meaningful response to enzalutamide 
or abiraterone (i.e. PSA response rates approaching 0%). 
The primary hypothesis of the current study is that the combination of ipilimumab 
plus nivolumab will have a manageable safety profile, and will produce PSA responses 
in a significant proportion of patients with AR-V7–expressing mCRPC. In addition, we 
propose to serially examine AR-V7 status during the course of treatment with 
ipilimumab plus nivolumab, to determine how AR-V7 expression changes and 
correlates with PSA response. If the current study shows preliminary evidence of 
clinical activity, our ultimate goal is to compare the clinical efficacy of combined 


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checkpoint blockade versus abiraterone or enzalutamide in patients with AR-V7–
positive mCRPC. 
Objectives 
Primary efficacy objective: 
To evaluate PSA responses (>50% PSA decline) in mCRPC patients with detectable AR-
V7 transcript in CTCs  
In Cohort 2 (amendment 1): 
To evaluate PSA responses (>50% PSA decline) and/or Objective Response in mCRPC 
patients with detectable AR-V7 transcript in CTCs. 
Secondary safety objective: 
To evaluate the safety and tolerability of ipilimumab + nivolumab in AR-V7–positive 
patients 
 
Secondary correlative/biomarker objective: 
To evaluate changes in AR-V7 detection (or expression levels) before and after 
treatment with ipilimumab + nivolumab and correlate with PSA responses. 
Endpoints 
Primary Endpoint: 
PSA response rate (proportion of men with >50% PSA decline) 
In Cohort 2 (amendment 1): 
PSA response rate (proportion of men with >50% PSA decline) and/or Objective 
response rates (ORR) in patients with measurable disease. This is a composite 
endpoint. 
 
Key Secondary Endpoints: 
1. Frequency and intensity of adverse events (CTCAE v. 4) 
2. Proportion of patients converting from AR-V7–positive to –negative (or changes in 
AR-V7 expression) during treatment 
 
Additional Secondary Endpoints: 
3. PSA progression-free survival (PSA-PFS) [PCWG2 criteria] 
4. Clinical/radiographic progression-free survival (PFS) [PCWG2 criteria] 
5.“urablePS”,definedaslackofclinical/radiographicprogressionfor≥24weeks 
6. Objective response rates (ORR) in patients with measurable disease 


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7.  Response duration in patients who develop an objective response 
8. Overall survival (OS) 
 
Additional Exploratory/Correlative Endpoints: 
1. To explore the predictive value of baseline PD-L1 tumor expression in men 
with biopsy-amenable disease (or in CTCs) 
2. To explore the relationship between baseline tumor mRNA immune profiling 
panel and clinical outcomes. 
3. To explore the relationship between peripheral-blood absolute lymphocyte 
count (ALC) and clinical outcomes 
 
4. To explore the relationship between serum cytokine profiles and clinical 
outcomes 
 
5. To explore the relationship between serum antibody profiles and clinical 
outcomes 
 
6.  To explore the relationship between DNA damage repair mutations (including 
mutational load, hypermutation, and loss of heterozygosity) and clinical 
outcomes 
 
7.  To explore the relationship between MANAFEST assay and clinical outcomes 
 
Study Drug, 
Dosage, and 
Route of 
Administration 
 
Ipilimumab  1 mg/kg IV  +  Nivolumab  3 mg/kg IV, according to the schedule shown 
below 
Study design 
This will be a single-arm, open-label phase II trial.          
 
Administration of ipilimumab + nivolumab will generally follow the treatment 
protocol used in the phase 3 trials of concurrent ipilimumab/nivolumab: concurrent 
administration every 3 weeks for fourDoses, followed by nivolumab alone every 2 
weeks.  The dosing regimen of nivolumab 3 mg/kg combined with ipilimumab 1 
mg/kg was chosen because it exhibits similar clinical activity compared with 


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nivolumab 1mg/kg combined with ipilimumab 3 mg/kg along with a more favorable 
safety profile. 
Treatment will continue until week 48 or until radiographic progression or 
unmanageable toxicity. 
 
 
 
Correlative 
Research 
CTCs will be collected from participants at 3 time points: 
- 
Baseline 
- 
12 weeks 
- 
Progression 
 
At each time point, CTCs will be interrogated using qRT-PCR for the following 
transcripts: 
- 
AR-FL (full-length AR, i.e. wild type) 
- 
AR-V7 (AR splice variant-7) 
- 
PSA 
- 
PSMA 
- 
PD-L1 
Our primary correlative analysis will be to investigate the proportion of men who 
convert from AR-V7–positive at baseline to AR-V7–negative during/after therapy 
with ipilimumab/nivolumab (as well as changes in AR-V7 expression with 
treatment). We further plan to correlate changes in AR-V7 with PSA responses to 
ipilimumab + nivolumab. 
1 
4
1 
3
5 
1 


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We also plan to explore the predictive value of baseline PD-L1 expression at the 
mRNA level in CTCs and at the protein level in metastatic biopsies (from patients with 
biopsy-amenable disease) in the context of ipilimumab + nivolumab treatment.  We 
will also perform exploratory analyses of tumor immune-related mRNA expression, 
whole-exome tumor DNA sequencing, tumor RNA sequencing, and T-cell receptor 
(TCR) sequencing.   Lastly, we will explore the circulating cytokine and antibody 
profiles in serum.  
 
Statistical 
method 
Our primary efficacy hypothesis is that we will observe PSA responses (>50% PSA 
declines) in a significant proportion of patients treated with ipilimumab plus 
nivolumab. Because there are currently no effective AR-directed therapies for men 
with AR-V7–associated CRPC (and PSA response rates with enzalutamide/ 
abiraterone approach 0%), we would consider ipilimumab + nivolumab promising if 
the PSA response rate is higher than 5%. We plan to enroll 15 patients. If we observe 
≥3 PS
 responses in 15 patients, the lower bound of 90% confidence interval of
response rate would be above 5% (90% CI: 5.6% - 44%), and future study would be 
warranted.  
If we observe ≥3PSresponsesin15patients, we will proceed with subsequent 
largertrials.Ifwesee≤2outof15PS
responses, wewillconsiderthis therapy
unworthy of further study in AR-V7-positive mCRPC. 
 
For cohort #2 (amendment 1) 
Our primary efficacy hypothesis is that we will observe PSA responses (>50% PSA 
declines) and/or Objective response rates (ORR) in patients with measurable disease 
in a significant proportion of patients treated with ipilimumab plus nivolumab. 
Because there are currently no effective AR-directed therapies for men with AR-V7–
associated CRPC (and PSA response rates with enzalutamide/ abiraterone approach 
0%), we would consider ipilimumab + nivolumab promising if the composite endpoint 
of PSA response rate and/or ORR is higher than 5%. We plan to enroll 15 patients. If 
weobserve≥3PS
responses and/or ORR in 15 patients, the lower bound of 90% 
confidence interval of response rate would be above 5% (90% CI: 5.6% - 44%), and 
future study would be warranted.  
If weobserve≥3PS
responses and/or ORR in 15 patients, we will proceed with 
subsequentlargertrials.Ifwesee≤2outof15PS
responses and/or ORR, we will 
consider this therapy unworthy of further study in AR-V7-positive mCRPC. 
 
Safety analysis 
Standard safety summaries will be provided for treatment exposure, patient 
disposition, adverse events leading to discontinuation, serious adverse events, and all 
events resulting in death, including those up to 100 days after treatment 
discontinuation. The incidence of adverse events will be tabulated and reviewed for 
potential significance and clinical importance. 


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TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................................................................................... 11 
1.1 
Disease Background .......................................................................................................................................................... 11 
1.2 
Nivolumab .............................................................................................................................................................................. 13 
1.3 
Ipilimumab ............................................................................................................................................................................ 16 
1.4 
Benefits and Risks .............................................................................................................................................................. 16 
1.5 
Rationale and Dose Selection ........................................................................................................................................ 18 
2. 
OBJECTIVES ................................................................................................................................................................... 21 
2.1 
Objectives ............................................................................................................................................................................... 21 
2.2 
Endpoints ............................................................................................................................................................................... 21 
3. 
STUDY DESIGN ............................................................................................................................................................. 23 
3.1 
Study Design ......................................................................................................................................................................... 23 
3.2 
Schedule of Assessments ................................................................................................................................................ 25 
4. 
PATIENT SELECTION ................................................................................................................................................. 28 
4.1 
Target Population ............................................................................................................................................................... 29 
4.2 
Inclusion Criteria ................................................................................................................................................................ 29 
4.3 
Exclusion Criteria ............................................................................................................................................................... 31 
4.4 
Concomitant Medications ............................................................................................................................................... 33 
4.5 
Disallowed Concomitant Therapy .............................................................................................................................. 34 
5. 
STUDY DRUGS .............................................................................................................................................................. 34 
5.1  
Investigational Product ................................................................................................................................................... 34 
5.2  
Non-investigational Product ......................................................................................................................................... 34 
5.3 
Storage and Dispensing ................................................................................................................................................... 35 
5.4 
Administration ..................................................................................................................................................................... 35 
6 
STUDY PROCEDURES ................................................................................................................................................. 36 
6.1 
Screening/Pretreatment Assessment ....................................................................................................................... 36 
6.2 
Treatment/Intervention Period .................................................................................................................................. 37 
6.3 
Correlative/Special Studies ........................................................................................................................................... 40 
7 
DOSE ADJUSTMENT AND DELAY, TREATMENT DISCONTINUATION, WITHDRAWAL, AND 
TERMINATION CRITERIA ..................................................................................................................................................... 43 
7.1  
Dose adjustments ............................................................................................................................................................... 43 
7.2 
Dose delay and treatment discontinuation ............................................................................................................ 43 
7.3 
Dose Delay Criteria ............................................................................................................................................................ 43 
7.4  
 Criteria to Resume Treatment..................................................................................................................................... 44 
7.5         Discontinuation Criteria .............................................................................................................................................. 45 
7.6 
   Treatment of Nivolumab or Ipilimumab-Related Infusion Reactions .................................................... 45 
7.7     Treatment Beyond Disease Progression ............................................................................................................... 47 
7.8       
Immunotherapy Adverse Event Management ................................................................................................ 47 
7.9 
Removal of Subjects from the Study, Therapy Assessment ............................................................................ 47 
7.10       Treatment Compliance ................................................................................................................................................ 48 
7.11       Destruction of Study Drug .......................................................................................................................................... 48 
7.12   Return of Study Drug ........................................................................................................................................................ 48 
8 
ENROLLMENT PLAN ................................................................................................................................................... 48 
9  
SAFETY ............................................................................................................................................................................ 49 
9.2 
Assessment of AE; Seriousness, Causality, Severity and Expectedness .................................................... 52 
9.3 
Reporting of Adverse Events ........................................................................................................................................ 53 
9.4 
Reporting of Serious Adverse Events ........................................................................................................................ 54 
9.5 
Procedures to be Followed in the Event of Abnormal Laboratory Tests ................................................. 56 
9.6 
Other Safety Parameters Including Demographics ............................................................................................ 57 


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9.7 
Safety Monitoring ............................................................................................................................................................... 60 
10 
EFFICACY ASSESSMENT ............................................................................................................................................ 61 
10.1 PSA ............................................................................................................................................................................................ 61 
10.2 Secondary Endpoints ........................................................................................................................................................ 61 
11 
STATISTICAL CONSIDERATIONS ........................................................................................................................... 63 
11.1 Statistical Hypothesis and Sample Size .................................................................................................................... 63 
11.2 Analysis Populations ......................................................................................................................................................... 63 
11.3 Statistical Method ............................................................................................................................................................... 64 
12 
DATA REPORTING AND REGULATORY REQUIREMENTS ................................................................... 65 
12.1 Data Reporting and Regulatory Requirements .................................................................................................... 65 
12.2  Data Management ............................................................................................................................................................. 66 
12.3 Good Clinical Practice ....................................................................................................................................................... 67 
12.4  Record Retention ............................................................................................................................................................... 68 
13 
REFERENCES ................................................................................................................................................................. 68 
  
 
 


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1. 
INTRODUCTION 
1.1 
Disease Background 
Prostate cancer is the second most common cause of cancer deaths in men in the US. 
Approximately one in every six American men will be diagnosed with the disease during his 
lifetime [Siegel et al. Cancer Statistics 2012]. The disease continuum has been modeled as a 
series of states defined by the presence or absence of detectable metastases and whether 
testosterone levels are in the castrate or non-castrate range (figure 1). Each state 
represents a significant milestone in the illness that forms the basis for clinical research and 
for medical decision making in the context of routine clinical practice. The standard 
treatment for patients with metastatic disease is to block testosterone action with a 
gonadotropin releasing hormone (GnRH) analog and an anti-androgen. The results are 
predictable, with a decline in PSA followed by tumor regression, a period of stability in 
which the tumor does not proliferate and PSA remains stable, followed by rising PSA and 
regrowth as a castration resistant lesion. Prostate cancer progression despite castrate levels 
of testosterone represents a transition to a lethal disease phenotype referred to as 
castration-resistant prostate cancer (CRPC).  
 
Figure 1. Clinical states of prostate cancer 
 
 
 
It is now accepted that castration-resistant prostate cancer is not androgen-independent 
and continues to rely on androgen signaling (Longo NEJM 2010). Owing to this new 
understanding, several drugs have recently emerged for the treatment of castration-
resistant prostate cancer; these agents either suppress the synthesis of extragonadal 
androgens or target the androgen receptor directly.2Enzalutamide is an inhibitor of 
androgen-receptor signaling that exerts its activity by binding avidly to the ligand-binding 
domain of the androgen receptor, competing with and displacing the natural ligands of this 
receptor (testosterone and dihydrotestosterone) while also inhibiting translocation of the 
androgen receptor into the nucleus and impairing transcriptional activation of androgen-
responsive target genes (Tran et al. Science 2009; Scher et al. Lancet 2010). Abiraterone is 
an inhibitor of cytochrome P450 17A1 (CYP17A1) that impairs androgen-receptor signaling 
by depleting adrenal and intratumoral androgens (O’Donnell et al. Br J Cancer 2004; Attard 
et al. JCO 2008). After studies showed improved survival with these drugs, (Scher et al. 
Clinically
Localized
Disease
Clinical
Metastases:
Non-Castrate
Neoadjuvant
Adjuvant
1
Rising PSA:
Castrate
Rising
PSA
3
Clinical 
Metastases:
Castrate
1st Line
Docetaxel
4
Clinical 
Metastases:
Castrate
Post-
Cabazitaxel
Abiraterone
2
Clinical 
Metastases:
Castrate
Pre-
Provenge
Abiraterone


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NEJM 2012; de Bono et al. NEJM 2011; Ryan et al. NEJM 2013) both agents were approved 
by the Food and Drug Administration for the treatment of metastatic castration-resistant 
prostate cancer. 
 
Although enzalutamide and abiraterone represent breakthroughs in the treatment of 
metastatic castration-resistant prostate cancer, approximately 20 to 40% of patients have 
no response to these agents with respect to prostate-specific antigen (PSA) levels (i.e., they 
have primary resistance) Among patients who initially have a response to enzalutamide or 
abiraterone, virtually all eventually acquire secondary resistance. One plausible explanation 
for the resistance to both agents may involve the presence of androgen-receptor splice 
variants (Nadiminty et al Mol Cancer Ther 2013; Mostaghel et al. Clin Canc Res 2011). These 
alternatively spliced variants encode a truncated androgen-receptor protein that lacks the 
C-terminal ligand-binding domain but retains the transactivating N-terminal domain (Dehm 
et al.Cancer Res 2008; Hu et al.Cancer Res 2009).  Although the resultant truncated proteins 
are unable to bind ligand, they are constitutively active as transcription factors and capable 
of promoting activation of target genes. 
 
The presence of the androgen-receptor splice variant 7 (AR-V7) messenger RNA in 
circulatingtumorcells(0T0s)stronglypredictedforPS
responserate(PS
decline≥50%),
progression-free survival (PFS) and overall survival (OS) in a prospective study of men with 
CRPC who were beginning standard of care treatment with either enzalutamide or 
abiraterone.  Overall, 62 of 71 men about to begin treatment with either abiraterone or 
enzalutamide had detectable CTCs, an 87% yield.  39% (12 of 31 patients) of men about to 
begin treatment with enzalutamide were AR-V7+, as were 19% (6 of 31) about to begin 
treatment with abiraterone (Antonarakis et al. NEJM 2014). 
 
In the cohort of men who received enzalutamide, 0 of 12 men (0%) who carried detectable 
levels of AR-V7 in CTCs had a PSA response compared with 10 of 19 men (53%) who did 
not.  Likewise, 0 of 6 men (0%) who were AR-V7+ and received abiraterone had a PSA 
response compared with 17 of 25 men (68%) who were AR-V7-.  AR-V7 can be reliably 
detected from circulating tumor cells and appears to be associated with resistance to both 
enzalutamide and abiraterone, with essentially no clinical benefit seen in the largest 
prospective study. 
 
Men with CRPC who are AR-V7+ therefore represent a large unmet medical need.  
Treatment options are limited and may include chemotherapy (docetaxel and/or 
cabazitaxel), vaccine therapy (sipuleucel-T) for those with asymptomatic disease, or 
radiopharmaceutical therapy (radium-223 dichloride) for those with symptomatic bone-
only metastatic disease.  However, these therapies have not been evaluated prospectively in 
this specific population and there is evidence to suggest that expression of AR-V7 may be 
associated with resistance to taxane-based chemotherapy (Thadani-Mulero et al. Cancer 
Res 2014). 


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Therapies targeted at blocking escape from immune surveillance may remain effective in 
the setting of AR-V7 positivity.  This strategy has been clinically successful in melanoma, 
kidney cancer, and lung cancer, using monoclonal antibodies against CTLA-4 and the PD-
1/PD-L1 pathway.   These pathways have complementary and non-overlapping roles in 
regulating adaptive immune responses. While PD-1 contributes mainly to T-cell exhaustion 
at peripheral sites, CTLA-4 inhibits T-cells at an earlier point in their maturation cycle.  In 
CRPC, ipilimumab monotherapy has demonstrated PSA responses of approximately 15% 
with radiographic responses of approximately 5%.  The addition of PD-1 blockade via 
nivolumab is hypothesized to improve this response rate in a population of men with AR-
V7+ CRPC. 
 
1.2 
Nivolumab 
 
1.2.1            Introduction 
Nivolumab  (also  referred  to  as  BMS-936558  or  MDX1106)  is  a  fully  human  
monoclonal antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the 
programmed death-1 (PD-1) cluster of differentiation 279 (CD279) cell surface membrane 
receptor. PD-1 is a negative regulatory molecule expressed by activated T and B 
lymphocytes.  Binding of PD-1 to its ligands, programmed death–ligands 1 (PD-L1) and 2 
(PD-L2), results in the down-regulation of lymphocyte activation. Inhibition of the 
interaction between PD-1 and its ligands promotes immune responses and antigen-specific 
T-cell responses to both foreign antigens as well as self-antigens. Nivolumab is expressed in 
Chinese hamster ovary (CHO) cells and is produced using standard mammalian cell 
cultivation and chromatographic purification technologies. The clinical study product is a 
sterile solution for parenteral administration. 
 
1.2.2            Nonclinical Studies 
Nivolumab has been shown to bind specifically to the human PD-1 receptor and not to 
related members  of  the  CD28  family,  such  as  CD28  inducible  co-stimulator  (ICOS),  
cytotoxic T lymphocyte antigen-4 (CTLA-4), and B and T lymphocyte attenuator (BTLA). 
Nivolumab 
inhibits the interaction of PD-1 with its ligands, PD-L1 and PD-L2, resulting in enhanced T-
cell proliferation and interferon-gamma (IFN-γ)releaseinvitro.4,5,6luorescent-activated 
cell sorter (FACS)  analysis  confirmed  that  nivolumab  binds to  transfected  CHO  and  
activated  human 
T-cells expressing cell surface PD-1 and to cynomolgus monkey PD-1, but not to rat or 
rabbit PD-1 molecules.2  Nivolumab has also been shown to bind to PD-1 on virus-specific 
CD8+ T-cells from chronically infected hepatitis C virus patients. 
PD-1   inhibition   in   a   mixed   lymphocyte   reaction   (MLR)   resulted   in   a   reproducible 
concentration-dependent enhancement of IFN-γreleaseintheMLRupto50μg/mL. No 


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effect was observed with a human IgG4 isotype control or CD4+ T cells and dendritic cell 
(DC) controls.9 
In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, nivolumab was 
well tolerated at doses up to 50 mg/kg, administered weekly for 5 weeks, and at doses up to 
50 mg/kg, administered twice weekly for 27 doses. Nivolumab-related findings were 
limited to a reversible decrease of 28% in triiodothyronine (T3) among the females 
administered 27 doses of 50 mg/kg. No corresponding changes in the level of thyroxin (T4), 
thyroid-stimulating hormone (TSH), or histologic changes in the thyroid were 
observed.10,11 While nivolumab alone was well tolerated in  cynomolgus  monkeys,  
combination  studies  have  highlighted  the  potential  for  enhanced toxicity when 
combined with other immunostimulatory agents. 
Ipilimumab (BMS-734016), an anti-CTLA-4 monoclonal antibody (mAb) that blocks the 
down-regulation of T-cell activation, was used in combination with nivolumab to investigate 
the effects of concurrent inhibition of the PD-1 and CTLA-4 receptors in nonhuman 
primates.  Although gastrointestinal (GI) toxicity has not been observed in cynomolgus 
monkeys treated with nivolumab alone, dose-dependent GI toxicity was evident in 
cynomolgus monkeys treated weekly for 4 weeks with a combination of nivolumab + 
ipilimumab at combinations of 10 and 3 mg/kg  and  50  and  10  mg/kg,  respectively.  GI 
effects have also been observed at a low incidence after ipilimumab administration. 
 
Two    4-week     toxicity    studies     in     cynomolgus     monkeys     were    conducted     with 
2 anti-lymphocyte-activation gene 3 (LAG-3) mAbs that inhibit the function of LAG-3 on the 
surface of activated CD4+ and CD8+ T cells. The combination of nivolumab + MDX1408 was 
clinically well tolerated up to 50 mg/kg MDX1408 and 50 mg/kg nivolumab with findings 
limited to nonadverse and pharmacologically-mediated changes in the peripheral blood and 
lymphoid tissues, including increases in CD4+ T lymphocytes expressing CD25. However, 
the combination of 50 mg/kg nivolumab + 100 mg/kg BMS-986016, administered once 
weekly, was associated with moribundity (1 of 10 animals) attributed to central nervous 
system (CNS) vasculitis. Findings in surviving monkeys administered nivolumab alone or in 
combination with BMS-986016 were limited to minimal inflammation of the choroid plexus 
or vasculature of the brain parenchyma (1 male in the combination group), without 
evidence of other degenerative changes. These findings, which were observed at nivolumab 
exposures that were approximately 13x greater than those observed in humans at 3 mg/kg, 
every 2 weeks (Q2W), are consistent with an expected immunostimulatory pharmacologic 
effect of nivolumab and highlight the potential synergistic roles of PD-1 and LAG-3 in 
maintaining self-tolerance.14 
 
In addition, an enhanced pre- and postnatal development (ePPND) study in pregnant 
cynomolgus monkeys with nivolumab was conducted. Administration of nivolumab at up to 
50 mg/kg 2QW was well tolerated by pregnant monkeys; however, nivolumab was 
determined to be a selective developmental toxicant when administered from the period of 
organogenesis to parturition at10 mg/kg  (area  under  the  concentration-time  curve  
[AUC]  from  time  zero  to  168 hours [AUC(0-168h)]117,000μg•h/mL).Specifically,
increased developmental mortality (including late gestational fetal losses and extreme 


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prematurity with associated neonatal mortality) was noted in the absence of overt maternal 
toxicity. There were no nivolumab-related changes in surviving infants tested throughout 
the 6-month postnatal period. Although the cause of these pregnancy failures was 
undetermined, nivolumab-related effects on pregnancy maintenance are consistent with the 
established role of PD-L1 in maintaining fetomaternal tolerance in mice.16 
 
1.2.3            Effects in Humans 
The PK, clinical activity, and safety of nivolumab have been assessed in completed Phase 1 
and ongoing Phase 2 and 3 studies sponsored by Bristol-Myers Squibb Company (BMS) in 
subjects with non-small cell lung cancer (NSCLC), melanoma, and clear-cell renal cell 
carcinoma (RCC) in addition to other tumor types. The current Phase 3 clinical program 
focuses on squamous and nonsquamous NSCLC, malignant melanoma, and RCC. Clinical 
activity and safety information presented here focuses primarily on that obtained from 
CA209063 (Phase 2 study in refractory squamous NSCLC), CA209037 (Phase 3 study in 
melanoma), MDX1106-03 (also known as CA209003; Phase 1 study in metastatic NSCLC, 
colorectal cancer (CRC), melanoma, RCC, or metastatic castrate-resistant prostate cancer 
[mCRPC]), CA209010 (Phase 2 study in advanced/metastatic clear-cell RCC). Data are also 
provided from Phase 1 studies CA209004 (also known as MDX1106-04), CA209012, 
CA209016, CA209038, and CA209039. Nivolumab is being investigated both as 
monotherapy and in combination with chemotherapy, targeted therapies, and other 
immunotherapies. 
 
1.2.4.         Clinical Pharmacokinetics 
The single-dose pharmacokinetics (PK) of nivolumab was linear and dose-proportional in 
the range of 0.3 mg/kg to 10 mg/kg.  The multiple-dose PK of nivolumab was linear with 
dose-proportional increases in maximum serum concentration (Cmax) and area under the 
concentration-time curve over the dosing interval (AUC[TAU]) in the range of 0.1 mg/kg to 
10 mg/kg. Both elimination and distribution of nivolumab in the dose range studied appear 
to be independent of dose in the dose-ranging studies, while the end of infusion and 
minimum serum concentration (Cmin) after the first dose were approximately dose 
proportional. Based on population PK (PPK) results (preliminary data), clearance of 
nivolumab is independent of dose in the dose range (0.1 mg/kg to 10 mg/kg) and tumor 
types studied. Body weight normalized dosing showed approximately constant trough 
concentrations over a wide range of body weights and, therefore, is appropriate for future 
clinical trials with nivolumab. 
 
1.2.5.         Clinical Efficacy 
Nivolumab has demonstrated clinical activity as monotherapy and as combination therapy 
with ipilimumab in several tumor types, including RCC, melanoma, NSCLC, and some 
lymphomas. The majority of responses were durable and exceeded 6 months.  Nivolumab 
has now been FDA-approved for the treatment of metastatic melanoma and metastatic 
squamous non-small cell lung cancer. 


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1.2.6.         Clinical Safety 
The overall safety experience with nivolumab, as a monotherapy or in combination with 
other therapeutics, is based on experience in approximately 4,000 subjects treated to date. 
For monotherapy, the safety profile is similar across tumor types. The only exception is 
pulmonary inflammation adverse events (AEs), which may be numerically greater in 
subjects with NSCLC, because in some cases, it can be difficult to distinguish between 
nivolumab-related and unrelated causes of pulmonary symptoms and radiographic changes. 
There is no pattern in the incidence, severity, or causality of AEs to nivolumab dose level. 
In several ongoing clinical trials, the safety of nivolumab in combination with other 
therapeutics such as ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and targeted 
therapies is being explored. Most studies are ongoing and, as such, the safety profile of 
nivolumab combinations continues    to    evolve.    
1.3 
Ipilimumab 
 
Ipilimumab is a recombinant, human monoclonal antibody that binds to the cytotoxic T-
lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is an IgG1 kappa immunoglobulin 
with an approximate molecular weight of 148 kDa. Ipilimumab is produced in mammalian 
(Chinese hamster ovary) cell culture.  CTLA-4 is a negative regulator of T-cell activation. 
Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, 
CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and 
proliferation. The mechanism of action of ipilimumab’s effect in patients with melanoma is 
indirect, possibly through T-cell mediated anti-tumor immune responses. 
Ipilimumab 3 mg/kg is globally approved for advanced melanoma based on the results of a 
phase study III, MDX010-20. In MDX010-20, the ipilimumab monotherapy arm was 
administered 3 mg/kg ipilimumab every 3 weeks for four doses. In this arm, there were 
79% drug related adverse events, with 21% being Grade 3/4 and 3/131 (2%) Grade 5. The 
most frequent adverse events of interest were rash (30%), pruritis (33%), diarrhea (33%), 
colitis (8%), endocrine disorders (9%), AST/ALT increased (2%), and hepatitis (1%). Any 
grade immune related adverse events were 60% and the Grade 3/4 immune related 
adverse events for the same cohort was 13% with the most frequent adverse events being 
diarrhea (5%), colitis (5%), rash (2%), and endocrine disorders (3%). Additional details on 
the safety profile of ipilimumab, including results from other clinical studies, are also 
available in the ipilimumab IB. 
 
1.4 
Benefits and Risks 
The combination of nivolumab and ipilimumab is an experimental treatment for patients 
with AR-V7+ CRPC, for whom there is a significant unmet need given the lack of efficacy of 
further hormonal treatments.  Ipilimumab has demonstrated evidence of clinical activity as 
a monotherapy in CRPC.  The addition of nivolumab to ipilimumab has increased the 
response rate and PFS in other cancers while exhibiting an acceptable safety profile.  These 


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responses are expected to be more durable than those induced by other agents in CRPC and 
may translate into improvements in PFS and OS. 
Anticipated benefits of the treatment include the following: 
• Anti-tumor efficacy as measured by radiographic and PSA criteria 
• Manageable toxicity (favorable safety profile) 
• Prolongation of overall survival 
 
Nivolumab monotherapy has demonstrated clinical activity across several tumor types, 
including advanced prior treated melanoma, with objective response rates of 20 - 41% in 
106 melanoma subjects treated at various dose levels in CA209003. Nivolumab has also 
demonstrated a manageable safety profile. The most common AEs included fatigue, rash, 
pruritis, diarrhea, and nausea (Nivolumab IB). 
 
In the setting of post-chemotherapy CRPC (CA184-043), ipilimumab monotherapy has 
demonstrated statistically significant improvement in PFS over placebo, although an 
improvement in OS has not yet been demonstrated in an intent-to-treat population.  The 
most common AEs included diarrhea, fatigue, nausea, anorexia, and pruritis.   Other notable 
immune-related events occurring more frequently than placebo included hepatitis, 
hypothyroidism, and adrenal insufficiency (Kwon et al Lancet Oncology 2014).    
 
The combination of nivolumab and ipilimumab has the potential for increased benefit 
compared to both ipilimumab monotherapy and nivolumab monotherapy.  However, the 
combination of nivolumab and ipilimumab also has the potential for increased frequencies 
of adverse events. In phase I trials of the combination, the most common (reported at > 10% 
incidence) treatment related AEs are fatigue, rash, pruritus, diarrhea, lipase increased, 
pyrexia, ALT increase, AST increased, amylase increased and vitiligo. Although the 
preliminary data suggests an increase in adverse event frequency of nivolumab combined 
with ipilimumab compared to ipilimumab monotherapy or nivolumab monotherapy, there 
were no unexpected adverse events noted in the combination of nivolumab and ipilimumab.  
 
In addition, many of the Grade 3-4 adverse events associated with the nivolumab combined 
with ipilimumab were laboratory in nature, without clinical sequalae and adverse events 
have been manageable and reversible following intervention dose delays or with systemic 
steroid treatment. 
 
 
• 
Anticipated risks of the combination: 
 
While a synergistic clinical benefit is hypothesized, a theoretical risk exists that nivolumab 
may, on the contrary, exert a deleterious effect on the efficacy of ipilimumab in these 
patients.   
 
Additive or synergistic immune-related adverse events are expected as per prior 
nivolumab/ipilimumab combination studies in other tumor types, however there may be a 
risk of unexpected adverse events specific to this patient population. 


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1.5 
Rationale and Dose Selection 
1.5.1      Rationale for conducting the study 
Escape from immune surveillance is a recognized feature of cancer growth and progression, 
and the clinical success of immune checkpoint blockade using monoclonal antibodies 
against CTLA-4 and PD-1 has been demonstrated in patients with melanoma, kidney cancer 
and lung cancer. It is now understood that CTLA-4 and PD-1 have complementary and non-
overlapping roles in regulating adaptive immune responses. While PD-1 contributes mainly 
to T-cell exhaustion at peripheral sites, CTLA-4 inhibits T-cells at an earlier point in their 
maturation cycle. In preclinical models, combined blockade of both CTLA-4 and PD-1 
resulted in more pronounced antitumor activity than blockade of either pathway alone. This 
principal has been exemplified in a clinical study of advanced melanoma patients, where the 
combination of ipilimumab (anti–CTLA-4) plus nivolumab (anti–PD-1) resulted in rapid and 
deep tumor regressions above and beyond those reported in prior trials of ipilimumab or 
nivolumab monotherapy. Promising results have also been seen with this combination in 
kidney cancer. Importantly, the combination of ipilimumab and nivolumab is relatively safe, 
and immune-related adverse events are qualitatively similar to monotherapy treatments, 
and are generally reversible with steroid use. 
Biomarker-driven trials are sorely lacking in prostate cancer. AR-V7 is an androgen 
receptor splice variant that is missing the ligand-binding domain of AR (the target of 
androgens and antiandrogens) and remains constitutively active as a transcription factor in 
a ligand-independent fashion. We have recently shown that AR-V7 can be reliably detected 
at the mRNA level from circulating tumor cells (CTCs) in patients with metastatic CRPC, that 
AR-V7 is present in ~30% of men with mCRPC, and that AR-V7 expression is associated 
with primary and acquired resistance to both abiraterone and enzalutamide (Antonarakis et 
al. NEJM 2014). To this end, men with AR-V7–expressing mCRPC did not achieve 
biochemical or radiographic responses to abiraterone/enzalutamide, and had markedly 
inferior PFS and OS with abiraterone/enzalutamide compared to AR-V7–negative patients. 
In addition, emerging data suggest that expression of AR-V7 is also associated with 
resistance to taxane-based chemotherapy (Thadani-Mulero et al. Cancer Res 2014).  
Therefore, developing effective treatments for AR-V7–associated mCRPC represents an 
urgent unmet medical need. In this regard, combined immune checkpoint blockade may be 
one such therapeutic approach for these patients. 
The potential clinical utility of immune checkpoint blockade in prostate cancer is 
exemplified by the use of ipilimumab in men with mCRPC (Kwon et al. Lancet Oncol 2014). 
The collective aggregate of phase-2 and -3 data with ipilimumab monotherapy suggest a 
PS
responserate(≥50%PS
reduction)ofapproximately15%,andaradiographic
response rate of about 5% among men with measurable soft-tissue disease. These results 
are distinct from those seen with active immunotherapies (e.g. sipuleucel-T, ProstVac-VF) in 
men with mCRPC, where PSA or tumor responses are only observed in <1% of patients. 
Furthermore, the clinical application of PD-1/PD-L1–blocking antibodies in men with 
mCRPC is supported by data from our group and others showing that 1) prostate cancer cell 
lines can significantly up-regulate PD-L1 expression when treated with IFN-γ in vitro; 2) 
treatment of the same cell lines with anti-androgens (including enzalutamide) can induce or 
increase PD-L1 expression; and 3) that enzalutamide-resistant prostate cancer cell lines 
demonstrate striking expression of PD-L1 (Bishop et al. Oncotarget 2004). Taken together, 


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these data support a clinical paradigm in which combination immune checkpoint blockade 
with ipilimumab plus nivolumab is utilized in men with AR-V7–positive mCRPC. This study 
is driven by our novel data on AR-V7: we can use expression of this splice variant as 
evidence that these patients will not have any meaningful response to enzalutamide or 
abiraterone (i.e. PSA response rates approaching 0%). 
1.5.2      Rationale for dosage selection 
Ipilimumab is currently approved for metastatic melanoma at a dose of 3mg/kg every 3 
weeks for four doses.  In CRPC, doses of 3 mg/kg, 5 mg/kg, and 10 mg/kg have been 
evaluated without a clear dose response for efficacy, though toxicity appeared more 
prominent at the 10 mg/kg dose, which served as the basis for the phase 3 CA184-043 trial.    
Nivolumab has been evaluated in combination with ipilimumab in melanoma, renal cell 
carcinoma, and non-small cell lung carcinoma.  In CA209012, there was similar efficacy 
between nivolumab 1mg/kg with ipilimumab 3mg/kg compared with nivolumab 3mg/kg 
with ipilimumab 1mg/kg with respect to overall response rate in NSCLC and RCC.  However, 
toxicity appeared greater with ipilimumab 3mg/kg, particularly with respect to 
autoimmune hepatitis (Nivolumab IB). 
 
1.5.3      Rationale for correlative studies 
 
1.5.3.1  Rationale for evaluation of baseline PD-L1 tumor expression 
PD-L1 is expressed by many tumor types and its expression has been noted to correlate 
with decreased immune system function and worse clinical prognosis. In enzalutamide-
resistant CRPC, PD-L1 expression is highly expressed relative to enzalutamide-naïve tumors 
(Bishop et al. Oncotarget 2014).  It is hypothesized that PD-L1 expression within the tumor 
microenvironment, either on tumor cells, macrophages or lymphocytes is a means of 
evading immune system detection and destruction. Still others postulate that PD-L1 
expression on tumor cells is a surrogate for interferon-gamma release from neighboring 
activated T cells and thus portends a good prognosis for immunotherapy agents, and in 
particular, agents targeting the PD-1/PD-L1 axis.  
The limited preliminary evidence suggests that PD-L1 expression may be a prognostic 
marker that may also predict for nivolumab clinical activity, although there was minimal 
difference in response seen in PD-L1-positive vs negative tumors in a trial of the 
combination of nivolumab and ipilimumab (Wolchok et al NEJM 2014).  These observations 
bear exploration in the setting of CRPC.  Therefore, baseline PD-L1 expression status will be 
prospectively assessed via an optional metastatic tumor biopsy in those men with 
accessible lesions as well as via CTCs.  
 
1.5.3.2 Rationale for exploring the correlation between peripheral-blood absolute 
lymphocyte count (ALC) and clinical outcomes 
The absolute lymphocyte count (ALC) is a potential pharmacodynamic biomarker for 
ipilimumab, withthe
L0at7weeks(≥1000cells/uL)andmagnitudeof
L0increaseswith


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therapy demonstrating correlations with outcome in melanoma (Ku et al 2010, Postow and 
Panageas 2012).  Baseline eosinophil and relative eosinophil count have also been 
associated with improved survival in these patients (Delyon et al 2013).  However, in the 
nivolumab-ipilimumab trial in melanoma, there was no correlation noted between ALC and 
response.  Nevertheless, ALC should be assessed as a potential biomarker in this trial. 
1.5.3.3  Rationale for evaluation of changes in AR-V7 detection (or expression levels) 
before and after treatment with ipilimumab + nivolumab 
AR-V7 appears to be a dynamic marker of resistance to androgen-receptor-targeted 
therapies.  In a prospective trial of AR-V7 assessment, 6 of 42 men with undetectable AR-V7 
prior to treatment with either enzalutamide or abiraterone converted to AR-V7-positive 
status during treatment (Antonarakis et al 2014).  Clinical outcomes were intermediate 
between those that were negative vs positive at baseline.  To further evaluate the utility of 
AR-V7 status as a biomarker, it will be important to determine whether immunotherapy 
may cause AR-V7-positive patients to lose AR-V7 detectability and whether this may 
correlate with clinical outcome.   
CTCs will be collected for evaluation of AR-V7 status at baseline, week 12, and at 
progression/off-study (end-of-study visit).  These time-points will allow dynamic 
evaluation of AR-V7 status following completion of the intensive treatment cycles (i.e. 
following concurrent therapy) and at time of potential development of resistance. 
1.5.3.4  Rationale for Intratumoral and Peripheral Immunologic Profiling 
The Nanostring nCounter PanCancer Immune Profiling Panel allows  multiplexed 
quantitative profiling of immune-related mRNAs present in the tumor biopsy sample.  
Nanostring includes 109 genes that define 24 immune cell types and populations.   A 
broadly-based evaluation of intratumoral immune parameters will be useful to identify 
biomarkers that may predict response to checkpoint inhibitors. 
Similarly, broad antibody and cytokine profiling using pre- and post-treatment sera can be 
used to screen for novel anti-prostate antibody responses and determine patterns of 
cytokine and chemokine modulation that may predict clinical benefit with ipilimumab and 
nivolumab therapy.  The Life Technologies (Carlsbad, CA) ProtoArray technology will be 
used to evaluate over 8000 proteins to determine antibody response and the Life 
Technologies Luminex 25-Plex cytokine panel will be used to evaluate cytokine profiles. 
These data will be visualized per patient for both groups using heatmaps.   Additionally, 
100mL of serum will be cryopreserved for future antigen response assays. 
 
  
 
 
 


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2. 
OBJECTIVES 
2.1 
Objectives 
Primary objective: 
To evaluate the effect of administration of nivolumab and ipilimumab on the proportion of 
PSA responses (>50% PSA decline) in mCRPC patients with detectable AR-V7 transcript in 
CTCs  
 
In Cohort 2 (amendment 1): 
To evaluate the effect of administration of nivolumab and ipilimumab on the proportion of 
PSA responses (>50% PSA decline) and/or ORR in mCRPC patients with detectable AR-V7 
transcript in CTCs  
 
Secondary safety objective: 
To evaluate the safety and tolerability of ipilimumab + nivolumab in AR-V7–positive 
patients 
 
Secondary efficacy objectives: 
1. To determine the progression free survival (PFS) 
2. To determine the PSA-PFS 
3. To determine the proportion of “durable” responses 
4. To determine the overall response rate (ORR) 
5. To determine the overall survival (OS) 
Secondary correlative/biomarker objectives: 
1. To evaluate changes in AR-V7 detection (or expression levels) before and after treatment with 
ipilimumab + nivolumab and correlate with PSA responses.  
2. To explore potential biomarkers associated with clinical efficacy (ORR, PFS, and OS) of 
nivolumab and ipilimumab by analyzing absolute lymphocyte count in peripheral blood as 
well as PD-L1 expression in CTCs and/or in tumor biopsies, and immune profiling of sera 
and tumor tissue. 
3. To explore the relationship between DNA damage repair mutations (including mutational 
load, hypermutation, and loss of heterozygosity) and clinical outcomes 
4.  
5.  To explore the relationship between MANAFEST assay and clinical outcomes 
6.  
 
2.2 
Endpoints 
2.2.1 
Efficacy Endpoints: 
 


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1. The proportion of subjects with PSA response (>50% PSA decline) 
§ 
PSA decline will be reported on all patients.  Using PCWG2 guidelines, the percentage of 
change in PSA from baseline to 12 weeks, as well as the maximum decline in PSA will be 
reported for each patient using a waterfall plot. 
§ 
2.2.1.1 In Cohort 2 (amendment 1): 
§ 
Primary efficacy endpoint will be a composite endpoint of PSA response rate (proportion of 
men with >50% PSA decline) and/or Objective response rates (ORR) in patients with 
measurable disease.  
 
2. PSA progression-free survival (PSA-PFS) [PCWG2 criteria] 
§ 
PSA progression (PSA progression free survival; PSA-PFS) will be defined per the PCWG2 
guidelines 
§ 
For those subjects showing an initial decline in PSA from baseline, is defined as an increase 
inPS
thatis≥25%and≥2ng/mLabovethenadir,andwhichisconfirmedbyasecond
value 3 or more weeks later (i.e., a confirmed rising trend). 
§ 
For those subjects with no decline in PSA from baseline, is defined as an increase in PSA that 
is≥25%and≥2ng/mLafter12weeks. 
Note: PSA progression as such will not lead to study discontinuation 
3. Time to radiographic or clinical progression or death, whichever comes first (progression 
free survival; PFS). Based on RECIST version 1.1 and Prostate Cancer Working Group 2 
(PCWG2) definitions including: 
§ 
Progression of soft tissue lesions according to RECIST 1.1  
§ 
Progression of bone lesions detected with bone scan according to PCWG2 criteria  
§ 
Radiologically-confirmed spinal cord compression or pathological fracture due to malignant 
progression, or other clinical event deemed to be cancer-related 
4. “urablePS”,definedaslackofclinical/radiographicprogressionfor≥24weeks 
5. Objective response rate (ORR) by RECIST 1.1 criteria in patients with measurable disease 
6. Response duration in patients with objective response, defined as the time from treatment 
initiation until time of disease progression by PCWG2 definitions. 
7. Time to death after start of study treatment (overall survival; OS) 
2.2.2 
Safety Endpoints: 
 
1. Incidence and severity of adverse events and serious adverse events graded according to 
the National Cancer Institute – Common Terminology Criteria for adverse events (CTCAE) 
version 4.0 
2. Changes in laboratory variables: hematology and serum biochemistry 


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3. Changes in vital signs (systolic/diastolic blood pressure, respiratory rate, and heart rate) 
during the treatment period 
4. Changes in physical examination during the treatment period 
 
3. 
STUDY DESIGN 
3.1 
Study Design 
This study is a phase 2 single-arm, single center, open-label study of nivolumab 3mg/kg 
combined with ipilimumab 1mg/kg every 3 weeks for 4 doses, followed by nivolumab 
3mg/kg alone every 2 weeks. .  Treatment will continue until week 48, or until radiographic 
progression or unmanageable toxicity. 
The target population is men with metastatic CRPC and detectable AR-V7 splice-variant in 
CTCs.  The study is expected to enroll 15 subjects.  Detectable AR-V7 from CTCs must be 
present in order to enroll.  Prior vaccine therapy is allowed (e.g. sipuleucel-T) if completed 
at least 6 weeks prior to enrollment.  Prior therapy with CTLA-4 or PD-1/PD-L1 inhibitors is 
not allowed.  No dose increases or reductions will be allowed for nivolumab or ipilimumab.  
 Subjects will be assessed for PSA response beginning 6 weeks (±3 days) from enrollment 
and continuing every 6 weeks (±3 days for cycle 2, subsequently (±7 days). Subjects will be 
assessed for radiologic responses (RECIST 1.1) by CT beginning 12 weeks (±1 week) after 
enrollment and continuing every 12 weeks (±1 week).   Bone scan progression (PCWG2 
criteria) will be assessed beginning 12 weeks (±1 week) after enrollment and continuing 
every 12 weeks (±1 week).   
Subjects will be allowed to continue study therapy after initial investigator-assessed 
PCWG2-defined progression if assessed by the investigator to be deriving clinical 
benefit and tolerating study drug. Such subjects should discontinue study therapy when 
further progression  is  documented. 
 
The key endpoints of the study are: 
• 
Primary efficacy objective: 
To evaluate PSA responses (>50% PSA decline) in mCRPC patients with detectable AR-V7 
transcript in CTCs  
In Cohort 2 (amendment 1): 
To evaluate PSA response rate (proportion of men with >50% PSA decline) and/or Objective 
response rates (ORR) in patients with measurable disease 
• 
Secondary safety objective: 
To evaluate the safety and tolerability of ipilimumab + nivolumab in AR-V7–positive patients, 
with attention to irAEs 
The key correlative/biomarker objective is to evaluate changes in AR-V7 detection (or 
expression levels) before and after treatment with ipilimumab + nivolumab 


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The treatment design schematic is presented below: 
 
 
This study will consist of three phases: screening, treatment, and follow-up.  
 
Screening Phase: 
 
• Begins by establishing the subject’s initial eligibility and signing of the informed consent 
form (ICF). 
• Patients must have detectable CTCs with detectable AR-V7 splice-variant. 
 
Treatment Phase: 
 
• Within 7 days from enrollment, the subject must receive the first dose of study medications 
(Day 1 of Cycle 1) 
• 
On-study laboratory assessments (Cycle 1  D a y  2 2  and beyond) should be drawn 
within 72 hours prior to dosing.   
• 
Adverse event assessments should be documented at each clinic visit. 
• 
Study drug dosing may be delayed for toxicity. 
1 
4
1 
3
5 
1 


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25 
 
• 
Each cycle during the treatment phase is expected to last 6 weeks, unless there are delays. 
• 
Treated subjects will be evaluated for response according to the RECIST 1.1 guidelines 
beginning  12  weeks  (±  1  week)  after  enrollment and  continuing  every 12  weeks (± 1 
week) as well as PCWG2 criteria (including PSA, bone scan, and symptoms) until disease 
progression or treatment discontinuation, whichever occurs later. 
• 
This treatment phase ends when the subject is discontinued from study therapy. 
 
Follow-Up Phase 
 
• 
Begins when the decision to discontinue a subject from study therapy is made (no 
further treatment with study therapy). 
• 
Subjects who discontinue treatment for reasons other than tumor progression will 
continue to have radiographic and PSA assessments beginning 12 weeks (± 1week) after 
enrollment and continuing every 12 weeks (± 1 week) thereafter until documented 
progression. 
• 
Subjects will be followed for drug-related toxicities until these toxicities resolve, return 
to baseline or are deemed irreversible. All adverse events will be documented for a 
minimum of 100 days after last dose. 
• 
After completion of the first two follow-up visits, subjects will be followed every 3 
months for survival. Follow-up visits can be done by telephone. 
The total duration of the study from start of randomization to final analysis of PSA 
response is expected to be 24 months (12 months of accrual + 12 months of follow-up), 
assuming a fixed accrual rate of 1.5 subjects per month (given approximately 4 subjects 
with AR-V7+ metastatic CRPC seen at Hopkins per month).  
3.2 
Schedule of Assessments 
The following table (Table 1) reflects the assessments that will occur during the study, i.e. 
screening period, treatment period, and end-of-study visit. 
Each cycle is 6 weeks and treatment will continue up to W48. 
Visits should occur within a window of ±3 days during the first 2 cycles. Visits may occur 
within a window of ±7 days during subsequent cycles. 
For radiologic evaluations, a window of ±1 week is acceptable.
 
The Investigator may perform more frequent examinations than shown in Table 1 if clinically 
indicated. Data from such additional examinations are also to be reported in the eCRF. 


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Table 1 Study 
Calendar 
 
 
 
Pre-
stud
y 
 
Treatment/Intervention Period (1 cycle = 6 weeks) 
 
Cycle 1 
±3 days 
Cycle 2 ±3 
days 
Cycle 3-8 
± 7 days 
End of 
treatment 
Follow-up 
1m 
Follow-up 
2n 
 
Day -
28 to 
0a 
W
k 1  
(±
3 
d) 
W
k 
4 
(±
3
d) 
W
k 1 
(±
3 
d) 
Wk 
4   
(±3 
d) 
Wk 
1 
(±7
d) 
Wk 
3 
(±7 
d) 
Wk 
5 
(±7 
d) 
Wk 49 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Nivolumabb 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Ipilimumab 
 
X 
X 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
Xc 
X 
X 
X 
X 
 
 
X 
X 
X 
Physical assessment 
X 
Xc 
 
X 
 
X 
X 
X 
X 
X 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
Xc 
 
X 
 
X 
 
 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Toxicity assessment 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
Histologic 
confirmation 
X 
 
 
 
 
 
 
 
 
 
 
Disease assessment 
(Radiologic tests)e,f 
X 
 
 
 
 
Xf 
 
 
 
 
 
CBC with diff 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comp Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TSHg 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Hepatitis B/Ch 
X 
 
 
 
 
 
 
 
 
 
 
PSA 
X 
 
 
X 
 
X 
 
 
X 
 
 
Serum amylase and 
lipase 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Serum Testosterone 
X 
 
 
 
 
 
 
 
 
 
 
Metastatic tumor 
biopsyi 
X 
 
 
 
 
 
 
 
 
 
 
AR-V7 Screeningj 
X 
 
 
 
 
 
 
 
 
 
 
CTCso 
X 
 
 
 
 
X 
 
 
Xl 
 
 
Sera for 
immunoassays k 
X 
 
 
 
 
X 
 
 
X 
 
 
Blood (100 mL) for 
PBLsp 
X 
 
 
 
 
X 
 
 
X 
 
 
Plasma for ctDNAq 
X 
 
 
 
 
 
 
 
 
 
 


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Abbreviations: CBC, complete blood count; CMP, complete metabolic panel; CTC, 
circulating tumor cells; CT, computerized tomography; EKG, electrocardiogram; MRI, 
magnetic resonance imaging; PSA, prostate-specific antigen 
a 
Informed consent and radiologic assessments should be obtained within 8 weeks of 
study start date. 
b       Beginning cycle 3, subjects will return to clinic every 2 weeks and receive nivolumab 
every 2 weeks 
c        Only needed if pre-study visit was >14 days prior to C1D1 
d 
Including heart rate, blood pressure, pulse oximetry, pain, respiratory rate and 
weight 
e       CT c/a/p and bone scan. Radiologic documentation will be provided for subjects 
removed    from study for progressive disease. 
f       And every subsequent 12 weeks until progression 
g       With reflexive T3 and fT4 
h        HBV sAg, HCV Ab 
i        Optional image-guided core biopsy (CT/MRI-guided or ultrasound-guided biopsy) may 
be obtained at baseline for patients with metastases that are amenable to biopsy 
j        AR-V7 Screening test should be performed within 4 weeks from screening visit. Order 
will be placed by provider in EPIC. Samples must be drawn before 12pm. 
k      Serum samples will be collected at three time points (pre-treatment, cycle 3, and end 
of treatment). At each time point, 2 SST (tiger top, i.e. BD Vacutainer Cat #367985) 
tubes shouldbecollected,eachcontaining≥5mLofblood.ftercentrifugation,
serum should be transferred into plastic cryovials and frozen at –20°C or colder until 
the time of analysis (see Appendix C section  5).     
l        3rd CTC sample to be collected either at end of study or at time of progression if 
patient is continuing on treatment despite progression 
m     Follow-up 1 should occur 30 days after last treatment dose.   
n       Follow-up 2 should occur 84 days (6 weeks) after end of treatment. 
o      See Appendix C for CTC collection instructions 
p      Peripheral blood lymphocytes (PBLs) will be obtained by collecting 100 mL of blood 
into 50-mL heparinized conical tubes. PBLs will be prepared by Ficoll-Hypaque 
density gradient centrifugation according to standard protocols, and will be 
cryopreserved in a liquid nitrogen freezer at –140°C for further batched analyses (see 
Appendix C section 6). 
q.      See Appendix C for ctDNA plasma collection instructions 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 2 Study 
Calendar for 
Cohort 2 
(Amendment 1) 
 
 
 
Pre-
stud
y 
 
Treatment/Intervention Period (1 cycle = 6 weeks) 
 
Cycle 1 
±3 days 
Cycle 2 ±3 
days 
Cycle 3-8 
± 7 days 
End of 
treatment 
Follow-up 
1m 
Follow-up 
2n 
 
Day -
28 to 
0a 
W
k 1  
(±
3 
d) 
W
k 
4 
(±
3
d) 
W
k 1 
(±
3 
d) 
Wk 
4   
(±3 
d) 
Wk 
1 
(±7
d) 
Wk 
3 
(±7 
d) 
Wk 
5 
(±7 
d) 
Wk 49 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Nivolumabb 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Ipilimumab 
 
X 
X 
X 
X 
 
 
 
 
 
 
Enzalutamide daily 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
Xc 
X 
X 
X 
X 
 
 
X 
X 
X 
Physical assessment 
X 
Xc 
 
X 
 
X 
X 
X 
X 
X 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
Xc 
 
X 
 
X 
 
 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Toxicity assessment 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
Histologic 
confirmation 
X 
 
 
 
 
 
 
 
 
 
 
Disease assessment 
(Radiologic tests)e,f 
X 
 
 
 
 
Xf 
 
 
 
 
 
CBC with diff 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comp Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TSHg 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Hepatitis B/Ch 
X 
 
 
 
 
 
 
 
 
 
 
PSA 
X 
 
 
X 
 
X 
 
 
X 
 
 
Serum amylase and 
lipase 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Serum Testosterone 
X 
 
 
 
 
 
 
 
 
 
 
Metastatic tumor 
biopsyi 
X 
 
 
 
 
 
 
 
 
 
 
AR-V7 Screeningj 
X 
 
 
 
 
 
 
 
 
 
 
CTCso 
X 
 
 
 
 
X 
 
 
Xl 
 
 
Sera for 
immunoassays k 
X 
 
 
 
 
X 
 
 
X 
 
 
Blood (100 mL) for 
PBLs/MANAFESTp 
X 
 
 
 
 
X 
 
 
X 
 
 


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Plasma for ctDNAq 
(PGDx) 
X 
 
 
 
 
 
 
 
 
 
 
Plasma for ctDNAr 
(Hurley lab) 
X 
 
 
 
 
X 
 
 
X 
 
 
 
Abbreviations: CBC, complete blood count; CMP, complete metabolic panel; CTC, 
circulating tumor cells; CT, computerized tomography; EKG, electrocardiogram; MRI, 
magnetic resonance imaging; PSA, prostate-specific antigen 
a 
Informed consent and radiologic assessments should be obtained within 8 weeks of 
study start date. 
b       Beginning cycle 3, subjects will return to clinic every 2 weeks and receive nivolumab 
every 2 weeks 
c        Only needed if pre-study visit was >14 days prior to C1D1 
d 
Including heart rate, blood pressure, pulse oximetry, pain, respiratory rate and 
weight 
e       CT c/a/p and bone scan. Radiologic documentation will be provided for subjects 
removed    from study for progressive disease. 
f       And every subsequent 12 weeks until progression 
g       With reflexive T3 and fT4 
h        HBV sAg, HCV Ab 
i        Optional image-guided core biopsy (CT/MRI-guided or ultrasound-guided biopsy) may 
be obtained at baseline for patients with metastases that are amenable to biopsy 
j        AR-V7 Screening test should be performed within 4 weeks from screening visit. Order 
will be placed by provider in EPIC. Samples must be drawn before 12pm. 
k      Serum samples will be collected at three time points (pre-treatment, cycle 3, and end 
of treatment). At each time point please follow Appendix C section 5.  
l        3rd CTC sample to be collected either at end of study or at time of progression if 
patient is continuing on treatment despite progression 
m     Follow-up 1 should occur 30 days after last treatment dose.   
n       Follow-up 2 should occur 84 days (6 weeks) after end of treatment. 
o      See Appendix C sections 2, 3, and 4 for CTC collection instructions 
p      Peripheral blood lymphocytes (PBLs) will be obtained by collecting 100 mL of blood (as 
per Appendix C section 6). 
q.      See Appendix C section 7 for ctDNA plasma collection instructions 
r.      Refer to Appendix C section 8 for ctDNA plasma collection instructions for Hurley lab 
 
 
 
 
 
 
 
 
 
 
 
4. 
PATIENT SELECTION 
4.1 
Target Population 
The target population is men with AR-V7-positive metastatic castration-resistant prostate 
cancer. 
4.2 
Inclusion Criteria 
To be included in this study, subjects should meet all of the following criteria: 
1. Age at least 18 years at the time of signing the ICF 
2. Histologically or cytologically confirmed adenocarcinoma of the prostate 
3. Metastatic disease as defined by two or more bone metastases confirmed by bone 
scintigraphy or radiographic soft tissue metastasis 
4. Detectable circulating tumor cells (CTCs) with detectable AR-V7 splice-variant by RT-PCR 


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5. Known castration-resistant disease, defined according to PCWG2 criteria as: 
a) 0astrateserumtestosteronelevel:≤50ng/dL(≤1.7nmol/L) 
b) Subjects who have failed initial hormonal therapy, either by orchiectomy or by using a 
GnRH agonist in combination with an anti-androgen, must first progress through 
antiandrogen withdrawal prior to being eligible. The minimum timeframe to document 
failure of anti-androgen withdrawal will be four weeks 
c) Serum PSA progression defined as two consecutive increases in PSA over a previous 
reference value within 6 months of first study treatment, each measurement at least one 
weekapart.SerumPS
atscreening≥2ng/mL 
Or 
Documented bone lesions by the appearance of two or more new lesions by bone 
scintigraphy 
Or 
Bidimensionally-measureable soft tissue metastatic lesion assessed by CT or MRI 
6. KarnofskyPerformanceStatus(KPS):≥70%within14daysbeforestartofstudytreatment
(ECOG ≤1) 
7. Life expectancy: at least 6 months 
8. Laboratory requirements: 
Screening laboratory values must meet the following criteria and should be obtained within 
14 days prior to randomization/registration 
§ 
WBC   
≥2000/μL 
§ 
Neutrophils  
≥1500/μL 
§ 
Platelets 
 ≥100x103/μL 
§ 
Hemoglobin  
> 9.0 g/dL 
§ 
Serumcreatinine≤ 1.5xULNorcreatinineclearance(0r0l)≥ 40 mL/min (if using the 
Cockcroft-Gault formula below): 
Female CrCl = (140 - age in years) x weight in kg x 0.85 
                           72 x serum creatinine in mg/dL 
 
Male CrCl = (140 - age in years) x weight in kg x 1.00  
                            72 x serum creatinine in mg/dL 
§ 
AST/ALT  
≤ 3 x ULN  
§ 
TotalAilirubin≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total 
bilirubin < 3.0 mg/dL)  
9. Men who are sexually active with women of childbearing potential (WOCBP) must use any 
contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab 
and who are sexually active with WOCBP will be instructed to adhere to contraception for a 
period of 31 weeks after the last dose of investigational product. 
a) WOCBP is defined as any female who has experienced menarch and has not undergone 
surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not 
postmenopausal.  Menopause is defined clinically as 12 months of amenorrhea in a woman 


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over 45 in the absence of other biological or physiological causes.  In addition, women 
under the age of 55 must have a documented serum follicle stimulating hormone (FSH) 
level less than 40 mIU/mL.   
10. No evidence (within 5 years) of prior malignancies (except successfully treated basal cell or 
squamous cell carcinoma of the skin). 
11. The subject is willing and able to comply with the protocol, and agrees to return to the 
hospital for follow-up visits and examination 
12. The subject has been fully informed about the study and has signed the informed consent 
form and, where appropriate, HIPAA authorization for release of personal health 
information 
NOTE: HIPAA authorization may be included in the informed consent or obtained 
separately. 
4.2.1 
For second cohort (amendment 1): 1 additional eligibility criteria will apply.  
 
1.  The most recent therapy must be enzalutamide and enzalutamide will be 
continued for study duration despite progressive disease (asdefinedin4.2.5.c.) . The 
minimum required dose of Enzalutamide at enrolment should be no less than 80 mg once daily. 
 
4.3 
Exclusion Criteria 
Subjects that meet any of the criteria listed below will not be eligible for study entry: 
1. Has received an investigational therapeutic drug within the last 4 weeks prior to start of 
study treatment, or is scheduled to receive one during the treatment period. 
2. Has received external radiotherapy within the last 4 weeks prior to start of study treatment. 
3. Previous therapy with antiandrogens within 4 weeks 
4. Patients should be excluded if they have had prior systemic treatment with an anti-PD-1, 
anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically 
targeting T-cell costimulation or immune checkpoint pathways 
5. Symptomatic metastatic disease with signs of rapid progression per investigator’s clinical 
judgment 
6. Concurrent use of other anticancer agents or treatments, with the following exceptions:  
a) Ongoing treatment with LHRH agonists or antagonists, denosumab (Prolia) or 
bisphosphonate (eg, zoledronic acid) is allowed. Ongoing treatment should be kept at a 
stable schedule; however, if medically required, a change of dose, compound, or both is 
allowed. 
7. Any treatment modalities involving major surgery within 4 weeks prior to the start of study 
treatment. 
8. Symptomatic nodal disease, i.e. scrotal, penile or leg edema (≥CTCAE Grade 3) 


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9. Patients are excluded if they have active brain metastases or leptomeningeal metastases. 
Subjects with brain metastases are eligible if metastases have been treated and there is no 
magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks after 
treatment is complete and within 28 days prior to the first dose of nivolumab 
administration. There must also be no requirement for immunosuppressive doses of 
systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to 
study drug administration. 
10. Patients should be excluded if they have an active, known or suspected autoimmune disease 
(e.g. inflammatory bowel disease, rheumatoid arthritis, autoimmune hepatitis, lupus, celiac 
disease). Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, 
residual hypothyroidism due to autoimmune condition only requiring hormone 
replacement, psoriasis not requiring systemic treatment, or conditions not expected to 
recur in the absence of an external trigger 
11. Patients should be excluded if they have a condition requiring systemic treatment with 
either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive 
medications within 14 days of study drug administration. Inhaled or topical steroids and 
adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the 
absence of active autoimmune disease. 
12. Permitted therapies include topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Physiologic replacement doses of 
systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A brief 
course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-
autoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by contact 
allergen) is permitted. 
13. As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab 
combinations, drugs with a predisposition to hepatoxicity should be used with caution in 
patients treated with nivolumab-containing regimen. 
14. Patients should be excluded if they have a positive test for hepatitis B virus surface antigen 
(HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic 
infection 
15. Patients should be excluded if they have known history of testing positive for human 
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) 
16. Allergies and Adverse Drug Reaction 
17. History of allergy to study drug components 
18. History of severe hypersensitivity reaction to any monoclonal antibody 
19. Other primary tumor (other than CRPC) including hematological malignancy present within 
the last 5 years (except non-melanoma skin cancer or low-grade superficial bladder cancer). 
20. Has imminent or established spinal cord compression based on clinical findings and/or 
MRI. 
21. Any other serious illness or medical condition that would, in the opinion of the investigator, 
make this protocol unreasonably hazardous, including, but not limited to: 
a) Any uncontrolled infection 
b) Cardiac failure NYHA (New York Heart Association) III or IV 


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c) Crohn’s disease or ulcerative colitis 
d) Bone marrow dysplasia 
e) Known allergy to any of the compounds under investigation 
f) Unmanageable fecal incontinence 
4.3.1 For second cohort (amendment 1): Concurrent therapy with enzalutamide will be permitted 
and is a requirement for enrollment. 
 
4.4 
Concomitant Medications 
Because of potential drug-drug interactions, the eCRF must capture the concurrent use of all 
other drugs, over-the-counter medications, or alternative therapies. Any concomitant 
therapy, given to or taken by a subject from screening visit until 6 weeks after the last dose 
of study drugs will be recorded in the eCRF together with the indication. The generic or 
trade name, indication, dosage and, when applicable, the start and stop date will be 
recorded. 
 
4.4.1 
Blood transfusions/erythropoietin 
Erythropoietin is not allowed during the study period or within the last 4 weeks prior to 
inclusion into the study. 
Blood transfusions are allowed during the study period but not within the last 4 weeks 
prior to inclusion into the study. 
 
4.4.2 
Concomitant prostate cancer therapy 
EBRT is not to be introduced until the follow-up period unless deemed absolutely 
necessary. 
 
Patients will be allowed to continue prior LHRH agonist/antagonist therapy. Patients on 
bisphosphonates (eg, zoledronic acid) or denosumab (Prolia) will also be permitted to 
continue treatment. Preferably, ongoing treatment should be kept at a stable schedule; 
however, if medically required, a change of dose and/or compound will be allowed. If 
medically required, LHRH agonist/antagonist, denosumab, and bisphosphonates can be 
started during the study and preferably should be kept at a stable dose. 
 
Systemic treatment with corticosteroids at doses corresponding to a prednisone dose above 
10 mg/day must be avoided unless medically required.. 
 
4.4.3 
Other concomitant therapies 
Other medications, excluding those mentioned under “Disallowed Concomitant Therapy,” 
may be given concomitantly as needed for the patient’s welfare. Caution and, if possible 
monitoring, is advised with drugs with a predisposition to hepatoxicity given the risk for 
hepatotoxicity in ipilimumab- and nivolumab-containing regimens. 


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4.5 
Disallowed Concomitant Therapy 
Requirement for concomitant systemic treatment with any of the following therapies will 
lead to withdrawal from study treatment.  
• 
Bicalutamide (eg, Casodex®) or other antiandrogens 
• 
Use of all concomitant medications will be recorded in the patient’s medical records and 
eCRF. This will include all prescription drugs, herbal products, vitamins, minerals, and 
over-the-counter medications. Any changes in concomitant medications also will be 
recorded in the patient’s medical records and eCRF. 
Any concomitant medication deemed necessary for the welfare of the patient during the 
study may be given at the discretion of the investigator. However, it is the responsibility of 
the investigator to ensure that details regarding the medication are recorded in full in the 
patient’s medical records and eCRF. 
 
5. 
STUDY DRUGS 
 
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-
investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following: 
• 
All products, active or placebo, being tested or used as a comparator in a clinical trial. 
• 
Study-required premedication, and 
• 
Other drugs administered as part of the study that are critical to claims of efficacy(eg, 
background therapy, rescue medications) 
5.1  
Investigational Product 
An investigational products (nivolumab and ipilimumab), also known as investigational 
medicinal product in some regions, is defined a pharmaceutical form of an active substance 
or placebo being tested or used as a reference in a clinical study, including products already 
with a marketing authorization but used or assembled (formulated or packaged) differently 
than the authorized form, or used for an unauthorized indication, or when used to gain 
further information about the authorized form. 
The investigational product should be stored in a secure area according to local regulations. 
It is the responsibility of the investigator to ensure that investigational product is only 
dispensed to study subjects. The investigational product must be dispensed only from 
official study sites by authorized personnel according to local regulations. 
 
5.2  
Non-investigational Product 
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products. 
In this protocol, non-investigational product(s) is/are: medications used to treat nivolumab 
infusion-related reactions (eg, steroids, anti-emetics); these non-investigational products 
should be sourced by the investigator sites if available and permitted by local regulations. 


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5.3 
Storage and Dispensing 
The investigator should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as per product information 
and the Investigator Brochure and per local regulations. It is the responsibility of the 
investigator to ensure that investigational product is only dispensed to study subjects. The 
investigational product must be dispensed only from official study sites by authorized 
personnel according to local regulations. If concerns regarding the quality or appearance of 
the study drug arise, the study drug should not be dispensed and contact BMS immediately. 
Please refer to the current version of the Investigator Brochure and/or shipment reference 
sheets for additional information on storage, handling, dispensing, and infusion information 
for nivolumab. 
 
PRODUCT INFORMATION TABLE: Please also see respective Product Investigator Brochures 
Table 
Product Description 
Product 
Description and 
Dosage Form 
Potency 
Primary 
Packagin
g 
(Volume
)/ Label 
Type 
Secondary 
Packaging 
(Qty) /Label 
Type 
Appearance 
Storage Conditions 
(per label) 
Nivolumab BMS-
936558-01 
Solution for 
Injectiona 
100 mg 
(10 
mg/mL) 
10 mL 
viall 
5-10 vials per 
carton/ Open-
label 
Clear to opalescent 
colorless to pale 
yellow liquid. May 
contain particles 
2 to 8C. Protect 
form light and 
freezing 
Ipilimumab 
Solution for 
Injection 
200 mg (5 
mg/mL) 
40 mL 
vial 
4 vials per 
carton/Open-
label 
Clear, colorless to 
pale yellow liquid. 
May contain 
particles 
2 to 8°C. Protect 
from light and 
freezing. 
*Nivolumab may be labeled as BMS-936558-01 Solution for Injection 
 
If stored in a glass front refrigerator, vials should be stored in the carton. Recommended 
safety measures for preparation and handling of nivolumab and ipilimumab include 
laboratory coats and gloves. 
For additional details on prepared drug storage and use time of nivolumab or ipilimumab 
under room temperature/light and refrigeration, please refer to the BMS-936558 
(nivolumab) and Ipilimuab Investigator Brochure section for “Recommended Storage and 
Use Conditions”  
 
 
5.4 
Administration 
Nivolumab and ipilimumab will be given together every 3 weeks for 4 doses.  
 
Nivolumab dose = 3 mg/kg 


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Ipilimumab dose =  1 mg/kg 
 
Following these 4 concurrent doses, nivolumab will be administered alone every 2 weeks 
until progression or end of study. 
 
When study drugs (ipilimumab or nivolumab) are to be administered on the same day, 
separate infusion bags and filters must be used for each infusion. Nivolumab should be 
administered first. The second infusion will be ipilimumab, and will start approximately 30 
minutes after completion of the nivolumab infusion. 
BMS-936558 (nivolumab) is to be administered as a 60 minute IV infusion. Ipilimumab 
should be administered as a 90 minute infusion following. 
Ipilimumab and nivolumab may be diluted in 0.9% Sodium Chloride Solution or 5% 
Dextrose solution.  
The dosing calculations should be based on the body weight obtained at the visit 
immediately prior to infusion visit. If the subject’s weight on the day of dosing differs by > 
10% from the weight used to calculate the dose, the dose must be recalculated. All doses 
should be rounded up or to the nearest milligram per institutional standard.  
 
Following the first 4 doses of the combination of nivolumab and ipilimumab, nivolumab will 
be given every two weeks at a dose of 3mg/kg.  
 
Dose Modifications 
There will be no dose modifications permitted. Dose reductions or dose escalations are not 
permitted. 
 
During cycles 1 and 2, subjects may be dosed no less than 19 days from the previous dose of 
drug and dosed up to 7 days after the scheduled date if necessary. 
Starting from cycle 3, subjects may be dosed no less than 12 days from the previous dose of 
drug and dosed up to 7 days after the scheduled date if necessary. 
Treatment compliance will be monitored by drug accountability as well as the subject’s 
medical record and eCRF. 
 
6 
STUDY PROCEDURES  
6.1 
Screening/Pretreatment Assessment  
Before initiating any screening activities, the scope of the study should be explained to each 
subject. Subjects should be advised of any known risks inherent in the planned procedures, 
any alternative treatment options, their right to withdraw from the study at any time for 
any reason, and their right to privacy. After this explanation, subjects should be asked to 
sign and date a Notice of Privacy Practice research authorization/HIPAA form and an IRB-


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approved statement of informed consent that meets the requirements of the Code of 
Federal Regulations (Federal Register Vol. 46, No. 17, January 27, 1981, part 50). 
The screening visit will determine subject eligibility according to the inclusion/exclusion 
criteria (Sections 4.2 and 4.3). The following assessments will be performed during this 
period: 
Imaging can be done before obtaining informed consent if done routinely. If appropriate 
bone scan, and CT/MRI exist within the required study timeline, these images will be used 
in the study and there will not be a requirement to obtain new images for the study 
protocol. 
Within 8 weeks prior to treatment start: 
1. Bone Technetium scan with careful identification of all disease related hotspots. 
Number of lesions related to metastatic disease should be recorded as follows (PCWG2 
recommendation): 1, 2-4, 5-9, 10-20 or >20. 
2. CT of chest/abdomen/pelvis. 
Within 28 days prior to treatment start: 
1. Record demographics and medical history (including detailed information about medical 
history of prostate carcinoma and bone metastases and previous treatments). 
2. Conduct physical exam (abbreviated physical examination, vital signs, height/weight, etc). 
3. ECG - a standard 12-lead ECG will be performed at screening and then as clinically indicated 
throughout the duration of the study. Results will be recorded as normal or abnormal with 
abnormal findings described in the eCRF. Clinically significant ECG changes observed at 
baseline should be recorded as symptoms, while clinically significant ECG changes observed 
after treatment should be recorded as adverse events. 
4. Obtain histologic or cytologic confirmation of adenocarcinoma of the prostate (from patient 
records). 
5. Perform laboratory tests: 
a) Circulating tumor cell (CTC) analysis for AR-V7 expression 
b) Hematology: Hematocrit, hemoglobin, platelet counts, red blood cell counts, white blood cell 
counts, whole blood cell differential 
c) Serum biochemistry: Sodium, potassium, chloride, calcium, phosphate, magnesium, AST, 
ALT, creatinine, urea, bilirubin (total), albumin, total protein, amylase, lipase 
d) PSA: The PSA value within 28 days prior to treatment start has to be at least 2 ng/mL. PSA 
progression (25% increase over reference not older than 6 months) has to be observed in 
two measurements, each measurement at least 1 week apart 
e) Testosterone(castrateserumtestosteronelevelsof≤50ng/dLrequired) 
f) Thyroid stimulating hormone (TSH) 
g) Research labs (cytokine and antibody profiles, serum for cryopreservation) 
6. Assess Karnofsky performance status (Table 3). 
7. Record concomitant medications. Relevant information should be captured in the eCRF. 
6.2 
Treatment/Intervention Period  
 
The Treatment Phase will start on the first day of treatment (Day 1) and last until any 
criteria for withdrawal from study treatment is reached and study treatment is withdrawn.  


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According the schedule of visits, subjects will attend the clinic every 3 weeks for the first 4 
cycles, then subsequently every 2 weeks for nivolumab infusion and assessments. The visits 
will be primarily in place to judge any safety issues, both in terms of clinical adverse events 
but also for laboratory values. The laboratory values must be checked prior to each dosing 
of nivolumab and ipilimumab to ensure they are within the defined limits for dosing. Should 
the values not be within these limits, then dosing should be delayed to await recovery from 
toxicity prior to re-dosing. 
 
The Treatment Phase will continue until week 48 or if  any criteria for withdrawal from 
study treatment are reached a.   The End-of-Study Treatment Visit will occur 100 days after 
the last dose of study drug for AE assessment. 
 
6.2.1 
Clinical and laboratory assessments 
 
A schedule for study assessments is provided in section 3.2. 
 
Subjects will have the following assessments PRIOR to administration of nivolumab and/or 
ipilimumab on day 1 of cycles 
• 
Medical history (May use pre-treatment assessment for day 1, cycle 1)  
• 
Physical Examination (abbreviated physical examination, Karnofsky performance status, 
vital signs (including pulse oximetry), weight, etc) 
• 
Serum biochemistry (sodium, potassium, chloride, calcium, phosphate, magnesium, AST, 
ALT, creatinine, bilirubin (total), albumin, total protein, urea), amylase, lipase, LDH 
• 
Hematology/CBC (hematocrit, hemoglobin, platelets, red blood cells, white blood cells, 
white blood cell differential) 
• 
TSH with reflex T3/fT4 
• 
PSA 
• 
Recording of Adverse Events 
• 
Recording of all Concomitant Medication/Treatment 
 
The following will be obtained at the mid-cycle visit (3 weeks after administration of study 
drug(s) during cycles 1 and 2  
• 
Serum biochemistry (sodium, potassium, chloride, calcium, phosphate, magnesium, AST, 
ALT, creatinine, bilirubin (total), albumin, total protein, urea), amylase, lipase 
• 
Hematology/CBC (hematocrit, hemoglobin, platelets, red blood cells, white blood cells, 
white blood cell differential) 
• 
Medical history 
• 
Physical Examination 
• 
Recording of Adverse Events 
• 
Recording of all Concomitant Medication/Treatment 
 
During cycles 3-8 at Week 3: 


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• 
Medical history 
• 
Physical examination 
• 
Recording of Adverse Events 
• 
Recording of all concomitant medication/treatment 
• 
CBC with diff 
• 
Comp Panel 
• 
TSH 
 
During cycles 3-8 at Week 5: 
• 
Serum biochemistry, amylase, lipase  
• 
CBC with diff  
• 
Medical history 
• 
Physical examination 
• 
Recording of Adverse Events 
• 
Recording of all concomitant medication/treatment 
• At week 13 and end-of-study visit 
CTCs and research labs 
 
 
At week 13 and every subsequent 12 weeks: 
• Radiologic evaluation (bone scan, CT/MRI of chest/abdomen/pelvis) to assess progression 
of disease – any progression noted prior to week 12 should not result in treatment 
discontinuation (as per PCWG2 Guidelines) 
 
6.2.2 
Safety assessments 
Adverse events (AEs) will be monitored at each scheduled visit and throughout the study. 
Toxicity will be assessed using the most recent National Cancer Institute (NCI) guidance: 
Common Terminology Criteria for Adverse Events (CTCAE version 4.0.  In addition, safety 
will be assessed by the following parameters: 
• Laboratory values: Laboratory values with CTCAE grade 3 or higher that are considered 
clinically significant by the treating physician have to be reported as an adverse event 
• ECG: Clinically relevant changes from baseline, as judged by the Investigator, will be 
recorded as adverse events. A copy of the ECG page, signed and dated, including diagnosis 
should be stored in the patient file. 
• Physical Examination: Any physical examination finding that is classified by the Investigator 
as a clinically significant change (compared to previous examination) will be considered an 
adverse event and documented on the eCRF and followed until the outcome is known.  
6.2.3 
Safety follow-up visit (6 weeks after End of Treatment) 
An initial safety follow-up visit must occur 6 weeks after the completion or discontinuation 
of treatment.). Subjects withdrawn from the study because of AEs will be followed until the 
adverse event has either resolved or stabilized. Reasons for premature withdrawal should 
be determined and noted on the eCRF. The visit will include the following assessments: 


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• Physical Examination (abbreviated physical examination, Karnofsky performance status, 
vital signs etc.) 
• Hematology/CBC (hematocrit, hemoglobin, platelets, red blood cells, white blood cells, 
white blood cell differential) 
• Serum biochemistry (sodium, potassium, chloride, calcium, phosphate, magnesium, AST, 
ALT, creatinine, urea, bilirubin (total), albumin, total protein), amylase, lipase 
• PSA 
• TSH with reflex T3/fT4 
• Recording of Adverse Events 
• Recording of all concomitant medication/treatment 
6.3 
Correlative/Special Studies 
6.3.1 
Circulating tumor cells 
At baseline, at the start of cycle 3, and at the end-of-treatment visit, blood samples will be 
collected by a Cancer Center phlebotomist from peripheral veins for analysis of circulating 
tumor cells (CTCs). This will serve as a “liquid” biopsy. 
6.3.1.1  AR-V7 evaluation 
CTC analyses will be conducted using the commercially-available AlereTM CTC AdnaTest 
platform (AdnaGen, Langenhagen, Germany). This assay does not enable CTC enumeration. 
Isolation and enrichment of CTCs will be performed using the ProstateCancerSelect kit, and 
mRNA expression analyses will be performed using the ProstateCancerDetect kit with 
multiplexed reverse-transcription polymerase-chain-reaction (qRT-PCR) primers to detect 
the presence of CTCs, and custom primers will be designed to detect the full-length-AR (AR-
FL) and AR splice variant-7 (AR-V7).  The relative AR-V7 transcript abundance will be 
determined by calculating the ratio of AR-V7 to AR-FL 
Blood samples will be collected using standard BD Vacutainer® lavender top blood 
collection tubes (Becton Dickinson, Franklin Lakes, NJ) (Product #: 367862) by 
venipuncture, and carried to the lab on ice. Laboratory processing will be carried out within 
2 hours of collection, according to instructions provided by the AlereTM CTC AdnaTest 
(Alere Inc., San Diego, CA). The AdnaTest is a CE-marked, RNA-based CTC enrichment and 
detection test with two components/kits. Briefly, the ProstateCancerSelect (Product No. T-
1-520) kit will be used to enrich CTC from 5ml blood using magnetic particles coated with a 
combination of antibodies recognizing prostate cancer cells, while the ProstateCancerDetect 
(Product No. T-1-521) kit will be used to make cDNA for detection of prostate cancer-
associated RNA transcripts using multiplexed polymerase chain reaction (PCR). On the basis 
of detection of PCR signals for PSA, PSMA, or EGFR (very rarely detected) by the Agilent 
Bioanalyzer (Agilent Technologies, Palo Alto, CA), CTC calls will be made for each sample 
tested.  
The test was previously adapted for detection and quantification of AR-FL and AR-V7 by 
quantitative real-time PCR using custom primers specific for AR-FL (Antonarakis et al, NEJM 
2014): (forward: 5'- CAGCCTATTGCGAGAGAGCTG-3', reverse: 5'-
GAAAGGATCTTGGGCACTTGC-3') and AR-V7 (forward: 5'-
CCATCTTGTCGTCTTCGGAAATGTTA-3', reverse: 5'-TTTGAATGAGGCAAGTCAGCCTTTCT-3'). 
Briefly, PCR reactions were carried out under optimized conditions at 95ᵒC x 10s, 58ᵒC x 
30s, and 72ᵒC x 30s for 39 cycles followed by melting curve analysis. 


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6.3.1.2 PD-L1 evaluation 
Standard qRT-PCR analysis of PD-L1 expression in CTCs will be carried out using cDNA 
derived from CTCs along with negative and positive controls. 
Platform:  Qiagen RotorGene (Qiagen, Milan, Italy) will be used and the level of PD-L1 mRNA 
will be calculated as the ratio of PD-L1 mRNA level and 18S housekeeping gene level for 
each sample. Primers will be designed using Primer Blast 
(http://www.ncbi.nlm.nih.gov/tools/primer-blast/): set 1, 18S -FW (forward) 5' 
AAACGGCTACCACATCCAAG -3', 18S-RE (reverse) 5'-CCTCCAATGGATCCTCGTTA-3', and set 
2, PD-L1-FW (forward) 5'-TACTGGCATTTGCTGAACGC 3', PD-L1-RE (reverse) 5'-
CTTGTAGTCGGCACCACC.  
 
6.3.1.3 Epic Sciences PD-L1 evaluation 
Blood samples from lab draws concurrent with CTC analysis as discussed above will be sent 
to Epic Sciences (San Diego, CA) for PD-L1 evaluation on both CTCs and circulating 
leukocytes. 
6.3.2 
Tumor Biopsy 
For patients with soft-tissue (lymph node and visceral) metastases that are amenable to 
biopsy, an optional core biopsy may be obtained at baseline.    
Sample collection: Patients will be referred to the Johns Hopkins Biopsy Service for an 
image-guided core biopsy (CT/MRI-guided or ultrasound-guided biopsy). 
Four or more standard core biopsies will be obtained from a single metastatic site (soft 
tissue, lymph node). Half of the collected tissue (i.e. at least 2 cores will undergo standard 
formalin-fixation and paraffin-embedding (FFPE) in the Department of GU Pathology (Dr 
George Netto), while the other half (i.e. at least 2 cores) will be frozen fresh in liquid 
nitrogen. To minimize tissue autolysis during fresh tissue collection, a dedicated tissue 
technician will be paged to the biopsy suite to initiate processing steps including flash 
freezing in liquid nitrogen and FFPE preparation, within 30 minutes of the biopsy 
procedure. Tissue must be gently pat-dried with a sterile gauze prior to freezing to avoid 
formation of crystals. The frozen specimens will be stored in a–80o C freezer in the 
laboratory of Dr Jun Luo. Upon accumulation of core biopsies from 5 - 10 patients, the 
frozen biopsies will be sectioned using a cryostat and stained slides will delivered to the 
Dept. of GU Pathology for histological annotation along with the matched FFPE specimens. 
Amendment 1: Somatic DNA sequencing for DNA-repair and other mutations will be 
performed from pre-treatment (fresh or archival) metastatic or primary biopsies. 
Additional testing will include whole-exome sequencing, mutational load analysis, 
hypermutation analysis, and loss of heterozygosity analysis. Tumor RNA sequencing, and T-
cell receptor (TCR) sequencing will also be performed. 
6.3.2.1   
PD-L1 evaluation 
 
FFPE samples will be sent for IHC-based analyses aimed at quantifying the expression of 
proteins involved in PD-1 signaling such as PD-1, PD-L1, and PD-L2. Additional IHC analyses 


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may be completed to determine the relative abundance of other protein markers associated 
with tumor-infiltrating immune cells (eg, CD4, CD8). The abundance of each protein 
monitored (or combinations of proteins) will be correlated with clinical endpoints.  
FFPE tissue will also be evaluated for in situ PD-L1 mRNA expression via in situ 
hybridization (RISH).  This will performed to detect PD-L1 using the ACD (Advanced cell 
Diagnostics, Hayward, CA) RNAscope 2.0 Brown kit. Briefly, formalin-fixed paraffin-
embedded (FFPE) tissue or cell pellet blocks will be sectioned and the slides baked for one 
hour at 600C. The slide were subsequently de-paraffinized with xylene for 20 min at room 
temperature, and allowed to air dry following two rinses using 100% ethanol. Following a 
series of pretreatment steps, the cells were permeablized using protease to allow probe 
access to the RNA target. ACD target probes, a series of paired oligonucleotides forming a 
binding site for a preamplifier, were custom designed to detect RNA corresponding to PD-
L1 mRNA.  Hybridization of the probes to the RNA targets will be performed by incubation 
in the oven for 2 hours at 40C. Following two washes, the slides will be processed for 
standard signal amplification steps per manufacturer’s instructions. 
The FFPE tissue may also be evaluated using genetic mutation detection methods, and/or 
by qRT-PCR as part of additional exploratory analyses seeking biomarker associations with 
clinical endpoints. 
 
6.3.2.2   
AR-V7 
Analysis of FFPE tissues: We plan to carry out immunohistochemical (IHC) staining using 
validated antibodies against markers of the AR axis, including ARFL, AR-V7, the cell cycle 
protein UBE2C (induced by AR-V7), and PSA (induced by AR-FL). IHC analysis will be 
performed by Dr. George Netto at the Department of GU Pathology. Specific antibodies have 
been evaluated in Dr. Luo’s laboratory (Hu et al 2012), and will be provided to Dr. Netto. 
Analysis of fresh frozen tissues: Following histological analysis of frozen sections, tumor 
lesions will be identified and marked by Dr. George Netto at the Dept. of GU Pathology. This 
will be followed by manual trimming of the frozen blocks to enrich marked lesions for 
downstream molecular analyses. Following trimming and sectioning, tumor sections will be 
subject to RNA extraction. These RNA samples will undergo quality control using the Agilent 
Bioanalyzer in Dr. Jun Luo’s laboratory. Dr. Luo’s laboratory will perform standard qRT-PCR 
analysis of AR axis genes (namely AR-FL, AR-V, PSA, TMPRSS2, PSMA, UBE2C, and 
CYP17A1) along with negative and positive controls, as previously reported (Hu et al 2012). 
6.3.2.3 Tumor mRNA Profile 
RNA samples obtained from fresh frozen tissue as per section 6.3.2.2 will be analyzed via 
the Nanostring nCounter PanCancer Immune Profiling Panel, to allow  multiplexed 
quantitative profiling of immune-related mRNAs present in the tumor biopsy sample.   
 
6.3.3 
Circulating Immune Biomarker Profiling 
Serum will be obtained from patients at baseline, cycle 3, and end-of-study.  Cytokine panel 
will be assessed via the Luminex 25-Plex panel (Life Techonologies; Carlsbad, CA) and 
antibody profile will be assessed via ProtoArray (Life Technologies; Carlsbad, CA). 


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6.3.4 
Circulating tumor DNA (ctDNA) 
Plasma will be obtained from patients at baseline to determine DNA mismatch repair (MMR) 
markers from ctDNA. The ctDNA panel will be assessed via the PlasmaSelect assay (PGDx; 
Baltimore, MD) and Hurley lab protocol (appendix C, section 8). 
7 
DOSE ADJUSTMENT AND DELAY, TREATMENT DISCONTINUATION, 
WITHDRAWAL, AND TERMINATION CRITERIA 
7.1  
Dose adjustments 
Dose reductions or dose escalations of nivolumab or ipilimumab are not permitted.  
7.1.1 For second cohort (amendment 1): 
If≥grade3toxicityor intolerable side effects thought to be related to enzalutamide occur, 
enzalutamide should be withheldfor1weekoruntilsymptom(s)improveto≤grade2,then
resumed at same dose, or reduced to a dose of 120mg or 80 mg once daily at the discretion 
of the principal investigator. 
 
7.2 
Dose delay and treatment discontinuation 
Dose delay criteria apply for all drug-related adverse events (regardless of whether or not 
the event is attributed to nivolumab, ipilimumab, or both). All study drugs must be delayed 
until treatment can resume. 
7.2.1 
For second cohort (amendment 1): 
Enzalutamide may be held for adverse events thought to be related to enzalutamide. If a 
subject is off of enzalutamide for longer than 30 consecutive days, either directly prior to 
starting the study or after enrollment, the principal investigator needs to be alerted. 
  
7.3 
Dose Delay Criteria  
Nivolumab and ipilimumab administration should be delayed for the following: 
• 
Any Grade ≥2 non-skin, drug-related adverse event, with the following exceptions: 
• 
Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay 
• 
Any Grade 3 skin, drug-related adverse event 
• 
Any Grade 3 drug-related laboratory abnormality, with the following exceptions for AST, 
ALT, or total bilirubin: 
• 
If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, delay 
dosing for drug-related grade ≥ 2 toxicity 
• 
If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, delay 
dosing for drug-related Grade ≥ 3 toxicity 
• 
Grade 3 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis do not require a dose delay.  
• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication. 
 


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During cycles 1 and 2, both nivolumab and ipilimumab must be delayed at the same time. 
Because of the potential for clinically meaningful nivolumab or ipilimumab-related AEs 
requiring early recognition and prompt intervention, management algorithms have been 
developed for suspected pulmonary toxicity, GI, hepatotoxicity, endocrinopathy, skin 
toxicity, neurological toxicity and renal toxicity. 
 
In order to standardize the management across  subjects for the overlapping adverse event 
management algorithms present in both the nivolumab and ipilimumab IB (GI, hepatic, 
and endocrine algorithms), the recommendations are to follow the nivolumab IB adverse 
event algorithms as opposed to the ipilimumab IB algorithms (see nivolumab IB). 
 
7.4  
 Criteria to Resume Treatment 
Missed doses of nivolumab and/or ipilimumab should be administered as soon as the 
subject meets criteria to resume treatment. If a dose has been missed, the subject should 
not wait until the next scheduled dosing date. 
 
Subjects  may  resume  treatment  with  study  drug  when  the  drug-related  AE(s)  
resolve  to Grade ≤ 1 or baseline value, with the following exceptions: 
• 
Subjects may resume treatment in the presence of Grade 2 fatigue. 
• 
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity. 
• 
Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays 
for reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment 
in the presence of Grade 2 AST/ALT OR total bilirubin. 
• 
Subjects   with   combined   Grade   2   AST/ALT    AND   total   bilirubin   values   meeting 
discontinuation parameters should have treatment permanently discontinued. 
• 
Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline 
before treatment is resumed. 
• 
Drug-related   endocrinopathies   adequately   controlled   with   only   physiologic   
hormone replacement may resume treatment. 
If treatment is delayed > 6 weeks, the subject must be permanently discontinued from 
study therapy. 
 
During cycles 1 and 2, both nivolumab and ipilimumab must be resumed on the same day. 
All four doses of nivolumab combined with ipilimumab must be given prior to beginning 
nivolumab monotherapy (cycle 5 and beyond). 
 
If the subject is unable to resume both nivolumab and ipilimumab, permanent 
discontinuation is required. 


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7.5Discontinuation Criteria 
Treatment with nivolumab and ipilimumab should be permanently discontinued for any of 
the following: 
 
• Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment 
• Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for drug-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, 
diarrhea, colitis, neurologic toxicity, hypersensitivity reactions, and infusion reactions: 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic 
toxicity, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation 
o Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except: 
§ Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation 
§ Any drug-related liver  function  test  (LFT)  abnormality that  meets  the  following criteria 
require discontinuation: 
§ AST or ALT > 5 x ULN 
§ Total bilirubin > 3 x ULN 
§ Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
• Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events which do not require discontinuation 
o Grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis.  
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate   management   within 72 
hours of their onset 
• Any dosing interruption lasting > 6 weeks unless the investigator is consulted and agrees 
with the rationale for resuming therapy after a delay > 6 weeks. Note that tumor 
assessments should continue as per protocol even if dosing is interrupted. 
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued 
nivolumab or ipilimumab dosing 
During cycles 1 and 2, both nivolumab and ipilimumab must be discontinued at the same 
time. 
7.6 
   Treatment of Nivolumab or Ipilimumab-Related Infusion Reactions 
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, 
each is unlikely to be immunogenic and induce infusion or hypersensitivity reactions. 
However, if such a reaction were to occur, it might manifest with fever, chills, rigors, 
headache, rash, pruritis, arthralgias, hypo- or hypertension, bronchospasm, or other 
symptoms.  Infusion reactions should be graded according to NCI CTCAE (version 4.0) 
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Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines as appropriate: 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention 
not indicated) 
Remain at bedside and monitor subject until recovery from symptoms.  The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 
mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 
minutes before additional nivolumab administrations. 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for up to 24 hours). 
Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, and treat 
the subject with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 
to 1000 mg (acetaminophen); remain at bedside and monitor subject until resolution of 
symptoms. Corticosteroid or bronchodilator therapy may also be administered as 
appropriate. If the infusion is interrupted, then restart the infusion at 50% of the original 
infusion rate when symptoms resolve; if no further complications ensue after 30 minutes, 
the rate may be increased to 100% of the original infusion rate. Monitor subject closely. If 
symptoms recur then no further nivolumab or ipilimumab will be administered at that 
visit. Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the 
subject until resolution of symptoms. The amount of study drug infused must be 
recorded on the electronic case report form (eCRF). The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or 
equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) should be 
administered at least 30 minutes before additional nivolumab or ipilimumab 
administrations. If necessary, corticosteroids (recommended dose: up to 25 mg of IV 
hydrocortisone or equivalent) may be used. 
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical 
sequelae [eg, renal impairment, pulmonary infiltrates]). Grade 4: (life-threatening; pressor 
or ventilatory support indicated). 
Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV infusion of 
normal saline, and treat the subject as follows. Recommend bronchodilators, epinephrine 
0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 
1:10,000 solution injected  slowly  for  IV  administration,  and/or  diphenhydramine  50  
mg  IV  with methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be 
monitored until the investigator is comfortable that the symptoms will not recur. 
Nivolumab or ipilimumab will be permanently discontinued. Investigators should follow 
their institutional guidelines for the treatment of anaphylaxis. Remain at bedside and 
monitor subject until recovery from symptoms. In the case of late-occurring 
hypersensitivity symptoms (eg, appearance of a localized or generalized pruritis within 1 
week after treatment), symptomatic treatment may be given (eg, oral antihistamine, or 
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7.7   
  Treatment Beyond Disease Progression 
Accumulating evidence indicates a minority of subjects treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD. 
Subjects will be permitted to continue treatment beyond initial investigator assessed 
progression without reconsent as long as they meet the following criteria: 
• Investigator-assessed clinical benefit and Subject is tolerating study drug. 
• The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. 
 
• Subjects should discontinue study therapy upon evidence of further progression, defined as 
an additional 10% or greater increase in tumor burden volume from time of initial 
progression (including all target lesions and new measurable lesions). 
• New lesions are considered measurable at the time of initial progression if the longest 
diameter is at least 10 mm (except for pathological lymph nodes, which must have a 
short axis of at least 15 mm). Any new lesion considered non-measurable at the time 
of initial progression may become measurable and therefore included in the tumor 
burden measurement if the longest diameter increases to at least 10 mm (except for 
pathological lymph nodes, which must have an increase in short axis to at least 15 mm). 
7.8       Immunotherapy Adverse Event Management 
Because  of  the  potential  for  clinically  meaningful  nivolumab  or  ipilimumab-related  
AEs requiring early recognition and prompt intervention, management algorithms have 
been developed for suspected pulmonary toxicity, GI toxicity, hepatotoxicity, 
endocrinopathy, skin toxicity, neurological toxicity, and renal toxicity (Nivolumab IB). 
These adverse event management algorithms are included in Appendix A. 
7.9 
Removal of Subjects from the Study, Therapy Assessment 
7.9.1 
Subject withdrawal 
Single subject termination is by definition when the patient is withdrawn or when the 
patient has died or completed his 12 month follow-up visit (from start of study treatment). 
The study termination page in the eCRF must be completed. 
The Investigator also has the right to withdraw subjects from the study in the event of: 
• Occurrence of an exclusion criterion which is clinically relevant and affects the subject’s 
safety, and discontinuation is considered necessary by the Investigator and/or the Sponsor. 
• Therapeutic failure requiring urgent additional medication (if applicable) 
• Occurrence of AEs, if discontinuation of study medication is considered necessary by the 
• Investigator and/or subject (if applicable) 
• Intake of non-permitted concomitant medication as defined in Appendix A where the 
predefined consequence is withdrawal from the study  
• Progression of disease (subjects will only come off study after meeting PCWG2 criteria for 
radiographic progression and not for PSA) 
• Lack of subject compliance 
• Protocol violation 
 


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7.10       Treatment Compliance 
Trained medical personnel will administer nivolumab and ipilimumab and dispense other 
study medication. Treatment compliance will be monitored by drug accountability, as well 
as by recording administration of all medications in the CRF. The date and time of start and 
end of infusion and the exact amount given at each infusion will be recorded. Any missed 
doses will be recorded. In case the treatment has to be interrupted during an infusion and 
the dosing is not resumed, the medical personnel should evaluate the percentage of dose 
received by the patient and document it in the patient record. Any reason for non-
compliance should also be documented. 
7.11       Destruction of Study Drug 
Investigator drug destruction is allowed provided the following minimal standards are met: 
• 
On-site disposal practices must not expose humans to risks from the drug. 
• 
On-site disposal practices and procedures are in agreement with applicable laws 
and regulations, including any special requirements for controlled or hazardous substances. 
• 
Written procedures for on-site disposal are available and followed. The procedures 
must be filed with the Sponsor SOPs and a copy provided to BMS upon request. 
• 
Records are maintained that allow for traceability of each container, including the 
date disposed of, quantity disposed, and identification of the person disposing the 
containers. The method of disposal, ie, incinerator, licensed sanitary landfill, or licensed 
waste disposal vendor must be documented. 
• 
Accountability and disposal records are complete, up-to-date, and available for BMS 
to review throughout the clinical trial period as per the study agreement.  
If conditions for destruction cannot be met, please contact BMS.  
It is the Investigator’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to applicable 
federal, state, local, and institutional guidelines and procedures, and provided that 
appropriate records of disposal are kept. 
 
7.12   Return of Study Drug 
If study drug will not be destroyed upon completion or termination of the study, all 
unused and/or partially used study drug that was supplied by BMS must be returned to 
BMS. The return of study drug will be arranged by the investigator. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to 
applicable federal, state, local, and institutional guidelines and procedures, and provided 
that appropriate records of disposal are kept. 
Arrangements for the return of study drug will be made by the investigator. 
8 
ENROLLMENT PLAN 
The start date for the study (first patient first visit) is anticipated to be June 2015. 


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The total duration of the study is expected to be approximately 24 months including an 
enrollment period of 12 months.  All subjects will be followed up for 12 months after start 
of study treatment.  
9  
SAFETY 
The Investigator will review the safety data throughout the course of the study. The 
following safety variables will be evaluated: AEs, serum hematology values, serum 
biochemistry variables and abbreviated physical examination and changes in vital signs 
(systolic/diastolic blood pressure, respiratory rate, and heart rate). 
A baseline recording of any symptoms of illness will be performed before the first 
administration of nivolumab and ipilimumab. 
9.1 
Adverse Event and Serious Adverse Event 
9.1.1 
Definitions 
Adverse Event 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of 
a preexisting medical condition in a clinical investigation subject administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (such as 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of 
investigational product, whether or not considered related to the investigational product. 
The causal relationship to study drug is determined by a physician and should be used to 
assess all adverse events (AE). The casual relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and 
the AE. 
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.  
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should 
not be questioned regarding the specific occurrence of one or more AEs.) 
Serious Adverse Event or Serious Adverse Reaction 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any 
dose:  
• 
results in death 
• 
is life-threatening (defined as an event in which the subject was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe) 
• 
requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below) 
• 
results in persistent or significant disability/incapacity 


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• 
is a congenital anomaly/birth defect  
• 
is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention [eg, 
medical, surgical] to prevent one of the other serious outcomes listed in the definition 
above.) Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization.)  
• 
Potential drug induced liver injury (DILI) is also considered an important medical event.  
• 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the 
study drug is an SAE.  
• 
Although pregnancy, overdose, and cancer are not always serious by regulatory definition, 
these events must be handled as SAEs. 
 
The following hospitalizations are not considered SAEs:  
− 
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event) 
− 
elective surgery, planned prior to signing consent 
− 
admissions as per protocol for a planned medical/surgical procedure 
− 
routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy) 
− 
Medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases 
− 
Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
 
Potential Drug Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event.  All occurrences of potential 
DILIs, meeting the defined criteria, must be reported as SAEs.  Potential drug induced liver 
injury is defined as: 
1) ALT or AST elevation > 3 times upper limit of normal (ULN)  
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
AND 


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3) No other immediately apparent possible causes of AST/ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
 
Unexpected Adverse Reaction 
An unexpected AR is an AR of which the nature or severity is not consistent with the 
applicable product information (e.g., Investigator’s brochure for an unapproved 
investigational product or summary of product characteristics (SPC) for an authorized 
product). When the outcome of the AR is not consistent with the applicable product 
information this AR should be considered as unexpected. 
 
Treatment-Emergent Adverse Event 
Treatment-emergent AEs (TEAEs) are defined as events which occur following the first 
injection of study treatment, or that started prior to the first injection and worsened during 
treatment. 
9.1.2 
Responsibility 
Investigator’s Responsibilities 
The Investigator shall report all SAEs independent of causality to BMS as per sections 9.3 
and 9.4. 
AEs and/or laboratory abnormalities identified in the protocol as critical to safety 
evaluations shall be reported to the Sponsor according to the reporting requirements and 
within the time periods specified in the protocol. 
For reporting death of a subject, the Investigator shall supply the Institutional Review 
Board (IRB) with any additional information requested. 
Each individual AE should be evaluated by the Investigator with regard to date of onset, its 
seriousness, severity, and duration, causal relationship to the investigational medicinal 
product and/or concomitant therapy and outcome. 
IND Holder’s Responsibilities 
The IND Holder is responsible for the ongoing safety evaluation of the investigational 
product. 
The IND Holder is responsible for the prompt notification to all concerned Investigators, the 
ECs/IRBs and regulatory authorities where nivolumab and ipilimumab studies are ongoing, 
of findings that affect the health of the subjects, impact on the conduct of the study or alter 
the regulatory authority’s authorization to continue the study. 
The IND Holder has to keep detailed records of all AEs reported to him by the Investigators 
and to perform an evaluation with respect to seriousness, causality and expectedness. 
These records shall be submitted to the Competent Authorities in the countries where the 
clinical study is being conducted, if they so request. 


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Each individual AE should be evaluated by the IND Holder, with regard to its seriousness 
and causal relationship to the investigational medicinal product and/or concomitant 
therapy. The IND Holder will assess whether or not the AE is unexpected. 
9.2 
Assessment of AE; Seriousness, Causality, Severity and Expectedness 
Seriousness will be determined according to the definition, see Section 9.1. 
Causality will be determined based on the definition in Section 9.1. All AEs judged by the 
Investigator as having a reasonable suspected causal relationship to an investigational 
medicinal product qualify as ARs.  
All toxicities/AEs will be graded according to CTCAE version 4.0. In the eCRF the 
Investigator’s opinion of the relationship of the AE(s) to the investigational drug, will be 
categorized as unrelated, possibly or probably related, as defined below. 
Unrelated: An AE which after careful examination at the time of evaluation, is judged to be 
clearly and incontrovertibly due to extraneous causes (disease, environment, etc) and do 
not meet the criteria for drug relationship listed under possible or probable. 
Possible: An AE which after careful examination at the time of evaluation, the connection 
with the test drug administration, or placebo, cannot be ruled out. 
Probable: An AE which after careful examination at the time of evaluation, the connection 
to the test drug administration, or placebo, appears, with a high degree of certainty, to be 
related to test drug. 
Severity: The term “severe” is used to describe the intensity (severity) of a specific event. 
Note that it is not the same as “serious”, which is based on subject /event outcome or action 
criteria. 
The severity of all events will be graded according to the CTCAE version 4.0 by the 
Investigator. For events not listed in the toxicity table, severity should be recorded as: 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental ADL51 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5: Death related to AE 
Where: 
                                                             
 
 
 
1 Activities of Daily Living (ADL). Instrumental ADL refers to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. Self care ADL refers to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden. 


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Mild: The event causes discomfort without disruption of normal daily activities. 
Moderate: The event causes discomfort that affects normal daily activities. 
Severe: The event makes the subject unable to perform normal daily activities or 
significantly affects his/her clinical status. 
Life-threatening: The subject was at risk of death at the time of the event 
Disabling: The event causes a substantial disruption of a person’s ability to conduct normal 
life functions. 
Expectedness is defined in Section 8.1. Reports have to be considered as unexpected if they 
add significant information on the specificity or severity of an expected adverse reaction. 
The expectedness of an adverse event/reaction will be determined by the investigator. 
The event is unexpected if it is not consistent with the applicable product information, i.e. 
the Investigator’s Brochure for nivolumab and ipilimumab. 
 
9.3 
Reporting of Adverse Events 
 
NONSERIOUS ADVERSE EVENT 
• 
Nonserious Adverse Events are to be provided to BMS in aggregate via interim or final study 
reports as specified in the agreement or, if a regulatory requirement [e.g. IND US trial] as 
part of an annual reporting requirement.  
• 
The collection of nonserious AE information should begin at initiation of study drug. All 
nonserious adverse events (not only those deemed to be treatment-related) should be 
collected continuously during the treatment period and for a minimum of 100 days 
following the last dose of study treatment.  
• 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up is also required for nonserious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as 
appropriate.  
Laboratory Test Abnormalities 
• 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. Test results that constitute SAEs should be documented and 
reported as such. 
• 
The following laboratory abnormalities should be documented and reported appropriately: 
• 
any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
any laboratory abnormality that required the subject to have study drug discontinued or 
interrupted 
• 
any laboratory abnormality that required the subject to receive specific corrective therapy.  
Pregnancy 


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• 
Any pregnancy that occurs in a female partner of a male study participant should be 
reported to BMS. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form. 
• 
Overdose 
• 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as an SAE. 
 
Other Safety Considerations 
• 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x rays, and any other potential safety assessments, whether or not 
these procedures are required by the protocol, should also be recorded as a nonserious or 
serious AE, as appropriate, and reported accordingly. 
 
9.4 
Reporting of Serious Adverse Events 
 
Following the subject’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, must be collected, including those thought to be associated 
with protocol-specified procedures. All SAEs must be collected that occur within 100 days 
of discontinuation of dosing.  
All SAEs must be collected that occur during the screening period. If applicable, SAEs must 
be collected that relate to any protocol-specified procedure (eg, a follow-up skin biopsy).  
The investigator should report any SAE that occurs after these time periods that is believed 
to be related to study drug or protocol-specified procedure.  
 
IND application sponsors are required to notify FDA in a written safety report of: 
• 
Any adverse experience associated with the use of the drug that is both serious and 
unexpected or 
• 
Any findings from tests in laboratory animals that suggest a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, and carcinogenicity.  
  
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
 
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship between the 
drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty 
about causality than an adverse reaction. 


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Adverse reaction means any adverse event caused by a drug. Adverse reactions are a subset 
of all suspected adverse reactions where there is reason to conclude that the drug caused the 
event.   
 
Unexpected adverse event or suspected adverse reaction refers to an event or reaction that 
is not listed in the investigator’s brochure or is not listed at the specificity or severity that has 
been observed; or, if an investigator’s brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the 
current IND application. 
 
Serious adverse event or suspected adverse reaction refers to an event or reaction that, in the 
view of either the investigator or sponsor, results in any of the following outcomes: 
•eath, 
•
 life-threatening adverse event,   
•In-patient hospitalization or prolongation of existing hospitalization, 
•
 persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or   
•
 congenital anomaly or birth defect.    
 
Life-threatening adverse event or suspected adverse reaction is considered “life-threatening” 
if, in the view of the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an adverse event or suspected adverse reaction 
that, had it occurred in a more severe form, might have caused death. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or research subject and may require medical or surgical 
intervention to prevent one of the outcomes listed as serious.  
Mandatory Safety Reporting  
•Initial reporting: IND application sponsor must report any suspected adverse reaction or 
adverse reaction to study treatment that is both serious and unexpected.  
Unexpected serious suspected adverse reactions suggesting significant risk to human 
subjects must be reported to FDA as soon as possible but no later than within 15 calendar 
days following the sponsor’s initial receipt of the information. 
Unexpected fatal or life-threatening suspected adverse reactions represent especially 
important safety information and must be reported to FDA as soon as possible but no later 
than 7 calendar days following the sponsor’s initial receipt of the information. 
•Follow-up reporting: Any relevant additional information obtained by the sponsor that 
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Safety Report. Such report should be submitted without delay, as soon as the information is 
available but no later than 15 calendar days after the sponsor receives the information. 
 
All IND safety reports must be submitted on Form 3500A and be accompanied by Form 1571. 
The type of report (initial or follow-up) should be checked in the respective boxes on Forms 
3500A and 1571.  
 
The submission must be identified as: 
•“IND safety report” for 15-day reports, or 
•“7-day IND safety report” for unexpected fatal or life-threatening suspected adverse 
reaction reports, or 
•“Follow-up IND safety report” for follow-up information. 
 
The report must be submitted to an appropriate Review division that has the responsibility 
to review the IND application under which the safety report is submitted. Each submission to 
this IND must be provided in triplicate (original plus two copies). Send all submissions to the 
following address: 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Oncology Products 1 
5901-B Ammendale Road 
Beltsville, MD 20705-1266 
 
For the 7 days SAE submission, reports can be submitted by facsimile to DOP1/OHOP at 
(301)-796-9845 and to the attention of Sakar Wahby, PharmD, the division’s Regulatory 
Project Manager 
 
9.5 
Procedures to be followed in the Event of Abnormal Laboratory Tests 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. Test results that constitute SAEs should be documented and 
reported as such. 
The following laboratory abnormalities should be documented and reported appropriately: 
•
ny laboratory test result that is clinically significant or meets the definition of an SAE 
             •
ny laboratory abnormality that required the subject to have study drug discontinued or 
interrupted 


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•
ny laboratory abnormality that required the subject to receive specific corrective 
therapy. 
 
9.6 
Other Safety Parameters Including Demographics 
9.6.1 
Medical and surgical history of prostate cancer 
A summary of the subject’s relevant medical and surgical history of prostate cancer (i.e. 
time period from diagnosis of underlying malignancy to enrollment in the study, time of 
occurrence of skeletal metastases) should be recorded on the appropriate eCRF page. 
9.6.2 
Vital signs 
 
Vital signs include heart rate, systolic and diastolic blood pressures, pulse oximetry, and 
respiratory rate. Vital signs will be assessed pre administration as detailed in Section 6.1. 
Normal limits for vital signs are provided below in Table 2 below. 
Table 2. Criteria for normal limits for vital signs 
Vital signs parameter 
Normal limits 
Low 
High 
Systolic BP (mm Hg) 
85 
149 
Diastolic BP (mm Hg) 
60 
95 
Heart rate (bpm) 
60 
100 
O2 saturation 
95 
100 
Respiration rate (rpm) 
12 
22 
 
 
Both “new” and “worsening” vital signs abnormalities are anticipated in subject’s over the 
course of a clinical study. A “new” abnormality is defined as one that occurs when a 
subject’s normal baseline vital signs develop clinically significant values (“notable”) post 
baseline. A “worsening” abnormality is defined as one that occurs when a subject’s “notable” 
baseline vital signs become worse post baseline by 25%. 
Notable vital signs results should be interpreted in conjunction with the clinical situation of 
the subject. Once AE notification is decided upon, the Investigator is required to follow the 
procedure described for AE notification and document the clinically notable abnormality on 
the AE eCRF page. Any notable abnormal vital signs finding or related AE must be followed 
until the outcome is known. 
Before vital signs are recorded, the subject should be resting for at least 5 minutes. The 
same position will be used each time vital signs are recorded for a given subject, and blood 
pressure will be measured from the arm contra lateral to the site of administration of 
nivolumab and ipilimumab. 
9.6.3 
Physical examination 
An abbreviated physical examination consisting of general appearance, lungs, 
cardiovascular system and abdomen and other physical findings will be done at each 
hospital visit where the subject meets with the treating physician. 
Any physical examination finding that is classified by the Investigator as a clinically 
significant change (worsening compared to previous examination) will be considered as an 
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The Investigator will also assess the Karnofsky performance status at time points outlined 
in Section 6. 
 
Karnofsky performance status is defined as follows: 
Table 3. Karnofsky performance status 
Scale (%) Description 
100 
Normal; no complaints (ECOG 0) 
90 
Able to carry on normal activities; minor signs or symptoms of disease (ECOG 
0) 
80 
Normal activity with effort (ECOG 1) 
70 
Cares for self. Unable to carry out on normal activity or to do active work 
(ECOG 1) 
60 
Requires occasional assistance and frequent medical care (ECOG 2) 
50 
Requires considerable assistance and frequent medical care (ECOG 2) 
40 
Disabled; requires special care and assistance (ECOG 3) 
30 
Severely disabled; hospitalization indicated though death not imminent (ECOG 
4) 
20 
Very sick. Hospitalization necessary. Active supportive treatment necessary 
(ECOG 4) 
10 
Moribund (ECOG 4) 
0 
Dead (ECOG 5) 
 
It is of importance to evaluate the Karnofsky performance status thoroughly, since this is 
one of the efficacy parameters. Even if the subject has to withdraw from the study due to 
difficulties in returning to hospital visits, the Karnofsky performance status should be 
evaluated at withdrawal. 
9.6.4 
ECG 
A standard 12–lead ECG will be performed at screening. Results will be recorded as normal 
or abnormal; abnormal findings will be described in the eCRF and when clinically relevant, 
findings should be recorded as symptoms before administration and should be followed up 
during study as needed per the Investigator’s judgment. The ECG will be evaluated by the 
local Investigator. The signed and dated ECG page (including diagnosis) should be stored in 
the subject’s medical record. 
ECG does not need to be repeated during the study unless clinically indicated. 
9.6.5 
Clinical laboratory parameters 
Safety serum biochemistry and hematology parameters will be analyzed at each local 
laboratory as for standard of care. 
Blood samples for the determination of serum chemistry and hematology will be drawn at 
pre-specified time-points, see Section 7. Additional hematology, chemistry and/or urine 
assessment are under the Investigator’s judgment. 


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The following laboratory tests will be performed (Table 4): 
Table 4. Clinical laboratory parameters 
Serum biochemistry 
Hematology 
Alanine aminotransferase (ALT) 
Hematocrit 
Albumin 
Hemoglobin 
Aspartate aminotransferase (AST) 
Platelets 
Calcium 
Red blood cell count 
Chloride 
White blood cell count 
Creatinine 
Differential (percents and absolutes) 
Lactate Dehydrogenase (LDH) 
Neutrophils 
Magnesium 
Lymphocytes 
Phosphate 
Monocytes 
Potassium 
Eosinophils 
Protein, total 
Basophils 
Sodium 
 
 
 
 
Reference ranges from each laboratory will be provided to the PCCTC. If during the study, 
ranges should be changed, the Investigator is requested to provide updated laboratory 
normal values. 
Laboratory values with CTCAE Grade 3 or higher and considered clinically significant by the 
treating physician have to be reported as an AE during the treatment period. During the 
follow-up period only changes in laboratory values judged to be related to the study drug 
will be reported. 
The Investigator will interpret all clinical laboratory test results outside the reference 
range, using the following criteria: 
1 = Value out of reference range, but not a clinically significant worsening from previous 
examination 
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9.7 
Safety Monitoring 
 
The study will be continuously monitored for adverse events, which we define here as 
Grade 3 or 4 events that do not improve to Grade 1 or better within two weeks of 
implementing the adverse event monitoring algorithm (see Appendix A). If this toxicity rate 
appears to be higher than 30%, we will temporarily halt the study pending dose 
modification.  Specifically, we will apply a Bayesian toxicity monitoring rule that suspends 
the enrollment if the posterior probability of risk being larger than 0.3 is 75% or higher.  
 
In a study of the combination of ipilimumab and nivolumab in melanoma with greater 
ipilimumab dosing, 21% of patients developed Grade 3 or 4 treatment-related events that 
were dose-limiting.  
 
The monitoring rule uses beta(0.5, 3.5) as the prior distribution. This means that the prior 
guess for the proportion of toxicity is 12.5% and there is 90% probability that this 
proportion is between 0% and 44%.   
 
The decision rule for safety stopping is as follows: 
  
Stop if: 
#  AE 
3 
4 
5 
6 
7 
Out of 
3 
5 
8 
11 
13 
  
4 
6 
9 
12 
14 
  
 
7 
10 
 
15 
  
  
  
  
  
  
  
For example, if three out of the first 3 patients have adverse events, we will stop the accrual. 
If four or more out of the first 5-7 patients have adverse events, we will stop. 
  
The operating characteristics of the stopping rule are shown below and are based on 5000 
simulations: 
 
True AE rate 
% Simulated trials 
declaring unsafe 
Average sample size (out 
of15) 
0.15 
2.7 
14.8 
0.20 
7.2 
14.4 
0.25 
13.6 
13.9 
0.30 
24.7 
13.1 
0.35 
36.7 
12.2 
0.40 
50.5 
11.2 


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0.45 
66.4 
9.8 
10 
EFFICACY ASSESSMENT 
The efficacy assessments will be based on changes in biochemical markers and radiological 
evaluations. 
10.1 
PSA  
PSA will be measured at baseline, and according to the Schedule of Assessments,. The 
samples will be collected, shipped and analyzed according the laboratory manual. 
10.1.1 PSA response 
For PSA, response will be described as the proportion of patients achieving a >50% 
decrease at any time during therapy relative to baseline.  Using PCWG2 guidelines, the 
percentage of change in PSA from baseline to 12 weeks, as well as the maximum decline in 
PSA will be reported for each subject using a waterfall plot.  
10.1.2 PSA Progression-free Survival (PSA-PFS) 
Progression, for those subjects showing an initial decline in PSA from baseline, is defined as 
anincreaseinPS
thatis≥25%and≥2ng/mLabovethenadir,andwhichisconfirmedbya
second value 3 or more weeks later (i.e., a confirmed rising trend). Progression, for those 
subjects with no decline in PS
frombaseline,isdefinedasanincreaseinPS
thatis≥25%
and≥2ng/mLafter12weeks. 
 
PSA-PFS will be measured from the time of treatment initiation until the time of 
clinical progression, radiographic progression, or death (see Appendix B). For 
subjects who have not yet demonstrated progression by the follow-up visit, patients 
will be censored at the date of the last tumor assessment that shows a lack of 
progression. This outcome will be depicted via Kaplan-Meier analysis. 
 
10.2 
Secondary Endpoints 
 
 
10.2.1 Conversion from AR-V7-positive to AR-V7-negative 
Conversion of AR-V7 positivity will be defined as the proportion of patients with negative 
AR-V7 in CTCs at either the week 13 time-point or the end-of-study time-point.  Patients for 
whom CTCs cannot be detected at either of these two time-points will be considered to not 
be evaluable for this endpoint. 
 
10.2.2 Criteria for Response, Progression, and Relapse 
RECIST criteria will only apply to soft tissue lesions. PCWG2 discourages the use of overall 
response criteria, and in this protocol, such criteria will only apply to soft tissue lesions, will 
not incorporate bone lesions, and will not incorporate changes in tumor markers. 
Bone lesions: Post-treatment changes will be described as “new lesions” or “no new 
lesions.” 


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There will be no descriptions of post-treatment “responses” for bone metastases. As such, 
only progression will be defined in regards to bone lesions, using the following table as a 
descriptor. 
Patients are defined as progressing when they meet bone or soft tissue progression (both 
are not required). 
 
10.2.2.1 Progression-free survival (PFS) 
PFS will be defined as the duration of time from start of treatment to time of progression 
(per PCWG2 criteria) or death, whichever occurs first. 
For soft tissue lesions, this is based on RECIST 1.1; or for bone disease, based on PCWG2 
definitions which require the appearance of at least 2 new lesions with a confirmatory bone 
scan at least 6 or more weeks later. 
If an event was not observed for a subject, or the subject withdrew, the time to event will be 
censored at the date of last contact recorded on the eCRF. 
If a subject progresses according to both radiological and clinical criteria, the earlier 
response will determine the time of response for the endpoint. 
If the occurrence of an event requires subsequent confirmation, the time of the event will be 
taken as the time of the first observation rather than the confirmation. For example, for a 
subject with radiological progression, the time of the progression will be the date of the 
bone scan at which two or more new lesions were first observed, not the date of the follow-
up scan at which their presence was confirmed. 
A subject in whom clinical or radiographic progression has been observed but not 
confirmed and who then subsequently dies will be considered to have progressed at the 
time of the observation (that is, they will be treated as if a confirmatory observation had 
been made). A subject who dies before radiographic or clinical progression has been 
observed will be considered to have progressed at the date of death, regardless of cause. 
 
10.2.2.2 Durable PFS 
Durable PFS will be defined as the proportion of patients without clinical or radiographic 
progression or death at 24 weeks from start of treatment. 
 
10.2.2.3 Objective Response Rate (ORR) 
ORR will be defined as the proportion of patients with a complete response (CR) or partial 
response (PR) in measurable soft-tissue lesions as defined by RECIST 1.1 criteria (see 
Appendix B). 
 
10.2.2.4 Overall Survival (OS) 
Overall survival will be defined as the time from study enrollment to death.  This will be 
analyzed as a Kaplan-Meier plot. 
10.2.3 AR-V7 
The primary correlative analysis will be to investigate the proportion of men who convert 
from AR-V7–positive at baseline to AR-V7–negative during/after therapy with 
ipilimumab/nivolumab.  This will be assessed at the 12-week time point as well as at time of 
progression.    


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Additionally, the change in AR-V7 expression, expressed as a ratio of AR-V7 to full-length 
AR (AR-FL) will be assessed at each time point.   
 
11 
STATISTICAL CONSIDERATIONS 
11.1 
Statistical Hypothesis and Sample Size 
Our primary efficacy hypothesis is that we will observe PSA responses (>50% PSA declines) 
in a significant proportion of patients treated with ipilimumab plus nivolumab. Because 
there are currently no effective AR-directed therapies for men with AR-V7–associated CRPC 
(and PSA response rates with enzalutamide/ abiraterone approach 0%), we would consider 
ipilimumab + nivolumab promising if the PSA response rate is higher than 5%. We 
plantoenroll15patients.Ifweobserve≥3PS
responsesin15patients,thelower
bound of 90% confidence interval of response rate would be above 5% (90% CI: 
5.6% - 44%), and future study would be warranted. 
 
If we observe ≥3 PSresponsesin15 patients, we will proceed with subsequent larger 
trials. If we see ≤2 out of 15 PSA responses, we will consider this therapy unworthy of 
further study in AR-V7–positive mCRPC. 
 
For cohort #2 (amendment 1) 
Our primary efficacy hypothesis is that we will observe PSA responses (>50% PSA declines) 
and/or Objective response rates (ORR) in patients with measurable disease in a significant 
proportion of patients treated with ipilimumab plus nivolumab. Because there are currently 
no effective AR-directed therapies for men with AR-V7–associated CRPC (and PSA response 
rates with enzalutamide/ abiraterone approach 0%), we would consider ipilimumab + 
nivolumab promising if the composite endpoint of PSA response rate and/or ORR is higher 
than5%.Weplantoenroll15patients.Ifweobserve≥3PS
responses and/or ORR in 15 
patients, the lower bound of 90% confidence interval of response rate would be above 5% 
(90% CI: 5.6% - 44%), and future study would be warranted.  
Ifweobserve≥3PS
responses and/or ORR in 15 patients, we will proceed with subsequent 
largertrials.Ifwesee≤2outof15PS
 responses and/or ORR, we will consider this therapy 
unworthy of further study in AR-V7-positive mCRPC. 
 
11.2 
Analysis Populations 
 
Evaluable for safety: 
All subjects who are enrolled and receive at least one administration 
of nivolumab and/or ipilimumab will be considered the safety population. 
Evaluable for PSA response: 
All patients who have received at least one cycle (6 weeks) of 
therapy and have their PSA re-evaluated will be considered eligible for PSA response. 
Evaluable for objective response: All patients who have measureable disease present at 
baseline, have received at least one cycles (6 weeks) of therapy, and have had their disease 
re-evaluated will be considered evaluable for objective response. These patients will have 


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their response classified according to RECIST 1.1 criteria.  (Note: patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered evaluable). 
 
11.3 
Statistical Method 
11.3.1 Standard listings 
All individual data collected in the eCRF will be presented in data listings. Subjects screened 
but not included in the study will not be presented in any tables or listings.  
11.3.2 Analysis of demographic and baseline characteristics 
Demographic data and other baseline characteristics (including medical and disease 
history) will be summarized using the standard summary statistics. 
11.3.3 Analysis of primary objective 
The proportion of PSA responses (>50% PSA decline) and the corresponding 95% binomial 
confidence intervals will be reported. 
11.3.3.1 For second cohort (Amendment 1) 
The proportion of PSA responses (>50% PSA decline) and/or Objective responses in 
patients with measurable disease and  the corresponding 95% binomial confidence 
intervals will be reported.  
 
11.3.4 Analysis of secondary safety objective 
Standard safety summaries will be provided for treatment exposure, patient disposition, 
adverse events leading to discontinuation, serious adverse events, and all events resulting 
in death, including those up to 30 days after treatment discontinuation.  The incidence of 
adverse events will be tabulated and reviewed for potential significance and clinical 
importance. 
11.3.5 Analysis of secondary correlative/biomarker objectives 
The proportion of patients converting from AR-V7-positive to AR-V7-negative during 
treatment will be reported, along with the corresponding 95% binomial confidence interval, 
and compared across time points using McNemar’s test.  The changes in AR-V7 expression, 
expressed as a ratio of AR-V7 to full-length AR (AR-FL) will be analyzed over time using 
linear mixed effects models.. 
The relationships between binary measures (e.g. response) and candidate biomarkers will 
be investigated using logistic regression, and using cox regression for time-to-event-
endpoints (e.g. PFS). Associations will be summarized in terms of point and interval 
estimates of hazard ratios, odds ratios, or other statistics, as appropriate for the analyses 
completed. 
 
11.3.6 Analysis of other secondary objectives 
Time-to-event endpoints of PSA-PFS, PFS, and OS will be presented using Kaplan-Meier 
estimates and corresponding 95% confidence intervals. 


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The proportion of “Durable PFS”, defined as lack of clinical/radiographic progression for 
≥24weeks,willbereportedalongwiththecorresponding95%binomial CI. 
ORR will be estimated as the proportion of subjects whose best overall response is either a 
CR or PR with corresponding 95% binomial CI. 
 
11.3.7 Handling of drop-outs and/or missing data 
Subjects that withdraw/are being withdrawn for other reasons than safety prior to 
receiving one injection of nivolumab or ipilimumab (i.e. non-evaluable subjects) will be 
replaced. In safety and exploratory analyses, reason of missing/drop out will be 
documented. Analyses based on completers and missing imputation using the best available 
knowledge (or use multiple imputation when missing is completely at random) will be 
performed and compared. 
11.3.8 Sub-group analysis 
No sub-group analyses are planned. However, sub-groups may be identified on a data-
driven basis, and such analyses will be considered exploratory and hypothesis generating 
only.  
 
 
 
12 
DATA REPORTING AND REGULATORY REQUIREMENTS 
 
 
12.1 
Data Reporting and Regulatory Requirements 
 
12.2.1 
Data Entry  
Data collected during this study will be entered into a secure database. Staff at 
SKCCC will be responsible for the initial study configuration and setup in the 
database and for any future changes. 
 
12.2.2 
Case report forms 
Case report forms (e-crf) will be generated by Staff at SKCCC for the collection of all 
study data. Investigators will be responsible for ensuring that the CRFs are kept up-
to-date. 
 
 12.2.3 
Source documents 
Study personnel will record clinical data in each patient’s source documents (ie, the 
patient’s medical record). Source documentation will be made available to support 
the patient research record.  
 
 12.2.4 
Record retention 
The investigator will maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified. 


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After study closure, the investigator will maintain all source documents, study-
related documents, and the CRFs. Because the length of time required for retaining 
records depends upon a number of regulatory and legal factors, documents should 
be stored until the investigator is notified that the documents may be destroyed. In 
this study, records are to be retained and securely stored for a minimum of 7 years 
after the completion of all study activities. 
12.2  Data Management 
 
12.2.1 Lead research program coordinators 
A Lead Research Program Coordinator at SKCCC will be assigned to the study. A Lead 
Research Program Coordinator will manage the study activities. The responsibilities of the 
Lead Research Program Coordinator include project compliance, data collection, data entry, 
data reporting, regulatory monitoring, problem resolution and prioritization, and 
coordination of the activities of the protocol team. 
 
 
 
12.2.2   Study Monitoring and Quality Assurance 
Regularly scheduled registration reports will be generated to monitor patient accruals and 
the completeness of registration data. Routine data quality reports will be generated to 
assess missing data and inconsistencies. Accrual rates and the extent and accuracy of 
evaluations and follow-up will be monitored periodically throughout the study period, and 
potential problems will be brought to the attention of the principal investigator for 
discussion and action. 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team at least once a year, more frequently if indicated.  
All clinical work conducted under this protocol is subject to Good Clinical Practice (GCP) 
guidelines. This includes inspection of study-related records, sponsor, its designee, or 
health authority representatives at any time. 
 
12.2.3 Data and Safety Monitoring 
This is a DSMP Level II study under the SKCCC Data and Safety Monitoring Plan 
(12/6/2012). Data Monitoring of this protocol will occur on a regular basis with the 
frequency dependent on the rate of subject accrual and the progress of the study.  The 
protocol will be monitored internally at SKCCC by the Principal Investigator and externally 
by the SKCCC CRO in accordance with SKCCC guidelines.  Trial monitoring and reporting 
will be done through the Safety Monitoring Committee (SMC) at SKCCC.  
Additionally, scheduled meetings will take place monthly and will include the protocol 
principal investigator, research nurse, data manager, and, when appropriate, the 
collaborators, subinvestigators, and biostatistician involved with the conduct of the 
protocol. 
During these meetings the investigators will discuss matters related to: safety of protocol 
participants, validity and integrity of the data, enrollment rate relative to expectation, 
characteristics of participants, retention of participants, adherence to protocol (potential or 
real protocol violations), data completeness, and progress of data for secondary objectives. 
 


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12.3 
Good Clinical Practice 
The study will be conducted in accordance with the International Conference on 
Harmonisation (ICH) for Good Clinical Practice (GCP) and the appropriate regulatory 
requirement(s).  The investigator will be thoroughly familiar with the appropriate use of the 
study drug as described in the protocol and Investigator’s Brochure.  Essential clinical 
documents will be maintained to demonstrate the validity of the study and the integrity of 
the data collected.  Master files should be established at the beginning of the study, 
maintained for the duration of the study and retained according to appropriate regulations.   
    
 
12.3.1  Ethical Considerations 
The study will be conducted in accordance with applicable regulatory requirement(s) and 
will adhere to GCP standards.  The IRB/IEC will review all appropriate study documentation 
in order to safeguard the rights, safety and well-being of the patients.  The study will be 
conducted only at sites where IRB/IEC approval has been obtained.  The protocol, 
Investigator’s Brochure, informed consent form, advertisements (if applicable), written 
information given to the patients (including diary cards), safety updates, annual progress 
reports, and any revisions to these documents will be provided to the IRB/IEC by the 
investigator.  BMS requests that informed consent documents be reviewed by BMS or 
designee prior to IRB/IEC submission.   
    
 
12.3.2  
Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from 
either the patient or his/her guardian or legal representative before study participation.  
The method of obtaining and documenting the informed consent and the contents of the 
consent must comply with the ICH-GCP and all applicable regulatory requirements. 
   
  
12.3.3  
Patient Confidentiality 
In order to maintain patient privacy, all data capture records, drug accountability records, 
study reports and communications will identify the patient by initials and the assigned 
patient number.  If requested, the investigator will grant auditor(s) from BMS or its 
designees and regulatory authority(ies) access to the patient’s original medical records for 
verification of data gathered on the data capture records and to audit the data collection 
process.  The patient’s confidentiality will be maintained and will not be made publicly 
available to the extent permitted by the applicable laws and regulations. 
    
 
12.3.4  
Investigator Compliance 
The investigator will conduct the study in compliance with the protocol given 
approval/favorable opinion by the IRB/IEC and the appropriate regulatory authority(ies).  
Changes to the protocol will require approval from BMS and written IRB/IEC 
approval/favorable opinion prior to implementation, except when the modification is 
needed to eliminate an immediate hazard(s) to patients.  The IRB/IEC may provide, if 
applicable regulatory authority(ies) permit, expedited review and approval/favorable 
opinion for minor change(s) in ongoing studies that have the approval /favorable opinion of 
the IRB/IEC.  The investigator will submit all protocol modifications to BMS and the 
regulatory authority(ies) in accordance with the governing regulations.  
Any departures from the protocol must be fully documented in the source documents.   


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12.3.5  
On-site Audits 
Regulatory authorities, the IEC/IRB and/or BMS may request access to all source 
documents, data capture records, and other study documentation for on-site audit or 
inspection.  Direct access to these documents must be guaranteed by the investigator, who 
must provide support at all times for these activities. 
    
 
12.3.6  
Investigator and Site Responsibility for Drug Accountability 
Accountability for the study drug at all study sites is the responsibility of the principal 
investigator.  The investigator will ensure that the drug is used only in accordance with this 
protocol.  Drug accountability records indicating the drug’s delivery date to the site, 
inventory at the site, use by each patient, and amount returned to BMS or a designee or 
disposal of the drug (if applicable and if approved by BMS) will be maintained by the clinical 
site.  Accountability records will include dates, quantities, lot numbers, expiration dates (if 
applicable), and patient numbers.   
          12.4 
 
Record Retention 
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s).  
  
 
 
 
 
 
13 
REFERENCES 
 
Antonarakis, Emmanuel S., Changxue Lu, Hao Wang, Brandon Luber, Mary Nakazawa, 
Jeffrey C. Roeser, Yan Chen et al. "AR-V7 and resistance to enzalutamide and abiraterone in 
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Bishop, Jennifer L., Alexander Sio, Arkhjamil Angeles, Morgan E. Roberts, Arun A. Azad, Kim 
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Brahmer J, Tykodi S, Chow L, et. al. Safety and Activity of Anti–PD-L1 Antibody in Patients 
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de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate 
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Delyon J, Mateus C, Lefeuvre D, Lanoy E, Zitvogel L, Chaput N, Roy S, Eggermont AM, Routier 
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Hodi F, Topalian S, Brahmer J. Survival and long-term safety in patients (pts) with advanced 
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Hu, Rong, Changxue Lu, Elahe A. Mostaghel, Srinivasan Yegnasubramanian, Meltem Gurel, 
Clare Tannahill, Joanne Edwards et al. "Distinct transcriptional programs mediated by the 
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Hu R, Dunn TA, Wei S, et al. Ligand-independent androgen receptor variants derived from splicing of cryptic 
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Mostaghel EA, Marck BT, Plymate SR, et al. Resistance to CYP17A1 inhibition with 
abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and 
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Nadiminty N, Tummala R, Liu C, et al. NF-κA2/p52inducesresistancetoenzalutamidein
prostate cancer: role of androgen receptor and its variants. Mol Cancer Ther 2013;12:1629-
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O'Donnell A, Judson I, Dowsett M, et al. Hormonal impact of the 17alpha-
hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with 
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Opdivo (nivolumab) package insert.  Princeton: Bristol-Myers Squibb, 2015.  
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Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, Mu Z, Rasalan T, Adamow 
M, Ritter E, Sedrak C, Jungbluth AA, Chua R, Yang AS, Roman RA, Rosner S, Benson B, Allison 
JP, Lesokhin AM, Gnjatic S, Wolchok JD (2012) Immunologic correlates of the abscopal effect 
in a patient with melanoma. N Engl J Med 366(10): 925–931 
 
Postow MA, Panageas KS (2012) Evaluation of the absolute lymphocyte count as a 
biomarker for melanoma patients treated with the commercially available dose of 
ipilimumab(3Fmg/kg).The
mericanSocietyof0linicalOncology
nnualMeeting,0hicago,
USA. J Clin Oncol 30(Suppl): abstr 8595. 
 
Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous 
chemotherapy. N Engl J Med2013;368:138-148 
 
Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: 
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chemotherapy. N Engl J Med 2012;367:1187-1197 
 
Thadani-Mulero, Maria, Luigi Portella, Shihua Sun, Matthew Sung, Alexandre Matov, Robert 
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Topalian S, Sznol M, Brahmer J et al. Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in 
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Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M 
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Appendix A: Management algorithm for immuno-oncology agents 
 
These general guidelines constitute guidance to the Investigator. The guidance applies to all 
immuno-oncology agents and regimens. 
 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and 
appropriately treated.  
 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. 
The oral equivalent of the recommended IV doses may be considered for ambulatory 
patients with low-grade toxicity. The lower bioavailability of oral corticosteroids should be 
taken into account when switching to the equivalent dose of oral corticosteroids. 
 
For subjects expected who require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an adverse event, consider the following 
recommendations  
Antimicrobial/antifungal prophylaxis per institutional guidelines to prevent opportunistic 
infections such as Pneumocystis jiroveci and fungal infections. 
Early consultation with an infectious disease specialist should be considered. Depending on 
the presentation, consultation with a pulmonologist for bronchoscopy or a 
gastroenterologist for endoscopy may also be appropriate. 
In patients who develop recurrent adverse events in the setting of ongoing or prior 
immunosuppressant use, an opportunistic infection should be considered in the differential 
diagnosis. 
 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic 
or therapeutic procedure, is recommended. 
 
The frequency and severity of the related adverse events covered by these algorithms will 
depend on the immuno-oncology agent or regimen being used.


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Appendix B: 
Prostate Cancer Clinical Trials Working Group (PCWG2) Criteria for Response 
 
 
Pathology response criteria  
 
When evaluating measurable soft-tissue target lesions, the RECIST definitions will apply. The first assessment must show an increase in the 
sum longest diameter (LD) ofbothpreexistingandnewlesionsof≥20%whencomparedwiththesmallestsumLrecordedsince
treatment started. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. When the evaluation of complete response 
depends on this determination, it is recommended that the residual lesion be investigated further (e.g. by aspirate/biopsy) before 
confirming the complete response status. 
 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be 
identified as target lesions and will be recorded and measured at baseline. Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), be representative of all involved organs, and should be chosen based on their suitability for accurate 
repetitive measurements. Lymph nodesneedtobe≥20mminatleastonedimensiontobeconsideredtargetorevaluablelesionstoassess
changes in size. 
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible repeated measurements in which case the next 
largest lesion that can be measured reproducibly should be selected. A sum of the diameters (longest for all lesions, including nodes) for all 
target lesions will be calculated and reported as the baseline sum diameters. The baseline sum LD will be used as reference to further 
characterize the objective tumor response of the measurable dimension of the disease. 
Complete Response: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction 
in long axis to < 10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new non-osseous lesions is also considered 
progression). Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules, palpable lymph nodes) and at 


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least 10 mm in diameter as assessed using calipers (e.g., skin nodules). Per PCWG2 and Cou302: Visceral (lung, liver adrenal) or extranodal 
lesionsneedtobe≥10mminonedimension,usingspiral0T.However,lymphnodesneedtobe≥20mminatleastonedimension to be 
considered new. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest 
sum diameters while on study. 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. Non-target lesions include bone lesions. 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-
pathological in size (<10 mm long axis). Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response. 
Non-complete response (non-CR)/Non-progression (non-PD): Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal  limits. 
 
Evaluating best overall response 
 
The best overall response is the best response recorded from the start of treatment until disease progression/recurrence. The investigator’s 
determination of best overall response will be based on the response criteria and will not require confirmation scans. For defining disease 
progression, confirmation scans will only be required in the case where progression is seen on the first follow-up bone scan, but not if 
progression is shown on CT.  
Patients with global deterioration of health status who require discontinuation of treatment without objective evidence of disease 
progression should be classified as having symptomatic deterioration. Every effort should be made to document their objective progression, 
even after discontinuation of treatment. 
The table below summarized the recommendations of the PCWG2 for measuring response/progression outcomes in phase II clinical trials of 
prostate cancer. Although these guidelines have been largely followed in the design of the present trial, this table should not be used as a 
substitute for the clinical protocol. 


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Prostate Cancer Clinical Trials Working Group (PCWG2) Outcome Measures 
 
Variable 
Control/Relieve/Eliminate 
PSA 
Record the percent change from baseline (rise or fall) at 12 weeks, 
and separately, the maximal change (rise or fall) at any time using 
a waterfall plot 
Soft-tissue 
lesions 
Use RECIST with caveats 
Only report changes in lymph nodes that were ≥ 2 cm in diameter 
at baseline 
Record changes in nodal and visceral soft tissue sites separately 
Record complete elimination of disease at any site separately 
Confirm favorable change with second scan 
Record changes using waterfall plot 
Bone 
Record outcome as new lesions or no new lesions 
   First scheduled reassessment: 
No new lesions: continue therapy 
New lesions: perform a confirmatory scan 6 or more weeks later 
Confirmatory scan: 
No new lesions: continue therapy 
Additional new lesions: progression 
   Subsequent re-assessments: 


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No new lesions: continue 
New lesions: progression 
Symptoms 
Consider independently of other outcome measures 
Document pain and analgesia at entry with a lead in period and 
measure repeatedly at 3- to 4-week intervals 
Perform serial assessments of global changes in HRQOL, urinary or 
bowel compromise, pain management, additional anticancer 
therapy 
Ignore early changes (< 12 weeks) in pain or HRQOL in absence of 
compelling evidence of disease progression 
Confirm response or progression of pain or HRQOL end points > 3 
weeks later 
 
Abbreviations:  PSA, prostate-specific antigen; HRQOL, health-related quality of life 
 
 
 
 


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Appendix C: Specimen Collection and Shipping for STARVE-PC study 
 
CTCs will be collected at screening visit, at the start of cycle 3, and at either the end of study visit or at time of progression if 
patient is continuing on treatment despite progression. 
 
1. Screening AR-V7 Assay (for eligibility) 
Please note: Specimens should be drawn in the morning and delivered by noon the same day. 
1) AR-V7 testing will be required to determine eligibility. This will be ordered by the provider in EPIC (AR-V7 Prostate Cancer). 
2) Specimens will be processed by the Molecular Diagnostics CLIA core lab. 
3) Specimen should be drawn in the morning and hand-delivered to the lab in Park SB202 by noon the same day (samples must begin 
processing within 4 hours of collection). Alternately, specimens may be delivered to tube station 141 in Weinberg building by 11:30AM 
the same day. 
4) Please note laboratory hours are Mon-Fri, 8:30-5:30. 
 
2. CTC Adnatest for AR-V7  
1) Blood draws should be scheduled on Monday-Friday. 
2) Blood samples will be collected in one BD Vacutainer ACD Solution A tubes (BD ACD-A) (yellow top). Product # for the BD ACD-A tube is 
364606 (US). 
3) Ensure that at least 8.5 mL of blood is drawn into each tube.  Avoid low volume to minimize agitation during shipping. 
4) Invert the tubes gently 180 degrees and back 3-4 times. 
5) After blood is drawn, page Danilo Piana Pager 3-3027 IMMEDITELY who will carry blood samples to Jun Luo’s lab in 415 Marburg 
Building (Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287). 
 
3. CTC PD-L1 Evaluation 
1) Collect Blood in 2 Streck Cell-Free DNA BCT tubes.  Product number from Streck, Inc, Omaha NE is 218961. 
2) Ensure that at least 10 mL of blood is drawn into each tube.  Avoid low volume to minimize agitation during shipping. 
3) Invert the tubes gently 180 degree and back 8-10 times 


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4) Maintain Blood at room temperature (6oC to 37oC) until pick-up 
5) After blood is drawn, page Danilo Piana Pager 3-3027 who will carry blood samples to Ken Pienta’s lab in Marburg 116 (delivery 
contact for the STARVE-PC samples will be Stephanie Glavaris). 
 
4. CTC for EPIC Sciences PD-L1 Evaluation 
SHIP ALL SAMPLES OVERNIGHT! 
Sample Collection:  
IMPORTANT: The first 5 mL of blood collected from the fresh venous puncture cannot be used for the collection into the Streck tubes. Please 
ensure that at least one blood tube of 5 ml or more is collected prior to collection of blood in Streck tube to avoid adversely affecting the test 
results. 
Prevention of Backflow: 
Since Streck Cell-Free DNA BCT tubes contain chemical additives, it is important to avoid possible backflow from the tube. To guard against 
backflow, observe the following precautions: 
• 
Keep patient’s arm in the downward position during the collection procedure. 
• 
Hold the tube with the stopper uppermost. 
• 
Release tourniquet once the blood starts to flow into the tube, or within 2 minutes of application. 
• 
Tube contents should not touch stopper or the end of the needle during the collection procedure. 
Blood Collection Instructions: 
**Schedule courier for same-day sample pic-up prior to collection 
1. Confirm blood tube is not expired. Expired tubes should not be used for blood collection. Tubes will be provided by EPIC Sciences. 
2. Draw whole blood sample into 10 mL Streck Cell-Free DNA BCT tube (*see note regarding prevention of backflow). Fill tube until blood 
flow stops. NOTE: Epic requires a minimum of 4mL blood per sample, but a full 10 mL tube of blood should be provided when possible. 
3. Remove tube from adapter and immediately mix by gentle inversion 8 to 10 times. Tube inversion prevents clotting. Inadequate or delayed 
mixing may result in inaccurate test results. 
4. Label the tube with subject’s identification and date and time of blood draw. 
5. Keep sample at room temperature and ship on day of collection. 
Sample Shipment Instructions: 


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1. Place blood tube into foam insert in provided kit, and place in aluminum canister. Place canister in supplied cardboard box. 
2. Open pre-assembled reusable specimen shipping container, remove insulation panel. 
3. Place two liquid (red) E23 panels that have been stored at room temperature in the bottom of the shipping container rotated at 90 degrees 
from each other. 
4. Place box containing canister with blood specimen directly on top of previously placed panel (see lab manual for figure). 
5. Place one liquid (red) E23 panel that has been stored at room temperature on top of the box rotated at 90 degrees from the panel below it. 
6. Place one solid (red) E23 panel that has been stored at 4 degrees Celsius on top of box. 
7. Place locking lid on top of the 4th panel with the seam facing up to ensure insulation. 
8. Close shipping box and tape appropriately.  
 
Ship to: 
Epic Sciences 
c/o Dena Marrinucci 
9381 Judicial Drive, STE 200 
San Diego, CA 92121 
Tel: 858-356-6610 
 
Samples may be mailed to Epic Sciences for Monday–Saturday delivery 
 
Send Email to: 
partners@epicsciences.com 
Include:  
1. Tracking number 
2. Number of samples being shipped 
3. Date and time of each blood draw 
4. Case report form including white blood cell count of patient(s) 
 
5. Sera for Immunoassays  
At each time point (Pre-treatment, cycle 3, and end of treatment visit), the following research blood samples should be collected and 
processed as outlined below:  
•rawapproximately10mLofperipheralbloodinto 1 SST (tiger top, i.e. BD Vacutainer Cat #367985) tube.  


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•
llowbloodtocoagulatefor20minutes,thencentrifugeat25o0,1500xg(2700-3000 rpm), for 15 minutes.  
•Pipettetheseruminto10cryotubes/snap-top tubes (about 0.5 mL/tube).  
•Storecryotubes/snap-top tubes frozen, below –20oC (–70oC preferred), until the time of analysis. 
 
Please Ping “Vaccine Team” (pager 410-283-0693)  and the Immune Core will be notified to pick up the sample after draw. 
     
 
6. Peripheral blood lymphocytes (PBLs)  
 
At each time point (Pre-treatment, cycle 3, and end of treatment visit), the following research blood samples should be collected and 
processed as outlined below: 
 
• 
Draw approximately 100 mL of peripheral blood into ten 10-mL heparinized tubes.  
 
• 
PBLs will be prepared by Ficoll-Hypaque density gradient centrifugation according to standard protocols 
 
• 
Samples will be cryopreserved in a liquid nitrogen freezer at –140°C for further batched analyses. 
Please Ping “Vaccine Team” (pager 410-283-0693)  and the Immune Core will be notified to pick up the sample after draw. 
 
7. Plasma for ctDNA for PGDx 
At pre-treatment visit, the following research blood samples should be collected and processed as outlined below:  
• 
Draw approximately 10 ml of peripheral blood into 2 Streck Cell-Free DNA BCT tubes. 
• 
Invert tubes several times after collection. 
• 
 
• 
Please Ping “Vaccine Team” (pager 410-283-0693) and the Immune Core will be notified to pick up the sample after draw.The 
following steps should then be followed for plasma processing: 
o Transport the tube immediately to the laboratory. 
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o  Transfer supernatant to a 50 ml tube without disturbing the cellular layer using a 2 or 10 ml pipette. 
o Aliquot 1.05 ml plasma from the large tube to 1.5 ml tubes. (Note: About 5 ml of the 10 ml of blood will be plasma so 
approximately 5 aliquots). 
o Discard cell pellet. 
o Spin tubes at 18,000 g (~14,000 rpm, Beckman) for 10 min at room temperature. 
o Transfer 1 ml of plasma from the 1.5 ml tube to a fresh 2 ml tube without disturbing the pellet. 
o Store plasma vials at -80°C 
 
8. Plasma for ctDNA for Hurley Lab 
At the pre-treatment, 12 week, and end of treatment (week 49) visits, the following research blood samples should be collected and 
processed as outlined below: 
• 
Draw approximately 10 ml of peripheral blood into 2 Streck Cell-Free DNA BCT tubes.  
• 
Gently invert tubes several times after collection, but do not shake. 
• 
Leave tubes at room temperature. 
• 
Leave tubes in the blue research bin in the phlebotomy suite of Weinberg. 
• 
Please immediately contact Paula Hurley at (cell) 410-271-8417 or (office) 410-614-9453forpickup.